Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new depakote research articles will be listed here shortly after becoming available to us.
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Antimicrob Agents Chemother. 2008 Jun 23;
Dicenzo R, Peterson DR, Cruttenden K, Mariuz P, Rezk NL, Hochreiter J, Gelbard H, Schifitto G
Background: Minocycline and valproic acid are potential adjuvant therapies for the treatment of HIV-associated cognitive impairment. The purpose of the study was to determine if minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Methods: Twelve adult HIV-infected subjects whose regimen included atazanavir/ritonavir 300/100 mg daily for at least 4 weeks were enrolled. Each subject received atazanavir/ritonavir on Day 1, atazanavir/ritonavir plus minocycline 100 mg twice daily on Days 2 - 15, and atazanavir/ritonavir plus minocycline 100 mg twice daily and valproic acid 250 mg twice daily on Days 16 - 30 with meals. Subjects had 11 plasma samples drawn over a dosing interval on Days 1, 15, and 30. Results: Minocycline and valproic acid coadministration was well tolerated in all 12 subjects (6 male; mean (SD) age = 43.1 (8.2) years). The geometric mean ratio (GMR (95% CI)) for atazanvir AUC24h, Cmin and Cmax with and without minocycline was 0.67 (0.50 - 0.90), 0.50 (0.28 - 0.89) and 0.75 (0.58 - 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMR (95% CI) for atazanavir AUC24h, Cmin and Cmax with and without minocycline plus valproic acid was 0.68 (0.43 - 1.06), 0.50 (0.24 - 1.06) and 0.66 (0.41 - 1.06), respectively. Neither minocycline nor minocycline plus valproic acid coadministration appeared to influence the plasma concentrations of ritonavir (p > 0.2). Conclusions: Minocycline coadministration resulted in decreased atazanavir exposure and there was no evidence that the addition of valproic acid mediated this effect.
[Dementia syndrome in an elderly subject related to valproic acid use: A case report.]
Rev Med Interne. 2008 Jun 20;
Manckoundia P, Disson-Dautriche A, Rouaud O, Richard D, Tavernier-Vidal B, Pfitzenmeyer P
In addition to the usual adverse effects, the chronic use of the valproic acid can entail dementia syndrome. We describe the case of a 68-year-old woman who had presented a dementia syndrome due to the use of valproic acid for one year. This drug was prescribed in order to prevent a potential convulsive crisis after an ischemic stroke in a patient who did not have a history of epilepsy. This case shows that each clinician must be careful about all medications consumed by the patient in the face of cognitive disorders.
Valproic Acid induces notch1 signaling in small cell lung cancer cells.
J Surg Res. 2008 Jul; 148(1): 31-7
Platta CS, Greenblatt DY, Kunnimalaiyaan M, Chen H
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells. MATERIALS AND METHODS: DMS53 human SCLC cells were treated with VPA (0-10 mm) for 2 d. Light microscopy was used to examine changes in cell morphology. Western analysis was performed using antibodies against various Notch1 pathway proteins to assess Notch1 activation. Additionally, immunoblotting was performed for two neuroendocrine tumor markers, chromogranin A and achaete-scute complex-like 1. Finally, a cell proliferation assay was used to measure the effects of VPA on SCLC growth over 8 d. RESULTS: After treatment with VPA, DMS53 cells underwent dramatic changes in morphology. VPA induced expression of the full-length and active forms of Notch1 protein. Furthermore, VPA suppressed levels of neuroendocrine tumor markers chromogranin A and ASLC-1. Importantly, VPA treatment led to dose-dependent inhibition of SCLC cell proliferation. CONCLUSIONS: The HDAC inhibitor VPA activates Notch1 signaling in SCLC cells. VPA induces changes in cell morphology and suppresses neuroendocrine tumor markers, indicating a change in phenotype. Additionally, VPA profoundly inhibits SCLC cell growth. These results suggest that VPA has potential as a novel therapeutic agent for SCLC.
Nat Biotechnol. 2008 Jun 22;
Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA
Reprogramming of mouse and human somatic cells can be achieved by ectopic expression of transcription factors, but with low efficiencies. We report that DNA methyltransferase and histone deacetylase (HDAC) inhibitors improve reprogramming efficiency. In particular, valproic acid (VPA), an HDAC inhibitor, improves reprogramming efficiency by more than 100-fold, using Oct4-GFP as a reporter. VPA also enables efficient induction of pluripotent stem cells without introduction of the oncogene c-Myc.
Sarcoma. 2008; 2008: 261589
Aguilera D, Hayes-Jordan A, Anderson P, Woo S, Pearson M, Green H
Desmoplastic Small Round Cell Tumor (DSRCT) has a very poor prognosis. This report illustrates novel chemotherapy and local control interventions in a 5-year old patient. The patient was treated in the outpatient setting, achieved remission, with excellent quality of life. The patient presented with massive ascites and >1000 abdominal tumors. Neoadjuvant chemotherapy included vincristine (1.5 mg/m(2)), ifosfamide (3 g/m(2)/day x 3), dexrazoxane/doxorubicin (750/75 mg/m(2)), and etoposide (150 mg/m(2)). Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (100 mg/m(2)) was given after extensive cytoreductive surgery. This was followed by irinotecan (10 mg/m(2)/day x 5 x 2 weeks) + temozolomide monthly x 2, then abdominal radiation 30 Gy with simultaneous temozolomide (100 mg/m(2)/day x 5). A total of 12 cycles of irinotecan and temozolamide were given. Except for initial chemotherapy, subsequent courses were in the outpatient setting. Focal retroperitoneal relapse at 18 months was treated with IMRT with bevacizumab (5 mg/kg) and 2 perihepatic metastases with radio frequency ablation/cryoablation followed by chronic outpatient maintenance chemotherapy (valproic acid, cyclophosphamide, and rapamycin). Almost 2 years from diagnosis, the patient maintained an excellent quality of life. This is a novel approach to the treatment of children with massive abdomino-pelvic DSRCT.
J Parasitol. 2008 Apr; 94(2): 555-7
Goodwin DG, Strobl J, Mitchell SM, Zajac AM, Lindsay DS
Toxoplasma gondii is a common intracellular protozoan infection of humans worldwide. Severe disease can occur in immunocompromised individuals and the in the fetuses of nonimmune pregnant women. Chronic infection is associated with vision and hearing problems, and functional mental alterations, including schizophrenia. The mood-stabilizing agent valproic acid has been shown to inhibit the development of T. gondii in vitro at dosages that are normally achieved in the serum and cerebral spinal fluid of human patients and to have positive effects on the behavior of rats chronically infected with T. gondii. The present study was done to examine the in vivo activity of valproic acid against acute toxoplasmosis in mice. Two studies were done with valproic acid given in the drinking water at concentrations of 1.5 mg/ml (Experiment 1) or 3.0 mg/ml (Experiment 2). In a third experiment (Experiment 3), valproic acid was injected intraperitoneally (i.p.) at doses of 200 or 300 mg/kg every 12 hr. Valproic acid was not effective in preventing acute toxoplasmosis. All mice treated with valproic acid died or were killed and did not (P > 0.05) live significantly longer than the controls. Tachyzoites were demonstrated in the tissues of infected valproic-acid-treated mice. A fourth study was done to determine if valproic acid has activity against T. gondii tissue cysts in chronically infected mice. Mice were chronically infected with the ME-49 strain of T. gondii for 8 wk and then treated orally with valproic acid at approximately 6.6 mg/ml (800 mg/kg/day) in the drinking water for 10 wk (amount was varied due to increasing mouse weights). No significant differences (P > 0.05) were present in tissue cyst numbers in valproic-acid-treated T. gondii chronically infected mice and in mice chronically infected with T. gondii but not given valproic acid. Our results indicate that valproic acid, although effective in vitro against T. gondii tachyzoites, is not effective as a preventative in mice inoculated with T. gondii tachyzoites. Additionally, no activity against tissue cysts was observed in chronically T. gondii-infected valproic-acid-treated mice.
Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 7;
Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro FE, de Leon J
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age >/=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.
Eur J Pharmacol. 2008 May 7;
Kim B, Rincón Castro LM, Jawed S, Niles LP
C6 glioma cells were treated with clinically relevant concentrations of valproic acid (0.5 or 1.0 mM) for 1-7 days and RT-PCR used to examine expression of the melatonin MT(1) receptor and selected epigenetic modulators. Valproic acid caused significant time-dependent changes in the mRNA expression of the melatonin MT(1) receptor, histone deacetylase (HDAC) 1, 2 and 3, and methyl CpG binding protein 2 (MeCP2). A structurally distinct HDAC inhibitor, trichostatin A, also caused a significant concentration-dependent induction of melatonin MT(1) receptor mRNA expression, suggesting involvement of an epigenetic mechanism. The ability of clinical concentrations of valproic acid to significantly alter melatonin MT(1) receptor expression, suggests a role for this receptor in the diverse neuropharmacological and oncostatic effects of this agent.
Assessment of chemical effects on neurite outgrowth in PC12 cells using high content screening.
Toxicol Sci. 2008 Jun 6;
Radio NM, Breier JM, Shafer TJ, Mundy WR
Identification of chemicals that pose a hazard to the developing nervous system is the first step in reducing human exposure and preventing health risks to infants and children. In response to the need for more efficient methods to identify potential developmental neurotoxicants, the present study evaluated the utility of an automated high content screening system to detect chemical effects on neurite outgrowth in Neuroscreen-1 cells (NS-1), a subclone of PC12 cells. Plating 2,000 NS-1 cells/well with 100 ng/ml nerve growth factor (NGF) for 96 hours produced optimal neurite growth in a 96-well format. Using this protocol, five chemicals that had been previously shown to inhibit neurite outgrowth in PC12 cells were examined. Inhibition of neurite outgrowth (assessed as total neurite length per cell) was observed for all five chemicals. For three of the chemicals, inhibition was associated with decreased cell viability. To demonstrate the utility of this approach for screening, a further set of chemicals (eight known in vivo developmental neurotoxicants and eight chemicals with little evidence of in vivo neurotoxicity) were tested over a wide concentration range (1 nM - 100 muM). Trans-retinoic acid, dexamethasone, cadmium, and methylmercury inhibited neurite outgrowth, although dexamethasone and cadmium only affected neurite outgrowth at concentrations that decreased viability. Amphetamine facilitated neurite outgrowth, while valproic acid, diphenylhydantoin, and lead had no effect. Of the chemicals that were not neurotoxic, there were no effects on cell viability, but two (dimethyl phthalate and omeprazole) increased neurite outgrowth at the highest concentration tested. These results demonstrate that a high content screening system can rapidly quantify chemical effects on neurite outgrowth in vitro. Concentration-response data for both neurite outgrowth and cell viability allowed for the determination of the specificity of chemical effects on a neurodevelopmental endpoint. Further studies will examine the utility of other in vitro preparations for cell-based assays of neurite outgrowth.
Epilepsy Res. 2008 Jun 4;
Hoffmann K, Czapp M, Löscher W
Valproic acid (VPA) is a major antiepileptic drug (AED) with efficacy against multiple seizure types. It has a rapid onset of action but its anticonvulsant activity increases during prolonged treatment, which cannot be explained by drug or metabolite accumulation in plasma or brain. Among numerous other effects on diverse drug targets, VPA is an inhibitor of histone deacetylases (HDACs) that are involved in modulation of gene expression. The functional consequences of HDAC inhibition typically develop slowly during treatment with HDAC inhibitors such as VPA. We therefore hypothesized that inhibition of brain HDACs by VPA and resultant increases in gene expression could explain the increase in anticonvulsant activity during prolonged treatment with this drug. This hypothesis was tested by comparing the effects of VPA and the selective HDAC inhibitor, trichostatin A (TSA), in a mouse model of generalized seizures. Intravenous infusion of pentylenetetrazole (PTZ) was used to determine the effects of the drugs on different seizure types, i.e., myoclonic, clonic and tonic seizures. VPA (200mg/kg b.i.d.) rapidly increased PTZ thresholds to all seizure types, but this effect increased up to threefold during prolonged treatment. Following low (0.5mg/kg b.i.d.) or high (5mg/kg b.i.d.) dose treatment with TSA, no dose-dependent anticonvulsant effects were determined. This finding argues against a role of HDAC inhibition for the anticonvulsant activity of VPA. In view of the multiple extra- and intracellular targets of VPA, the experimental strategy used in the present study may be helpful to assess which specific molecular effects of VPA are relevant for the antiepileptic activity of this drug, and which are not.