Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish

PubMed Central

Bailey, Jordan M.; Oliveri, Anthony N.; Karbhari, Nishika; Brooks, Roy A.J.; De La Rocha, Amberlene J.; Janardhan, Sheila; Levin, Edward D.

2015-01-01

BACKGROUND Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. METHODS During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0-5 dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2 nM) or valproic acid (0, 0.5, 5.0 or 50 uM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). RESULTS There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. CONCLUSIONS Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed. PMID:26439099

Valproic acid aggravates epilepsy due to MELAS in a patient with an A3243G mutation of mitochondrial DNA.

PubMed

Lin, Chih-Ming; Thajeb, Peterus

2007-03-01

Epilepsy is one of the most common presentations of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is typically caused by an A-to-G substitution at nucleotide position 3243 of mitochondrial DNA. Valproic acid, a common anticonvulsant, can actually increase the frequency of seizures in individuals with MELAS. Here, we report a single case-study of a 38-year-old man who presented with focal seizures and had MELAS Syndrome due to the A3243G mitochondrial DNA mutation. Manifestation of epilepsia partialis continua was aggravated by use of valproic acid. Convulsions abated after discontinuation of valproic acid. Our experience suggests that valproic acid should be avoided for the treatment of epilepsy in individuals with mitochondrial disease.

Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhai, Yingying; Chen, Xi; Yu, Dehai

2015-09-10

Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phasemore » blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.« less

Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3.

PubMed

Kumandas, Sefer; Koklu, Esad; Gümüs, Hakan; Koklu, Selmin; Kurtoglu, Selim; Karakukcu, Musa; Keskin, Mehmet

2006-04-01

To examine the effect of carbamezapine and valproate on bone mineral density (BMD), IGF-I and IGFBP-3 levels in children. The effects of at least 2 years valproic acid and carbamazepine therapy on BMD were evaluated in a cross-sectional and retrospective study. All children were ambulatory, prepubertal, and had normal activity and nutritionally adequate diets. Ambulatory epileptic patients were divided into two groups. Thirty-three patients (group 1; 17 boys, 16 girls; mean age: 8.8 +/- 2.0 years) were treated with valproic acid and 33 patients were treated with carbamazepine (group 2; 20 boys, 13 girls; mean age: 9.7 +/- 1.6 years). The control group consisted of 22 healthy children (13 boys, 9 girls; mean age: 8.9 +/- 2.3 years), who were age- and sex-matched with the patient groups. Children with metabolic bone disease, growth and neurological impairment, signs of malnutrition, or any chronic disease were excluded from the study. BMD values at lumbar spine in both the carbamazepine (-1.69 +/- 0.85 mean L1-4 BMD z-scores, mean 35.5 +/- 12.8 months treatment, and 19,478.6 +/- 6,301.3 mg/kg cumulative dose) and valproic acid (-1.28 +/- 0.80 mean L1-4 BMD z-scores, mean 33.7 +/- 15.0 months treatment, and 22,852.4 +/- 12,477.4 mg/kg cumulative dose) groups were significantly lower than that of the control group (-0.23 +/- 0.87 mean L1-4 BMD z-score). Serum ALP and PTH levels were significantly higher in the carbamazepine-treated group (65.4 +/- 21.1 pg/ml, 767 +/- 267 U/l, respectively) than those of the valproic acid-treated (39.1 +/- 12.8 pg/ml, 561 +/- 166 U/l, respectively) and control groups (36.3 +/- 4.9 pg/ml, 487 +/- 82 U/l, respectively). Serum 25-hydroxyvitamin D of the carbamazepine-treated group (9.8 +/- 3.2 microg/l) was significantly lower than the other groups (15.1 +/- 3.5, 16.6 +/- 4.7 microg/l, respectively). There were eight and 13 patients with plasma intact PTH above reference values in groups 1 and 2, respectively. Valproic acid and

Antimetastatic Efficacy of the Combination of Caffeine and Valproic Acid on an Orthotopic Human Osteosarcoma Cell Line Model in Nude Mice.

PubMed

Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Murakami, Takashi; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Hoffman, Robert M

2017-03-01

We have previously reported that caffeine can enhance chemotherapy efficacy of bone and soft tissue sarcoma via cell-cycle perturbation. Valproic acid has histone deacetylase (HDAC) inhibitory activity. We have also reported the anti-tumor efficacy of combination treatment with caffeine and valproic acid against osteosarcoma primary tumors in a cell-line orthotopic mouse model. In this study, we performed combination treatment of caffeine and valproic acid on osteosarcoma cell lines in vitro and in spontaneous and experimental lung metastasis mouse models of osteosarcoma. Survival of 143B-RFP human osteosarcoma cells after exposure to caffeine and valproic acid for 72 hours was determined using the WST-8 assay. IC 50 values and combination indices were calculated. Mouse models of primary osteosarcoma and spontaneous lung metastasis were obtained by orthotopic intra-tibial injection of 143B-RFP cells. Valproic acid, caffeine, and combination of both drugs were administered from day 7, five times a week, for four weeks. Six weeks after orthotopic injection, lung samples were excised and observed with a fluorescence imaging system. A mouse model of experimental lung metastasis was obtained by tail vein injection of 143B-RFP cells. The mice were treated with these agents from day 0, five times a week for four weeks. Both caffeine and valproic acid caused concentration-dependent cell kill in vitro. Synergistic efficacy of the combination treatment was observed. In the spontaneous lung-metastasis model, the number of lung metastasis was 9.0±2.6 in the untreated group (G1); 10.8±2.9 in the caffeine group (G2); 10.0±3.1 in the valproic-acid group (G3); and 3.0±1.1 in the combination group (G4); (p=6.78E-5 control vs. combination; p=0.006 valproic acid vs. combination; p=0.003 caffeine vs. combination). In the experimental lung-metastasis model, the combination group significantly reduced lung metastases and improved overall survival (p=0.0005). Efficacy of the

Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.

PubMed

Tomson, Torbjörn; Battino, Dina; Perucca, Emilio

2016-02-01

Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk-benefit assessment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Drug interaction between phenytoin and valproic acid in a child with refractory epilepsy: a case report.

PubMed

Carvalho, Indira Valadê; Carnevale, Renata Cavalcanti; Visacri, Marília Berlofa; Mazzola, Priscila Gava; de Fátima Lopes Ambrósio, Rosiane; dos Reis, Marcelo Conrado; de Queiroz, Rachel Alvarenga; Moriel, Patricia

2014-04-01

There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 µg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.

PubMed

Al-Amin, Md Mamun; Rahman, Md Mahbubur; Khan, Fazlur Rahman; Zaman, Fahmida; Mahmud Reza, Hasan

2015-06-01

Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity. Copyright © 2015 Elsevier B.V. All rights reserved.

Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment With Valproic Acid and Fresh Frozen Plasma.

PubMed

Nikolian, Vahagn C; Dekker, Simone E; Bambakidis, Ted; Higgins, Gerald A; Dennahy, Isabel S; Georgoff, Patrick E; Williams, Aaron M; Andjelkovic, Anuska V; Alam, Hasan B

2018-01-01

Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. Resuscitation with fresh frozen plasma results in improved expression of

Placebo-Controlled Trial of Valproic Acid Versus Risperidone in Children 3–7 Years of Age with Bipolar I Disorder

PubMed Central

Scheffer, Russell E.; Monroe, Erin; Delgado, Sergio; Altaye, Mekibib; Lagory, Denise

2015-01-01

Abstract Objective: The objective of this study was to determine the efficacy and safety of valproic acid versus risperidone in children, 3–7 years of age, with bipolar I disorder (BPD), during a mixed or manic episode. Methods: Forty-six children with Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar disorder, manic, hypomanic, or mixed episode, were recruited over a 6 year period from two academic outpatient programs for a double-blinded, placebo-controlled trial in which subjects were randomized in a 2:2:1 ratio to risperidone solution, valproic acid, or placebo. Results: After 6 weeks of treatment, the least-mean Young Mania Rating Scale (YMRS) total scores change, adjusted for baseline YMRS scores, from baseline by treatment group was: Valproic acid 10.0±2.46 (p=0.50); risperidone 18.82±1.55 (p=0.008); and placebo 4.29±3.56 (F=3.93, p=0.02). The mixed models for repeated measure (MMRM) analysis found a significant difference for risperidone-treated subjects versus placebo treated subjects (p=0.008) but not for valproic acid-treated subjects versus placebo-treated subjects (p=0.50). Treatment with risperidone over 6 weeks led to increased prolactin levels, liver functions, metabolic measures, and weight/body mass index (BMI). Treatment with valproic acid led to increases in weight/BMI and decreases in total red blood cells (RBC), hemoglobin, and hematocrit. Conclusions: In this small sample of preschool children with BPD, risperidone demonstrated clear efficacy versus placebo, whereas valproic acid did not. The laboratory and weight findings suggest that younger children with BPD are more sensitive to the effects of both of these psychotropics, and that, therefore, frequent laboratory and weight monitoring are warranted. PMID:25978742

Evaluation ofserum free carnitine/acylcarnitine levels and left ventricular systolic functions in children with idiopathic epilepsy receiving valproic acid.

PubMed

Kulhas Celik, Ilknur; Tasdemir, Haydar Ali; Ince, Hülya; Celik, Halil; Sungur, Metin

2018-07-01

In the study, the effect of valproic acid on serum free/acylcarnitine levels and left ventricular systolic function in pediatric patients with idiopathic epilepsy receiving valproic acid was investigated. Patients receiving valproic acid treatment for six months between January 2012 and December 2012 were evaluated. Blood samples were obtained from the participants twice (pretreatment and the sixth month of treatment) and serum-free and acylcarnitine levels (from C2 to C18:1-OH) were measured using tandem mass spectrometry. Cardiac functions (ejection fraction, shortening fraction, cardiac output, left ventricular systolic and diastolic diameters, left atrial diameter, aortic diameter, cardiac output, and myocardial performance index) were evaluated by echocardiography simultaneously. A total of fourty patients, 23 female (57.5%) and 17 male (42.5%), with the diagnosis of idiopathic epilepsy and receiving valproic acid monotherapy were studied. Comparison of serum-free and acylcarnitine levels measured pretreatment and sixth month of treatment revealed a decrease in average C0 and C5:1 (respectively p < 0.001, p = 0.013) and an increase in C2, C3, C5-OH, C8:1 and C4-DC levels (respectively p < 0.001, p < 0.001, p = 0.019, p = 0.013, p < 0.001). Other serum acylcarnitine levels did not change significantly (p > 0.05). No difference was observed in concurrent echocardiographic measurements of left ventricular systolic function (p > 0.05). The study demonstrated that valproic acid treatment results in low levels of free carnitine and changes in some acylcarnitine subgroups but has no influence on left ventricular systolic function. Copyright © 2018 Elsevier B.V. All rights reserved.

Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid.

PubMed

Rinaldi, Tania; Silberberg, Gilad; Markram, Henry

2008-04-01

Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render cortical modules more sensitive to stimulation and once activated, more autonomous, isolated, and more difficult to command. This could underlie some of the core symptoms observed in humans prenatally exposed to valproic acid.

Effect of time, injury, age and ethanol on interpatient variability in valproic acid pharmacokinetics after traumatic brain injury.

PubMed

Anderson, Gail D; Temkin, Nancy R; Awan, Asaad B; Winn, H Richard; Winn, Richard H

2007-01-01

Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL(u)) is equal to intrinsic or metabolic clearance. The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL(u). In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL(u). Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL(u) was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures. CL and CL(u) were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The

Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner.

PubMed

Hong, Ling-juan; Jiang, Quan; Long, Sen; Wang, Huan; Zhang, Ling-di; Tian, Yun; Wang, Cheng-kun; Cao, Jing-jing; Tao, Rong-rong; Huang, Ji-yun; Liao, Mei-hua; Lu, Ying-mei; Fukunaga, Kohji; Zhou, Nai-ming; Han, Feng

2016-03-01

Valproate exposure is associated with increased risks of autism spectrum disorder. To date, the mechanistic details of disturbance of melatonin receptor subtype 1 (MTNR1A) internalization upon valproate exposure remain elusive. By expressing epitope-tagged receptors (MTNR1A-EGFP) in HEK-293 and Neuro-2a cells, we recorded the dynamic changes of MTNR1A intracellular trafficking after melatonin treatment. Using time-lapse confocal microscopy, we showed in living cells that valproic acid interfered with the internalization kinetics of MTNR1A in the presence of melatonin. This attenuating effect was associated with a decrease in the phosphorylation of PKA (Thr197) and ERK (Thr202/Tyr204). VPA treatment did not alter the whole-cell currents of cells with or without melatonin. Furthermore, fluorescence resonance energy transfer imaging data demonstrated that valproic acid reduced the melatonin-initiated association between YFP-labeled β-arrestin 2 and CFP-labeled MTNR1A. Together, we suggest that valproic acid influences MTNR1A intracellular trafficking and signaling in a β-arrestin 2-dependent manner.

Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid.

PubMed

Nicolini, Chiara; Ahn, Younghee; Michalski, Bernadeta; Rho, Jong M; Fahnestock, Margaret

2015-01-20

The molecular mechanisms underlying autistic behaviors remain to be elucidated. Mutations in genes linked to autism adversely affect molecules regulating dendritic spine formation, function and plasticity, and some increase the mammalian target of rapamycin, mTOR, a regulator of protein synthesis at spines. Here, we investigated whether the Akt/mTOR pathway is disrupted in idiopathic autism and in rats exposed to valproic acid, an animal model exhibiting autistic-like behavior. Components of the mTOR pathway were assayed by Western blotting in postmortem fusiform gyrus samples from 11 subjects with idiopathic autism and 13 controls and in valproic acid versus saline-exposed rat neocortex. Additionally, protein levels of brain-derived neurotrophic factor receptor (TrkB) isoforms and the postsynaptic organizing molecule PSD-95 were measured in autistic versus control subjects. Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus. Similarly, phosphorylated and total Akt, mTOR and 4E-BP1 and phosphorylated S6 protein were decreased in valproic acid- versus saline-exposed rats. However, no changes in 4E-BP1 or eIF4E were found in autistic brains. In contrast to some monogenic disorders with high rates of autism, our data demonstrate down-regulation of the Akt/mTOR pathway, specifically via p70S6K/eIF4B, in idiopathic autism. These findings suggest that disruption of this pathway in either direction is widespread in autism and can have adverse consequences for synaptic function. The use of valproic acid, a histone deacetylase inhibitor, in rats successfully modeled these changes, implicating an epigenetic mechanism in these pathway disruptions.

An Evaluation of Peripapillary Retinal Nerve Fiber Layer Thickness in Children With Epilepsy Receiving Treatment of Valproic Acid.

PubMed

Dereci, Selim; Koca, Tuğba; Akçam, Mustafa; Türkyilmaz, Kemal

2015-07-01

We investigated the peripapillary retinal nerve fiber layer thickness with optical coherence tomography in epileptic children receiving valproic acid monotherapy. The study was conducted on children aged 8-16 years who were undergoing valproic acid monotherapy for epilepsy. The study group comprised a total of 40 children who met the inclusion criteria and 40 healthy age- and sex-matched children as a control group. Children with at least a 1-year history of epilepsy and taking 10-40 mg/kg/day treatment were included in the study. Peripapillary retinal nerve fiber layer thickness measurements were performed using Cirrus HD optical coherence tomography. All children and parents were informed about the study and informed consent was obtained from the parents of all the participants. The study group included 21 girls and 19 boys with a mean age of 10.6 ± 2.3 years. According to the results of optical coherence tomography measurements, the mean peripapillary retinal nerve fiber layer thickness was 91.6 ± 9.7 in the patient group and 95.5 ± 7.4 μm in the control group (P < 0.05). The superior peripapillary retinal nerve fiber layer thickness was 112.0 ± 13.2 in the patient group and 120.0 ± 14.7 μm in the control group (P < 0.02). According to the results of both measurements, the peripapillary retinal nerve fiber layer thickness was significantly lower in the patient group. Neither color vision loss nor visual field examination abnormality could be documented. According to the optical coherence tomography measurements, the average and superior peripapillary retinal nerve fiber layer thicknesses were thinner in patients with epilepsy who were receiving valproic acid monotherapy compared with healthy children. This situation can lead to undesirable results in terms of eye health. New studies are needed to investigate whether these findings are the result of epilepsy or can be attributed to valproic acid and whether there are adverse effects of

Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy.

PubMed

Jellett, Adam P; Jenks, Kyle; Lucas, Marcella; Scott, Rod C

2015-02-01

Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore, we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required. Copyright © 2014 Elsevier B.V. All rights reserved.

Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells.

PubMed

Langlands, Alistair J; Carroll, Thomas D; Chen, Yu; Näthke, Inke

2018-02-15

More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from Apc Min/+ mice recapitulate stages of intestinal polyposis in culture. They eventually form spherical cysts that reflect the competitive growth advantage of cells that have undergone loss of heterozygosity (LOH). We discovered that this emergence of cysts was inhibited by Chiron99021 and Valproic acid, which potentiates Wnt signalling. Chiron99021 and Valproic acid restrict the growth advantage of Apc mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of Apc mutant cells. As a proof of concept, we demonstrated that Chiron99021-treated Apc mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.

Effects of Switching from Depakene to Generic Valproic Acid on Individuals with Mental Retardation.

ERIC Educational Resources Information Center

Vadney, Victor J.; Kraushaar, Kevin W.

1997-01-01

Comparison of brand-name Depakene with generic valproic acid medication to control seizures in 64 subjects with mental retardation living in an intermediate care facility found no statistically significant differences in seizures or blood levels. Results suggest use of the generic medication can result in substantial cost savings. (Author/DB)

The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

ERIC Educational Resources Information Center

Bredy, Timothy W.; Barad, Mark

2008-01-01

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

Valproic Acid in Women and Girls of Childbearing Age.

PubMed

Gotlib, Dorothy; Ramaswamy, Rachel; Kurlander, Jacob E; DeRiggi, Alana; Riba, Michelle

2017-09-01

The aim of this paper is to evaluate recent literature on valproic acid (VPA) in women and girls of childbearing age and to emphasize new findings. Recent research confirms VPAs teratogenicity and risk of hormone disruption. VPA exposure in utero increases the risk for a variety of major congenital malformations (MCMs), reduced IQ and behavioral problems. In girls and women, VPA increases the risk of hormone abnormalities, obesity, and polycystic ovarian syndrome (PCOS). Despite guidelines recommending caution, VPA use continues to be prescribed to reproductive-aged women and girls. Despite significant and well-documented risk, adherence to guidelines in VPA use in reproductive-aged girls and women remains low.

Hydrofluoric acid poisoning

MedlinePlus

... your skin or eyes, you may have: Blisters Burns Pain Vision loss Hydrofluoric acid poisoning can have ... urine tests Camera down the throat to see burns in the esophagus and the stomach (endoscopy) Fluids ...

[Influence of valproic acid (depakine I.V.) on human placenta metabolism--experimental model].

PubMed

Semczuk-Sikora, Anna; Rogowska, Wanda; Semczuk, Marian

2003-08-01

The pregnancy in women with epilepsy is associated with an increased incidence of congenital malformations in offspring. Currently, anti-epileptic drugs (AEDs) are concerned to be a major etiologic factor of abnormal fetal development but the pathomechanism of teratogenicity of AEDs is complex and not well understood. The purpose of this study was to evaluate an influence of one of the AED-valproic acid (VPA) on placental metabolism (glucose consumption and lactate production). Term human placental cotyledons were perfused in vitro using a recycling perfusion of maternal and fetal circulations. A total 18 placentas were perfused either with 75 micrograms/ml of VPA (therapeutic dose) or with 225 micrograms/ml of VPA (toxic dose). Eight placentas were perfused with a medium without VPA and served as controls. During 2.5 h of experiment, both maternal and fetal glucose consumption and lactate production were measured every 30 minutes. The introduction of different concentrations of VPA into the perfusion system did not effect placental glucose consumption and lactate production rates in both maternal and fetal compartments. The teratogenic effect of valproic acid is not associated with metabolic disturbances of glucose or lactate in the placental tissue.

Effects of cytarabine on activation of human T cells - cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid.

PubMed

Ersvaer, Elisabeth; Brenner, Annette K; Vetås, Kristin; Reikvam, Håkon; Bruserud, Øystein

2015-05-02

Cytarabine is used in the treatment of acute myeloid leukemia (AML). Low-dose cytarabine can be combined with valproic acid and all-trans retinoic acid (ATRA) as AML-stabilizing treatment. We have investigated the possible risk of immunotoxicity by this combination. We examined the effects of cytarabine combined with valproic acid and ATRA on in vitro activated human T cells, and we tested cytarabine at concentrations reached during in vivo treatment with high doses, conventional doses and low doses. T cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with ATRA (1 μM), valproic acid (500 or 1000 μM) or cytarabine (0.01-44 μM). Cell characteristics were assessed by flow cytometry. Supernatants were analyzed for cytokines by ELISA or Luminex. Effects on primary human AML cell viability and proliferation of low-dose cytarabine (0.01-0.5 μM) were also assessed. Statistical tests include ANOVA and Cluster analyses. Only cytarabine 44 μM had both antiproliferative and proapoptotic effects. Additionally, this concentration increased the CD4:CD8 T cell ratio, prolonged the expression of the CD69 activation marker, inhibited CD95L and heat shock protein (HSP) 90 release, and decreased the release of several cytokines. In contrast, the lowest concentrations (0.35 and 0.01 μM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter activation marker expression (CD38, CD69) or the release of CD95L and HSP90, but inhibited the release of certain T cell cytokines. Even when these lower cytarabine concentrations were combined with ATRA and/or valproic acid there was still no or minor effects on T cell viability. However, these combinations had strong antiproliferative effects, the expression of both CD38 and CD69 was altered and there was a stronger inhibition of the release of FasL, HSP90 as well as several cytokines. Cytarabine (0.01-0.05 μM) showed a dose-dependent antiproliferative effect on

Study of Valproic Acid-Enhanced Hepatocyte Steatosis

PubMed Central

Chang, Renin; Chou, Mei-Chia; Hung, Li-Ying; Wang, Mu-En; Hsu, Meng-Chieh; Chiu, Chih-Hsien

2016-01-01

Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA-) induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG) synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36), low-density lipoprotein receptor-related protein 1 (Lrp1), diacylglycerol acyltransferase 2 (Dgat2), and perilipin 2 (Plin2) were increased, that of carnitine palmitoyltransferase I a (Cpt1a) was not affected, and those of acetyl-Co A carboxylase α (Acca) and fatty acid synthase (Fasn) were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ) nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation. PMID:27034954

Synthesis of valproic acid amides of a melatonin derivative, a piracetam and amantadine for biological tests.

PubMed

Chatterjie, N; Alexander, G; Wang, H

2001-10-01

Three new amide derivatives of valproic acid have been synthesized and characterized by spectrophotometric studies. The rationale for the preparation of such agents has been based on the observation that chemical combination of the anticonvulsant pharmacophore, valproic acid with amine moieties produces more effective and less toxic amides. The amine components selected in this work also exhibit neuroactivity with the prospect of these agents being biologically active in controlling not just seizures and but also possessing neuroprotective properties. We report here the synthesis and properties of the valproylamides of 5-methoxytryptamine, related to melatonin (1), of N-substituted 2-pyrrolidinone related to piracetam (2), and of adamantylamine related to amantadine (3). In preliminary tests these compounds showed low toxicity and a variety of anticonvulsive properties, including a delay in onset of activity. These compounds and their derivatives are now available to be tested additionally for control of subclinical seizures, enhancement of cognition, behavior modification and alleviation of symptoms and disorders due to neuronal damage.

The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.

PubMed

ter Heine, Rob; van Maarseveen, Erik M; van der Westerlaken, Monique M L; Braun, Kees P J; Koudijs, Suzanne M; Berg, Maarten J Ten; Malingré, Mirte M

2014-06-01

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity. © The Author(s) 2013.

Different Resuscitation Strategies and Novel Pharmacologic Treatment with Valproic Acid in Traumatic Brain Injury

DTIC Science & Technology

2017-07-25

which would thereby preserve long - term platelet function. Dekker et al. (2014a) demonstrated that the addition of VPA to FFP resuscita- tion results in...pharmacologic resuscitation: Results of a long - term survival study in a swine polytrauma model. Journal of Trauma, 70, 636–645. Anglin, C. O., Spence...Alam, H. B. (2015b). Addition of low-dose valproic acid to saline resuscita- tion provides neuroprotection and improves long - term outcomes in a large

The valproic acid-induced rodent model of autism.

PubMed

Nicolini, Chiara; Fahnestock, Margaret

2018-01-01

Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

PubMed

Orr, J M; Farrell, K; Abbott, F S; Ferguson, S; Godolphin, W J

1983-01-01

The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

Role of SMAD4 in the mechanism of valproic acid's inhibitory effect on prostate cancer cell invasiveness.

PubMed

Jiang, Wei; Zheng, Yi; Huang, Zhongxian; Wang, Muwen; Zhang, Yinan; Wang, Zheng; Jin, Xunbo; Xia, Qinghua

2014-05-01

To investigate the influence of the histone deacetylase inhibitor valproic acid (VPA) on SMAD4 expression and invasive ability of prostate cancer cell lines. DU145 and PC3 cell lines were treated with 0, 2, and 5 mMol/l of VPA; invasion of DU145 and PC3 cells were then examined by transwell assay. Immunohistochemistry and Western blot were used to examine SMAD4 protein expression in DU145 and PC3 cells. Compared with controls, VPA significantly suppressed invasiveness in both PC3 and DU145 cells in a dose-dependent way (P < 0.05). VPA also inhibited AKT protein (which was regarded as an effective indicator here), and meanwhile, SMAD4 expression was down-regulated after VPA treatment in a dose-dependent manner in both DU145 (P < 0.05) and PC3 (P < 0.01) cells. Valproic acid could suppress invasiveness of prostate cancer cell lines PC3 and Du145, possibly through multiple pathways other than the SAMD4 pathway. This implies that VPA treatment combined with other SMAD4 enhancers could form a basis for a novel prostate cancer treatment.

Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal.

PubMed

Çoban, Dilek; Kurtoğlu, Selim; Akın, Mustafa Ali; Akçakuş, Mustafa; Güneş, Tamer

2010-01-01

The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 μg/ml (50-100 μg/ml) and 6.37 μg/dl (10-20 μg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero.

Can valproic acid be an inducer of clozapine metabolism?

PubMed Central

Diaz, Francisco J.; Eap, Chin B.; Ansermot, Nicolas; Crettol, Severine; Spina, Edoardo; de Leon, Jose

2014-01-01

Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID:24764199

MicroRNA-134 plasma levels before and after treatment with valproic acid for epilepsy patients

PubMed Central

Wang, Xiaofeng; Luo, Yifeng; Liu, Shuangxi; Tan, Liming; Wang, Sanhu; Man, Rongyong

2017-01-01

Background Temporal lobe epilepsy is the second most common neurological disorders characterized by recurrent spontaneous seizures. MicroRNAs play a vital role in regulating synaptic plasticity, brain development and post-transcriptional expression of proteins. In both animal models of epilepsy and human patients, miR-134, a brain-specific microRNA has recently been identified as a potential regulator of epileptogenesis. Methods microRNA identified as targets for the actions of valproic acid (VPA) are known to have important effects in brain function. In this study, 59 new-onset epilepsy patients and 20 controls matched by sex and age were enrolled. Patients with a score < 3 were allocated into the mild group, 3-5 into the moderate group and >5 into the severe group. The plasma miRNA-134 level was quantitatively measured using real-time PCR. Results Plasma miRNA-134 level in new-onset epilepsy patients was significantly up-regulated when compared with that in healthy controls, and then considerably down-regulated after oral intake of valproic acid medication. The up-regulated plasma miRNA-134 levels may be directly associated with the pathophysiology and severity of epilepsy. Conclusion Plasma miRNA-134 in epilepsy may be considered as a potential peripheral biomarker that responds to the incidence of epilepsy and associates with use of anti-epilepsy drugs. PMID:29069823

Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics?

PubMed

Miranda Herrero, M Concepción; Alcaraz Romero, Andrés J; Escudero Vilaplana, Vicente; Fernández Lafever, Sarah Nicole; Fernández-Llamazares, Cecilia Martínez; Barredo Valderrama, Estibaliz; Vázquez López, María; de Castro, Pedro

2015-03-01

Valproic acid (VPA) is the most commonly used antiepileptic drug in pediatric patients, but its major drawback is its multiple pharmacological interactions. To study children who had been simultaneously treated with carbapenems and valproic acid, considering drug levels, pharmacological interactions and clinical follow-up. Retrospective study of children who simultaneously received treatment with VPA and carbapenems between January 2003 and December 2011. Demographic variables, indication of treatment, dose, VPA plasma levels, interactions, clinical manifestations and medical management were analyzed. 28 children with concomitant treatment with both drugs were included in the study. 64.3% were males. 78.6% of the interactions were observed in the Intensive Care Unit. 60.7% of children had been previously treated VPA and its major indication were generalized seizures. Basal plasma levels of VPA were recorded in 53% and at 24 h after admittance in 60%. "40% of basal VPA levels were below therapeutic range prior to the administration of carbapenem. After the introduction of carbapenem 88% of level determinations were below therapeutic range". 54.5% of the patients that were chronically receiving VPA and had good control of epilepsy before admission had seizures during the coadministration. One patient that was on VPA before admission but with bad control of epilepsy worsened, and one patient that acutely received VPA did not achieve seizure freedom. In these cases it was necessary to either increase VPA dose or change to a different antiepileptic drug. Little is known about the mechanism of pharmacologic interactions between carbapenems and VPA, but it leads to a reduction in plasma levels that may cause a loss of seizure control, so simultaneous use of both drugs should be avoided when possible. If not, VPA levels should be monitored. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

PubMed Central

Lee, Soo-Yun; Huh, Wooseong; Jung, Jin Ah; Yoo, Hye Min; Ko, Jae-Wook; Kim, Jung-Ryul

2015-01-01

Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. PMID:26309401

Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice.

PubMed

Mackenzie, Gerardo G; Huang, Liqun; Alston, Ninche; Ouyang, Nengtai; Vrankova, Kvetoslava; Mattheolabakis, George; Constantinides, Panayiotis P; Rigas, Basil

2013-01-01

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells.

PubMed

Lawrence, Johnathan E; Steele, Christopher J; Rovin, Richard A; Belton, Robert J; Winn, Robert J

2016-03-01

Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR.

Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.

PubMed

Luna-Palencia, Gabriela R; Martinez-Ramos, Federico; Vasquez-Moctezuma, Ismael; Fragoso-Vazquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Padilla-Martínez, Itzia I; Sixto-Lopez, Yudibeth; Mendez-Luna, David; Trujillo-Ferrara, Jose; Meraz-Rios, Marco A; Fonseca-Sabater, Yadira; Correa-Basurto, Jose

2014-01-01

Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xiaofei; Zhu, Yanshuang; He, Huabin

Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTTmore » assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.« less

[Mechanisms of action and biochemical toxicology of valproic acid].

PubMed

Strolin Benedetti, M; Rumigny, J F; Dostert, P

1984-01-01

The first part of this article presents the hypotheses of the mechanism of action of the anti-epileptic drug, valproic acid (VPA). In the case of the GABAergic hypothesis, two major types of mechanism of action have been proposed, one at the pre-synaptic level, the other at the post-synaptic level. The action at the pre-synaptic level brings into play one or more enzymes of the GABA shunt. The action at the postsynaptic level consists of the potentiation of the inhibitory effect of GABA by VPA. This has justified the examination of the possible action of VPA at the level of the postsynaptic GABAergic receptor complex. The non-GABAergic hypotheses have been also considered to explain the anti-epileptic action of VPA, one hypothesis depends on the effects of VPA directly on the membrane, another hypothesis brings into play aspartate, and finally a hypothesis depending on the inhibition of aldehyde reductases. The second part of this article concerns the possible mechanism for the undesirable effects of VPA such as hyperammonaemia, hepatotoxicity and hypoglycaemia. The role played by beta- and omega-oxidation of VPA in the explanation of the undesirable effects of this molecule is particularly discussed.

Gas chromatography-electron ionization-mass spectrometry quantitation of valproic acid and gabapentin, using dried plasma spots, for therapeutic drug monitoring in in-home medical care.

PubMed

Ikeda, Kayo; Ikawa, Kazuro; Yokoshige, Satoko; Yoshikawa, Satoshi; Morikawa, Norifumi

2014-12-01

A simple and sensitive gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) method using dried plasma spot testing cards was developed for determination of valproic acid and gabapentin concentrations in human plasma from patients receiving in-home medical care. We have proposed that a simple, easy and dry sampling method is suitable for in-home medical patients for therapeutic drug monitoring. Therefore, in the present study, we used recently developed commercially available easy handling cards: Whatman FTA DMPK-A and Bond Elut DMS. In-home medical care patients can collect plasma using these simple kits. The spots of plasma on the cards were extracted into methanol and then evaporated to dryness. The residues were trimethylsilylated using N-methyl-N-trimethylsilyltrifluoroacetamide. For GC-EI-MS analysis, the calibration curves on both cards were linear from 10 to 200 µg/mL for valproic acid, and from 0.5 to 10 µg/mL for gabapentin. Intra- and interday precisions in plasma were both ≤13.0% (coefficient of variation), and the accuracy was between 87.9 and 112% for both cards within the calibration curves. The limits of quantification were 10 µg/mL for valproic acid and 0.5 µg/mL for gabapentin on both cards. We believe that the present method will be useful for in-home medical care. Copyright © 2014 John Wiley & Sons, Ltd.

In utero exposure to valproic acid changes sleep in juvenile rats: a model for sleep disturbances in autism.

PubMed

Cusmano, Danielle M; Mong, Jessica A

2014-09-01

To determine whether sleep disturbances are found in the valproic acid model of autism spectrum disorders (ASD). Comparative study for sleep behavior, sleep architecture, electroencephalogram (EEG) spectral analysis, and glutamic acid decarboxylase (GAD) 65/67 protein expression in juvenile rats exposed to valproic acid (VPA), sodium salt, or saline in utero. N/A. Juvenile (postnatal day 32) male and female Sprague-Dawley rats. In utero exposure to either saline or 400 mg/kg VPA administered intraperitoneally to the dams on gestational day 12.5. On postnatal days 22-24, all rats were implanted with transmitters to record EEG and electromyogram (EMG) activity. During the light phase, when nocturnal animals are typically quiescent, the VPA-exposed animals spent significantly more time in wake (∼35 min) and significantly less time in non-rapid eye movement (NREM) sleep (∼26 min) compared to the saline controls. Furthermore, spectral analysis of the EEG revelled that VPA-exposed animals exhibited increased high-frequency activity during wake and rapid eye movement (REM) sleep and reduced theta power across all vigilance states. Interestingly, the gamma-aminobutyric acid (GABA)-ergic system, which modulates the induction and maintenance of sleep states, was also disrupted, with reduced levels of both GAD 65 and GAD67 in the cortical tissue of VPA-exposed animals compared to saline controls. To date, the current animal models of ASD have been underutilized in the investigation of associated sleep disturbances. The VPA animal model recapitulates aspects of sleep disruptions reported clinically, providing a tool to investigate cellular and molecular dysregulation contributing to sleep disruptions in ASD. © 2014 Associated Professional Sleep Societies, LLC.

Middle and inner ear malformations in two siblings exposed to valproic acid during pregnancy: a case report.

PubMed

Van Houtte, Evelyne; Casselman, Jan; Janssens, Sandra; De Kegel, Alexandra; Maes, Leen; Dhooge, Ingeborg

2014-11-01

Valproic acid (VPA) is a known teratogenic drug. Exposure to VPA during the pregnancy can lead to a distinct facial appearance, a cluster of major and minor anomalies and developmental delay. In this case report, two siblings with fetal valproate syndrome and a mild conductive hearing loss were investigated. Radiologic evaluation showed middle and inner ear malformations in both children. Audiologic, vestibular and motor examination was performed. This is the first case report to describe middle and inner ear malformations in children exposed to VPA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1β and TNF-α expression in rat hippocampus.

PubMed

Gómez, Carlos D; Buijs, Rudolf M; Sitges, María

2014-09-01

In the present study, the effects of the two classical anti-epileptic drugs, carbamazepine and valproic acid, and the non-classical anti-seizure drug vinpocetine were investigated on the expression of the pro-inflammatory cytokines IL-1β and TNF-α in the hippocampus of rats by PCR or western blot after the administration of one or seven doses. Next, the effects of the anti-seizure drugs were investigated on the rise in cytokine expression induced by lipopolysaccharides (LPS) inoculation in vivo. To validate our methods, the changes induced by the pro-convulsive agents 4-aminopyridine, pentylenetetrazole and pilocarpine were also tested. Finally, the effect of the anti-seizure drugs on seizures and on the concomitant rise in pro-inflammatory cytokine expression induced by 4-aminopyridine was explored. Results show that vinpocetine and carbamazepine reduced the expression of IL-1β and TNF-α from basal conditions, and the increase in both pro-inflammatory cytokines induced by LPS. In contrast, valproic acid failed to reduce both the expression of the cytokines from basal conditions and the rise in IL-1β and TNF-α expression induced by LPS. Tonic-clonic seizures induced either by 4-aminopyridine, pentylenetetrazole or pilocarpine increased the expression of IL-1β and TNF-α markedly. 4-aminopyridine-induced changes were reduced by all the tested anti-seizure drugs, although valproic acid was less effective. We conclude that the anti-seizure drugs, vinpocetine and carbamazepine, whose mechanisms of action involve a decrease in ion channels permeability, also reduce cerebral inflammation. The mechanism of action of anti-seizure drugs like vinpocetine and carbamazepine involves a decrease in Na(+) channels permeability. We here propose that this mechanism of action also involves a decrease in cerebral inflammation. © 2014 International Society for Neurochemistry.

Pediatric poisonings from household products: hydrofluoric acid and methacrylic acid.

PubMed

Perry, H E

2001-04-01

Household products continue to be a cause of poisoning morbibidity and mortality. Young children frequently are exposed to cleaning products and cosmetics in the course of exploring their environment. Most of these exposures are insignificant, but some result in death or permanent disability. This review discusses two products that have been responsible for serious injury and death in children: hydrofluoric acid and methacrylic acid. It also discusses federal initiatives designed to protect children from these and other household hazards.

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder.

PubMed

Kumar, Hariom; Sharma, B M; Sharma, Bhupesh

2015-12-01

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder. Copyright © 2015 Elsevier Ltd. All

Valproic acid and nonalcoholic fatty liver disease: A possible association?

PubMed Central

Farinelli, Edoardo; Giampaoli, David; Cenciarini, Anja; Cercado, Ephraim; Verrotti, Alberto

2015-01-01

Valproic acid (VPA) is one of the most prescribed drugs in children with newly diagnosed epilepsy. Weight gain and obesity have been observed as side effects of VPA. These are often linked with other metabolic disturbances such as development of insulin resistance, dyslipidemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a group of liver disorders with marked hepatic steatosis. It is associated with an increased incidence of cardiovascular diseases and overall reduced life expectancy. NAFLD occurs in 20%-25% of the general population and it is known to be the most common cause of chronic liver disease. NAFLD therefore represents a major public health issue worldwide. This study reviews and summarizes relevant literature that supports the existence of an association between VPA therapy and the development of NAFLD in children. Long-term VPA-therapy appears to be associated with an increased risk of developing NAFLD. Further studies are needed to clarify the pathogenic mechanisms that lie behind this association and to standardize the options for the use of this drug in overweight patients and in those with risks for developing MetS and NAFLD. PMID:26019740

Prevention of valproic acid-induced neural tube defects by sildenafil citrate.

PubMed

Tiboni, Gian Mario; Ponzano, Adalisa

2015-08-15

This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10mg/kg. One hour later, animals received a teratogenic dose of VPA (600mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

PubMed Central

Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

2014-01-01

The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents. PMID:24618639

Soybean greatly reduces valproic acid plasma concentrations: a food-drug interaction study.

PubMed

Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

2014-03-12

The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

Embryonic Exposure to Valproic Acid Impairs Social Predispositions of Newly-Hatched Chicks.

PubMed

Sgadò, Paola; Rosa-Salva, Orsola; Versace, Elisabetta; Vallortigara, Giorgio

2018-04-12

Biological predispositions to attend to visual cues, such as those associated with face-like stimuli or with biological motion, guide social behavior from the first moments of life and have been documented in human neonates, infant monkeys and domestic chicks. Impairments of social predispositions have been recently reported in neonates at high familial risk of Autism Spectrum Disorder (ASD). Using embryonic exposure to valproic acid (VPA), an anticonvulsant associated to increased risk of developing ASD, we modeled ASD behavioral deficits in domestic chicks. We then assessed their spontaneous social predispositions by comparing approach responses to a stimulus containing a face configuration, a stuffed hen, vs. a scrambled version of it. We found that this social predisposition was abolished in VPA-treated chicks, whereas experience-dependent mechanisms associated with filial imprinting were not affected. Our results suggest a specific effect of VPA on the development of biologically-predisposed social orienting mechanisms, opening new perspectives to investigate the neurobiological mechanisms involved in early ASD symptoms.

Early-onset absence epilepsy aggravated by valproic acid: a video-EEG report.

PubMed

Belcastro, Vincenzo; Caraballo, Roberto Horacio; Romeo, Antonino; Striano, Pasquale

2013-12-01

Early-onset absence epilepsy refers to patients with absence seizures beginning before age 4 and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a boy with absence seizures with onset at age 11 months, whose seizures increased in frequency after the introduction of valproic acid (VPA) treatment and substantially improved upon cessation of treatment. The mechanism of seizure worsening did not involve VPA toxicity, encephalopathy, Glut-1 deficiency or overdosage, and the reason for absence seizure aggravation remained unclear. The patient showed complete control of absence seizures with levetiracetam treatment and the course was benign, both in terms of seizure control and neuropsychological aspects. The similar overall electroclinical picture and outcome between children with early-onset absences and those with CAE support the view that these conditions are a continuum within the wide spectrum of IGE. [Published with video sequences].

Chemical Reaction between Boric Acid and Phosphine Indicates Boric Acid as an Antidote for Aluminium Phosphide Poisoning.

PubMed

Soltani, Motahareh; Shetab-Boushehri, Seyed F; Shetab-Boushehri, Seyed V

2016-08-01

Aluminium phosphide (AlP) is a fumigant pesticide which protects stored grains from insects and rodents. When it comes into contact with moisture, AlP releases phosphine (PH3), a highly toxic gas. No efficient antidote has been found for AlP poisoning so far and most people who are poisoned do not survive. Boric acid is a Lewis acid with an empty p orbital which accepts electrons. This study aimed to investigate the neutralisation of PH3 gas with boric acid. This study was carried out at the Baharlou Hospital, Tehran University of Medical Sciences, Tehran, Iran, between December 2013 and February 2014. The volume of released gas, rate of gas evolution and changes in pH were measured during reactions of AlP tablets with water, acidified water, saturated boric acid solution, acidified saturated boric acid solution, activated charcoal and acidified activated charcoal. Infrared spectroscopy was used to study the resulting probable adduct between PH3 and boric acid. Activated charcoal significantly reduced the volume of released gas (P <0.01). Although boric acid did not significantly reduce the volume of released gas, it significantly reduced the rate of gas evolution (P <0.01). A gaseous adduct was formed in the reaction between pure AlP and boric acid. These findings indicate that boric acid may be an efficient and non-toxic antidote for PH3 poisoning.

Chemical Reaction between Boric Acid and Phosphine Indicates Boric Acid as an Antidote for Aluminium Phosphide Poisoning

PubMed Central

Soltani, Motahareh; Shetab-Boushehri, Seyed F.; Shetab-Boushehri, Seyed V.

2016-01-01

Objectives: Aluminium phosphide (AlP) is a fumigant pesticide which protects stored grains from insects and rodents. When it comes into contact with moisture, AlP releases phosphine (PH3), a highly toxic gas. No efficient antidote has been found for AlP poisoning so far and most people who are poisoned do not survive. Boric acid is a Lewis acid with an empty p orbital which accepts electrons. This study aimed to investigate the neutralisation of PH3 gas with boric acid. Methods: This study was carried out at the Baharlou Hospital, Tehran University of Medical Sciences, Tehran, Iran, between December 2013 and February 2014. The volume of released gas, rate of gas evolution and changes in pH were measured during reactions of AlP tablets with water, acidified water, saturated boric acid solution, acidified saturated boric acid solution, activated charcoal and acidified activated charcoal. Infrared spectroscopy was used to study the resulting probable adduct between PH3 and boric acid. Results: Activated charcoal significantly reduced the volume of released gas (P <0.01). Although boric acid did not significantly reduce the volume of released gas, it significantly reduced the rate of gas evolution (P <0.01). A gaseous adduct was formed in the reaction between pure AlP and boric acid. Conclusion: These findings indicate that boric acid may be an efficient and non-toxic antidote for PH3 poisoning. PMID:27606109

Edaravone ameliorates the adverse effects of valproic acid toxicity in small intestine.

PubMed

Oktay, S; Alev, B; Tunali, S; Emekli-Alturfan, E; Tunali-Akbay, T; Koc-Ozturk, L; Yanardag, R; Yarat, A

2015-06-01

Valproic acid (VPA) is a drug used for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. Previous studies have reported an increased generation of reactive oxygen species and oxidative stress in the toxic mechanism of VPA. Edaravone, a free radical scavenger for clinical use, can quench free radical reaction by trapping a variety of free radical species. In this study, effect of edaravone on some small intestine biochemical parameters in VPA-induced toxicity was investigated. Thirty seven Sprague Dawley female rats were randomly divided into four groups. The groups include control group, edaravone (30 mg(-1) kg(-1) day(-1)) given group, VPA (0.5 g(-1) kg(-1) day(-1)) given group, VPA + edaravone (in same dose) given group. Edaravone and VPA were given intraperitoneally for 7 days. Biochemical parameters such as malondialdehyde, as an index of lipid peroxidation(LPO), sialic acid (SA), glutathione levels and glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, catalase, myeloperoxidase, alkaline phosphatase (ALP), and tissue factor (TF) activities were determined in small intestine samples by colorimetric methods. Decreased small intestine antioxidant enzyme activities, increased LPO and SA levels, and increased activities of ALP and TF were detected in the VPA group. Based on our results edaravone may be suggested to reverse the oxidative stress and inflammation due to VPA-induced small intestine toxicity. © The Author(s) 2014.

Dispensability of Annual Laboratory Follow-Up After More than 2 Years of Valproic Acid Use: A Systematic Review.

PubMed

Meijboom, Rosanne W; Grootens, Koen P

2017-11-01

The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial. We investigated the need for annual laboratory follow-up of liver enzymes, electrolytes, and full blood count (FBC) in patients treated with VPA. A systematic search in Evidence-Based Medicine Reviews (EBMR), MEDLINE, and EMBASE was undertaken in December 2016 to identify all published articles investigating or citing valproic acid, liver function disorders, electrolyte disorders, and FBC deviations. This review included 108 articles. As the number of participants and duration of the study was not adequate in most studies to detect rare adverse events, studies did not demonstrate a clear prevalence of hepatotoxicity. While a transient increase of transaminases is common and seldom harmful, severe hepatotoxicity is a rare phenomenon and is not prevented by routine laboratory monitoring. VPA had no relevant effect on serum calcium, sodium, potassium, and albumin. The prevalence of FBC varied from 0.6 to 27.8%, occurred mostly in the first 2 years of therapy, and was usually asymptomatic. Long-term monitoring in VPA treatment is only necessary when there have been dose adjustments, co-medication switches, or co-morbidity. In uncomplicated cases, annual laboratory follow-up may be discontinued after 2 years of VPA treatment. Encouraging patients to be vigilant is more effective in the detection of hepatotoxicity than laboratory testing. Follow-up of FBC at 3-6 months, 1 year, and 2 years after start or after a dose increase of VPA or interacting medication is sufficient.

Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures.

PubMed

Lego, Denise; Plaumann, Markus; Trantzschel, Thomas; Bargon, Joachim; Scheich, Henning; Buntkowsky, Gerd; Gutmann, Torsten; Sauer, Grit; Bernarding, Johannes; Bommerich, Ute

2014-07-01

Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd.

Histone deacetylase inhibitor valproic acid affects plasmacytoid dendritic cells phenotype and function.

PubMed

Arbez, Jessy; Lamarthée, Baptiste; Gaugler, Béatrice; Saas, Philippe

2014-08-01

Plasmacytoid dendritic cells (PDC) represent a rare subset of dendritic cells specialized in the production of type I IFN in response to microbial pathogens. Recent data suggested that histone deacetylase (HDAC) inhibitors possess potent immunomodulatory properties both in vitro and in vivo. In this study, we assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the phenotype and functional properties of human PDC isolated from peripheral blood. We showed that VPA inhibited the production of IFN-α and the proinflammatory cytokines TNF-α and IL-6 by CpG-activated PDC. VPA also affected the phenotype of PDC by reducing the expression of costimulatory molecules induced by CpG activation. Moreover, VPA reduced the capacity of CpG-stimulated PDC to promote CD4(+) T cell proliferation and IFN-γ production, while enhancing the proportion of IL-10 positive T cells. These results suggest that HDAC inhibition by VPA alters essential human PDC functions, highlighting the need for monitoring immune functions in cancer patients receiving HDAC inhibitors, but also making these drugs attractive therapies in inflammatory, and autoimmune diseases implicating PDC. Copyright © 2014 Elsevier GmbH. All rights reserved.

Ciliary body toxicities of systemic oxcarbazepine and valproic acid treatments: electron microscopic study.

PubMed

Göktaş, Güleser; Aktaş, Zeynep; Erdoğan, Deniz; Seymen, Cemile Merve; Karaca, Emine Esra; Cansu, Ali; Serdaroğlu, Ayşe; Kaplanoğlu, Gülnur Take

2015-01-01

Ciliary body is responsible for humour aqueous production in posterior chamber. Valproic acid (VPA) has been widely used for the treatment of epilepsy and other neuropsychiatric diseases such as bipolar disease and major depression. Oxcarbazepine (OXC) is a new anti-epileptic agent that has been used recently for childhood epilepsies such as VPA. In this study, we aimed to investigate the effects of VPA and OXC treatments used as antiepileptic in ciliary body by electron microscopy. In our study, 40 Wistar rats (21 days old) were divided equally into four groups which were applied saline (group 1), VPA (group 2), OXC (group 3) and VPA + OXC (group 4). The as-prepared ocular tissues were characterized by transmission electron microscopy (TEM) technique in scanning and transmission electron microscopy (SEM-TEM) (Carl Zeiss EVO LS10). The results confirmed that VPA caused dense ciliary body degeneration. Additionally, ciliary body degeneration in group 4 was supposed to be due to VPA treatment. Ciliary body damage and secondary outcomes should be considered in patients with long-term VPA therapy.

High-Flux Hemodialysis and Levocarnitine in the Treatment of Severe Valproic Acid Intoxication

PubMed Central

Temel, V.; Arikan, Müge; Temel, G.

2013-01-01

Valproic acid (VPA) intoxication incidence is increasing, because of the use of VPA in psychiatric disorders. The most common finding of VPA intoxication is central nervous system depression which leads to coma and respiratory depression. Pancreatitis, hyperammonemia, metabolic, and bone marrow failure (thrombocytopenia and leukopenia) have also been described. Treatment is mainly supportive. We present the case of an 18-year-old female patient, who made an attempt to autolysis with VPA. Our patient's VPA plasma level was very high (924 μg/mL), confirming that it was a severe intoxication. Our treatment including levocarnitine (50 mg/kg per day for 3 days), and high-flux hemodialysis was performed for four hours. The patient's hemodynamic status and mental function improved in conjunction with the acute reduction in VPA concentrations. Her subsequent hospital course was complicated by transient thrombocytopenia and levocarnitine induced hypophosphatemia. By day 6, the patient's laboratory values had completely normalized, and she was transferred to an inpatient psychiatric facility for continuing therapy. PMID:23762657

Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.

PubMed

Kang, Jaeseung; Kim, Eunjoon

2015-01-01

Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits.

Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

PubMed Central

Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

2013-01-01

It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts

PubMed Central

Sitarz, Kamil S.; Elliott, Hannah R.; Karaman, Betül S.; Relton, Caroline; Chinnery, Patrick F.; Horvath, Rita

2014-01-01

Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired. PMID:24725338

Association between the blood concentrations of ammonia and carnitine/amino acid of schizophrenic patients treated with valproic acid.

PubMed

Ando, Masazumi; Amayasu, Hideaki; Itai, Takahiro; Yoshida, Hisahiro

2017-01-01

Administration of valproic acid (VPA) is complicated with approximately 0.9% of patients developing hyperammonemia, but the pathogenesis of this adverse effect remains to be clarified. The aim of the present study was to search for mechanisms associated with VPA-induced hyperammonemia in the light of changes in serum amino acids concentrations associated with the urea cycle of schizophrenic patients. Blood samples (10 mL) were obtained from 37 schizophrenic patients receiving VPA for the prevention of violent behaviors in the morning after overnight fast. Blood concentrations of ammonia, VPA, free carnitine, acyl-carnitine, and 40 amino acids including glutamate and citrulline were measured for each patient. Univariate and multivariate regression analyses were performed to identify amino acids or concomitantly administered drugs that were associated with variability in the blood concentrations of ammonia. The blood ammonia level was positively correlated with the serum glutamate concentration ( r  = 0.44, p  < 0.01) but negatively correlated with glutamine ( r  = -0.41, p  = 0.01), citrulline ( r  = -0.42, p  = 0.01), and glycine concentrations ( r  = -0.54, p  < 0.01). It was also revealed that the concomitant administration of the mood stabilizers ( p  = 0.04) risperidone ( p  = 0.03) and blonanserin ( p  < 0.01) was positively associated with the elevation of the blood ammonia level. We hypothisized that VPA would elevate the blood ammonia level of schizophrenic patients. The observed changes in serum amino acids are compatible with urea cycle dysfunction, possibly due to reduced carbamoyl-phosphate synthase 1 (CPS1) activity. We conclude that VPA should be prudently prescribed to schizophrenic patients, particularly those receiving mood stabilizers or certain antipsychotics.

Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

PubMed Central

Juliandi, Berry; Tanemura, Kentaro; Igarashi, Katsuhide; Tominaga, Takashi; Furukawa, Yusuke; Otsuka, Maky; Moriyama, Noriko; Ikegami, Daigo; Abematsu, Masahiko; Sanosaka, Tsukasa; Tsujimura, Keita; Narita, Minoru; Kanno, Jun; Nakashima, Kinichi

2015-01-01

Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running. PMID:26677766

In vivo effects of naproxen, salicylic acid, and valproic acid on the pharmacokinetics of trichloroethylene and metabolites in rats.

PubMed

Rouhou, Mouna Cheikh; Charest-Tardif, Ginette; Haddad, Sami

2015-01-01

It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure.

Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups.

PubMed

Lee, Sung-Min; Kim, Bo-Kyun; Kim, Tae-Woon; Ji, Eun-Sang; Choi, Hyun-Hee

2016-06-01

Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2'-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits.

Topiramate increases the risk of valproic acid-induced encephalopathy.

PubMed

Noh, Young; Kim, Dong Wook; Chu, Kon; Lee, Soon-Tae; Jung, Keun-Hwa; Moon, Hye-Jin; Lee, Sang Kun

2013-01-01

Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET

PubMed Central

Kim, Sung Won; Hooker, Jacob M.; Otto, Nicola; Win, Khaing; Muench, Lisa; Shea, Colleen; Carter, Pauline; King, Payton; Reid, Alicia E.; Volkow, Nora D.; Fowler, Joanna S.

2013-01-01

The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profile. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using 11CO2 and the appropriate Grignard reagents. [11C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity was the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [11C]BA showed relatively high uptake in spleen and pancreas whereas [11C]PBA showed high uptake in liver and heart. Notably, [11C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects. PMID:23906667

Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET.

PubMed

Kim, Sung Won; Hooker, Jacob M; Otto, Nicola; Win, Khaing; Muench, Lisa; Shea, Colleen; Carter, Pauline; King, Payton; Reid, Alicia E; Volkow, Nora D; Fowler, Joanna S

2013-10-01

The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using (11)CO2 and the appropriate Grignard reagents. [(11)C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [(11)C]BA showed relatively high uptake in spleen and pancreas whereas [(11)C]PBA showed high uptake in liver and heart. Notably, [(11)C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects. © 2013.

Antifibrogenic role of valproic acid in streptozotocin induced diabetic rat penis.

PubMed

Kutlu, O; Karaguzel, E; Gurgen, S G; Okatan, A E; Kutlu, S; Bayraktar, C; Kazaz, I O; Eren, H

2016-05-01

We investigated the therapeutic effects of valproic acid (VPA) on erectile dysfunction and reducing penile fibrosis in streptozocin (STZ)-induced diabetic rats. Eighteen male rats were divided into three experimental groups (Control, STZ-DM, STZ-DM plus VPA) and diabetes was induced by transperitoneal single dose STZ. Eight weeks after, VPA and placebo treatments were given according to groups for 15 days. All rats were anesthetised for the measurement of in vivo erectile response to cavernous nerve stimulation. Afterward penes were evaluated histologically in terms of immune labelling scores of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Slides were also evaluated in terms of collagen/smooth muscle ratio and penile apoptosis. After the treatment with VPA, erectile responses were found as improved when compared with STZ-DM rats but not statistically meaningful. eNOS and VEGF immune expressions diminished in penile corpora of STZ-DM rats and improved with VPA treatment. VPA led to decrease in TGF-β1 expression and collagen content of diabetic rats' penes. Penile apoptosis was not diminished with VPA. In conclusion, VPA treatment seems to be effective for reducing penile fibrosis in diabetic rats and more prolonged treatment period may enhance erectile functions. © 2015 Blackwell Verlag GmbH.

Severe Hyponatremia Due to Valproic Acid Toxicity.

PubMed

Gupta, Ena; Kunjal, Ryan; Cury, James D

2015-09-01

Hyponatremia is a very commonly encountered clinical entity with potentially dangerous effects and for which many precipitating factors have been identified. We present a case of valproic acid (VPA) overdose causing profound hyponatremia, with one of the lowest serum sodium levels ever documented in literature. A 54-year-old woman with hypothyroidism, hypertension and bipolar disorder presented with somnolence after intentionally ingesting 7,500 mg VPA. She was drowsy but easily arousable with no hemodynamic compromise and an unremarkable physical exam. There was no clinical suspicion for organic neurological or pulmonary disease, adrenal insufficiency or volume depletion. She was found to have a serum sodium of 99 mEq/L, low plasma osmolality (211 mOsm/kg H2O), and high urine osmolality (115 mOsm/kg H2O). Her urine sodium was 18 mEq/L. She was euthyroid (TSH: 3.06 mIU/L) and compliant with thyroxine replacement. She was admitted to the intensive care unit for close monitoring and VPA was withheld. Over 36 hours her VPA level fell from 59.3 mg/L to 22.8 mg/L, serum sodium steadily rose to 125 mEq/L and there was concomitant improvement in her mental status. At 72 hours, she was transferred for an inpatient psychiatric evaluation and her sodium level was 135 mEq/L. She luckily did not experience any seizures or decline in neurological function. The clinical presentation in this patient is consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to a dramatic fall in sodium to a level of 99 mEq/L. Chronic VPA use has been associated with SIADH and chronic hyponatremia. Review of records in this patient from 1 year prior revealed that her last measured sodium level was 127 mEq/L. It is therefore most likely that our case is one of acute on chronic hyponatremia provoked by VPA overdose in the setting of chronic VPA use. Whilst our patient's course was relatively benign, this case illustrates a rare consequence of VPA toxicity, which

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method.

PubMed

Pope, Jeffrey D; Black, Marion J; Drummer, Olaf H; Schneider, Hans G

2017-08-01

Valproic acid (VPA) is a widely prescribed medicine, and acute toxicity is possible. As such, it should be included in any nontargeted urine drug screening method. In many published liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) methods, VPA is usually measured using a pseudo-multiple reaction monitoring (MRM) transition. We investigate a simple ultra-high-performance liquid chromatography-quadrupole time-of-flight (QTof) approach to detect the presence of VPA with more confidence. Three commercially sourced VPA metabolites were characterized and added to a nontargeted high-resolution MS urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof in negative electrospray ionization mode. The mass detector was operated in MS mode, and data were processed with UNIFI software. Sixty-eight patient urine samples, which were previously identified by a well-established gas chromatography-MS method as containing VPA, were analyzed on the Waters Xevo G2-XS LC-QTof, to validate this approach. VPA metabolite standards were characterized, and their detection data were added to the broad drug screening library. VPA metabolites were readily detectable in the urine of patients taking VPA. The inclusion of characterized VPA metabolites provides a simple and reliable method enabling the detection of VPA in nontargeted urine drug screening.

Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors.

PubMed

Griggs, Chanel A; Malm, Scott W; Jaime-Frias, Rosa; Smith, Catharine L

2018-01-15

Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop. In cells with an unsynchronized clock, VPA simultaneously upregulated the expression of genes encoding core circadian transcription factors that regulate the positive and negative limbs of the feedback loop. Using low dose glucocorticoid, we synchronized cultured fibroblast cells to a circadian oscillatory pattern. Whether VPA was added at the time of synchronization or 12h later at CT12, we found that VPA disrupted the oscillatory expression of multiple genes encoding essential transcription factors that regulate circadian rhythm. Therefore, we conclude that VPA has a potent effect on the circadian rhythm transcription-translation feedback loop that may be linked to negative VPA side effects in humans. Furthermore, our study suggests potential chronopharmacology implications of VPA usage. Copyright © 2017. Published by Elsevier Inc.

Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid.

PubMed

Juliandi, Berry; Abematsu, Masahiko; Sanosaka, Tsukasa; Tsujimura, Keita; Smith, Austin; Nakashima, Kinichi

2012-01-01

Within the developing mammalian cortex, neural progenitors first generate deep-layer neurons and subsequently more superficial-layer neurons, in an inside-out manner. It has been reported recently that mouse embryonic stem cells (mESCs) can, to some extent, recapitulate cortical development in vitro, with the sequential appearance of neurogenesis markers resembling that in the developing cortex. However, mESCs can only recapitulate early corticogenesis; superficial-layer neurons, which are normally produced in later developmental periods in vivo, are under-represented. This failure of mESCs to reproduce later corticogenesis in vitro implies the existence of crucial factor(s) that are absent or uninduced in existing culture systems. Here we show that mESCs can give rise to superficial-layer neurons efficiently when treated with valproic acid (VPA), a histone deacetylase inhibitor. VPA treatment increased the production of Cux1-positive superficial-layer neurons, and decreased that of Ctip2-positive deep-layer neurons. These results shed new light on the mechanisms of later corticogenesis. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: Case report and literature review.

PubMed

Johnson, Bridgette; Nichols, Scott

2015-12-01

Pseudobulbar affect/emotional incontinence is a potentially disabling condition characterized by expressions of affect or emotions out of context from the normal emotional basis for those expressions. This condition can result in diagnostic confusion and unrelieved suffering when clinicians interpret the emotional expressions at face value. In addition, the nomenclature, etiology, and treatment for this condition remain unclear in the medical literature. We report the case of a 60-year-old woman with multiple sclerosis who was referred to an inpatient psychiatry unit with complaints of worsening depression along with hopelessness, characterized by unrelenting crying. Our investigation showed that her symptoms were caused by pseudobulbar affect/emotional incontinence stemming from multiple sclerosis. The patient's history of multiple sclerosis and the fact that she identified herself as depressed only because of her incessant crying suggested that her symptoms might be due to the multiple sclerosis rather than to a depressive disorder. Magnetic resonance imaging demonstrated a new plaque consistent with multiple sclerosis lateral to her corpus callosum. Her symptoms resolved completely within three days on valproic acid but returned after she was cross-tapered to dextromethorphan plus quinidine, which is the FDA-approved treatment for this condition. This case provides important additional information to the current literature on pseudobulbar affect/emotional incontinence. The existing literature suggests a selective serotonin reuptake inhibitor (SSRI) and dextromethorphan/quinidine (Nuedexta) as first-line treatments; however, our patient was taking an SSRI at the time of presentation without appreciable benefit, and her symptoms responded to valproic acid but not to the dextromethorphan/quinidine. In addition, the case and the literature review suggest that the current nomenclature for this constellation of symptoms can be misleading.

Plasma oxalic acid and calcium levels in oxalate poisoning

PubMed Central

Zarembski, P. M.; Hodgkinson, A.

1967-01-01

Observations are reported on five cases of suicide or attempted suicide by poisoning with oxalic acid or ethylene glycol. Elevated oxalic acid levels were observed in the plasma, stomach contents, and a number of tissues. Raised oxalic acid levels in plasma were associated with reduced total and ultrafilterable calcium levels. It is suggested that the reduction in plasma total calcium level is due mainly to the deposition of calcium oxalate in the soft tissues, but inhibition of the parathyroid glands may be a contributory factor. Microscopic examination of various tissues indicated that oxalic acid is deposited in the tissues in two forms: (1) crystalline calcium oxalate dihydrate in the kidney and (2) a non-crystalline complex of calcium oxalate and lipid in liver and other tissues. PMID:5602563

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.

PubMed

Qin, Liyan; Dai, Xufang; Yin, Yunhou

2016-09-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Recent studies have demonstrated that Wnt signaling and mTOR signaling play important roles in the pathogenesis of ASD. However, the relationship of these two signaling pathways in ASD remains unclear. We assessed this question using the valproic acid (VPA) rat model of autism. Our results demonstrated that VPA exposure activated mTOR signaling and suppressed autophagy in the prefrontal cortex, hippocampus and cerebellum of autistic model rats, characterized by enhanced phospho-mTOR and phospho-S6 and decreased Beclin1, Atg5, Atg10, LC3-II and autophagosome formation. Rapamycin treatment suppressed the effect of VPA on mTOR signaling and ameliorated the autistic-like behaviors of rats in our autism model. The administration of VPA also activated Wnt signaling through up-regulating beta-catenin and phospho-GSK3beta. Suppression of the Wnt pathway by sulindac relieved autistic-like behaviors and attenuated VPA-induced mTOR signaling activation in autistic model rats. Our results demonstrate that VPA exposure sequentially activates Wnt signaling and mTOR signaling in rats. Suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR signaling pathway in VPA-exposed rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Valproic acid improves the tolerance for the stress in learned helplessness rats.

PubMed

Kobayashi, H; Iwata, M; Mitani, H; Yamada, T; Nakagome, K; Kaneko, K

2012-04-01

In this study, we investigated whether previously stressed rats with learned helplessness (LH) paradigm could recover from depressive-like behavior four weeks after the exposure, and also whether chronic treatment with valproic acid (VPA) could prevent behavioral despair due to the second stress on days 54 in these animals. Four weeks after induction of LH, we confirmed behavioral remission in the previously stressed rats. Two-way analysis of variance (ANOVA) performed with two factors, pretreatment (LH or Control) and drug (VPA or Saline), revealed a significant main effect of the drug on immobility time in forced swimming test. Post hoc test showed a shorter immobility time in the LH+VPA group than in the LH+Saline group. Immunohistochemical study of synapsin I showed a significant effect of drug by pretreatment interaction on immunoreactivity of synapsin I in the hippocampus: its expression levels in the regions were higher in the LH+VPA group than in the LH+Saline group. These results suggest that VPA could prevent the reappearance of stress-induced depressive-like behaviors in the rats recovering from prior stress, and that the drug-induced presynaptic changes in the expression of synapsin I in the hippocampus of LH animals might be related to improved tolerance toward the stress. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

PubMed

Kim, Ki Chan; Choi, Chang Soon; Gonzales, Edson Luck T; Mabunga, Darine Froy N; Lee, Sung Hoon; Jeon, Se Jin; Hwangbo, Ram; Hong, Minha; Ryu, Jong Hoon; Han, Seol-Heui; Bahn, Geon Ho; Shin, Chan Young

2017-10-01

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.

Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro.

PubMed

Lv, Lei; Han, Xiang; Sun, Yan; Wang, Xin; Dong, Qiang

2012-02-01

Previous studies have found that valproic acid (VPA), a histone deacetylases (HDAC) inhibitor, improves outcomes in a rat model of spinal cord injury (SCI). The study here aimed to further illuminate the neuroprotective effects of VPA against SCI, both in vivo and in vitro. First, spinal cord injury was performed in rats using NYU impactor. Delayed VPA injection (8 h following SCI) significantly accelerated locomotor recovery. VPA therapy also suppressed SCI-induced hypoacetylation of histone and promoted expressions of BDNF and GDNF. Next, the influence of VPA on axonal growth inhibited by a myelin protein was tested. Neurons from embryonic spinal cord or hippocampus were cultured on plates coated with Nogo-A peptide, and escalating concentrations of VPA were added into the cultures. VPA treatment, in a concentration dependent manner, allowed neurons to overcome Nogo-A inhibition of neurite outgrowth. Meanwhile, VPA exposure increased the level of histone acetylation and expression of BDNF in spinal neurons. Cumulatively, these findings indicate that VPA is possibly a promising medication and deserves translational trials for spinal cord injury. Copyright © 2011 Elsevier Inc. All rights reserved.

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

PubMed Central

Zhang, Li-fang; Liu, Ling-sheng; Chu, Xiao-man; Xie, Hao; Cao, Li-juan; Guo, Cen; A, Ji-ye; Cao, Bei; Li, Meng-jie; Wang, Guang-ji; Hao, Hai-ping

2014-01-01

Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg−1·d−1) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD. PMID:24442146

A simple and sensitive methodology for voltammetric determination of valproic acid in human blood plasma samples using 3-aminopropyletriethoxy silane coated magnetic nanoparticles modified pencil graphite electrode.

PubMed

Zabardasti, Abedin; Afrouzi, Hossein; Talemi, Rasoul Pourtaghavi

2017-07-01

In this work, we have prepared a nano-material modified pencil graphite electrode for the sensing of valproic acid (VA) by immobilization 3-aminopropyletriethoxy silane coated magnetic nanoparticles (APTES-MNPs) on the pencil graphite surface (PGE). Electrochemical studies indicated that the APTES-MNPs efficiently increased the electron transfer kinetics between VA and the electrode and the free NH 2 groups of the APTES on the outer surface of magnetic nanoparticles can interact with carboxyl groups of VA. Based on this, we have proposed a sensitive, rapid and convenient electrochemical method for VA determination. Under the optimized conditions, the reduction peak current of VA is found to be proportional to its concentration in the range of 1.0 (±0.2) to 100.0 (±0.3) ppm with a detection limit of 0.4 (±0.1) ppm. The whole sensor fabrication process was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) methods with using [Fe(CN) 6 ] 3-/4- as an electrochemical redox indicator. The prepared modified electrode showed several advantages such as high sensitivity, selectivity, ease of preparation and good repeatability, reproducibility and stability. The proposed method was applied to determination of valproic acid in blood plasma samples and the obtained results were satisfactory accurate. Copyright © 2017. Published by Elsevier B.V.

Alterations in the endocannabinoid system in the rat valproic acid model of autism.

PubMed

Kerr, D M; Downey, L; Conboy, M; Finn, D P; Roche, M

2013-07-15

The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder

PubMed Central

Modi, Hiren R.; Basselin, Mireille; Taha, Ameer Y.; Li, Lei O.; Coleman, Rosalind A.; Bialer, Meir; Rapoport, Stanley I.

2013-01-01

Background Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain acyl-CoA synthetase (Acsl)-4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl-4 catalyzed acylation, and thus have potential anti-BD action. Methods Rat Acsl4-flag protein was expressed in E. coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics. Results Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. Conclusions PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients. PMID:23354024

Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia.

PubMed

Main, Stacey L; Kulesza, Randy J

2017-01-06

Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Early valproic acid exposure alters functional organization in the primary visual cortex

PubMed Central

Pohl-Guimaraes, Fernanda; Krahe, Thomas E.; Medina, Alexandre E.

2018-01-01

Epilepsy is one of the most common neurologic disorders and affects 0.5 to 1% of pregnant women. The use of antiepileptic drugs, which is usually continued throughout pregnancy, can cause in offspring mild to severe sensory deficits. Neuronal selectivity to stimulus orientation is a basic functional property of the visual cortex that is crucial for perception of shapes and borders. Here we investigate the effects of early exposure to valproic acid (Val) and levetiracetam (Lev), commonly used antiepileptic drugs, on the development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets pups were exposed to Val (200 mg/kg), Lev (100 mg/kg) or saline every other day between postnatal day (P) 10 and P30, a period roughly equivalent to the third trimester of human gestation. Optical imaging of intrinsic signals or single-unit recordings were examined at P42–P84, when orientation selectivity in the ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in Val-but not Lev- or saline-treated animals. Moreover, single-unit recordings revealed that early Val treatment also reduced orientation selectivity at the cellular level. These findings indicate that Val exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in fetal anticonvulsant syndrome. PMID:21215743

Early valproic acid exposure alters functional organization in the primary visual cortex.

PubMed

Pohl-Guimaraes, Fernanda; Krahe, Thomas E; Medina, Alexandre E

2011-03-01

Epilepsy is one of the most common neurologic disorders and affects 0.5 to 1% of pregnant women. The use of antiepileptic drugs, which is usually continued throughout pregnancy, can cause in offspring mild to severe sensory deficits. Neuronal selectivity to stimulus orientation is a basic functional property of the visual cortex that is crucial for perception of shapes and borders. Here we investigate the effects of early exposure to valproic acid (Val) and levetiracetam (Lev), commonly used antiepileptic drugs, on the development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets pups were exposed to Val (200mg/kg), Lev (100mg/kg) or saline every other day between postnatal day (P) 10 and P30, a period roughly equivalent to the third trimester of human gestation. Optical imaging of intrinsic signals or single-unit recordings were examined at P42-P84, when orientation selectivity in the ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in Val- but not Lev- or saline-treated animals. Moreover, single-unit recordings revealed that early Val treatment also reduced orientation selectivity at the cellular level. These findings indicate that Val exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in fetal anticonvulsant syndrome. Copyright © 2011 Elsevier Inc. All rights reserved.

A case report of massive acute boric acid poisoning.

PubMed

Corradi, Francesco; Brusasco, Claudia; Palermo, Salvatore; Belvederi, Giulio

2010-02-01

Boric acid comes as colourless, odourless white powder and, if ingested, has potential fatal effects including metabolic acidosis, acute renal failure and shock. An 82-year-old male was brought to the emergency room 3 h after unintentional ingestion of a large amount of boric acid. Clinical course was monitored by collecting data at admittance, 12 h after admission, every 24 h for 5 days and again 1 week after admission. During the first 132 h, serum and urinary concentrations of boric acid were measured. Serum boric acid levels decreased from 1800 to 530 microg/ml after haemodialysis and from 530 to 30 microg/ml during the forced diuresis period. During dialysis, boric acid clearance averaged 235 ml/min with an extraction ratio of 70%. The overall patient's condition steadily improved over 84 h after admission. In conclusion, early treatment with forced diuresis and haemodialysis may be considered for boric acid poisoning, even if signs of renal dysfunction are not apparent, to prevent severe renal damage and its complications.

Chlorine poisoning

MedlinePlus

... the body to form hydrochloric acid and hypochlorous acid. Both are extremely poisonous. ... has been closed all winter) Mild cleaners Some bleach products ... This list may not include all uses and sources of chlorine.

Valproic acid attenuates nitric oxide and interleukin-1β production in lipopolysaccharide-stimulated iron-rich microglia.

PubMed

Mairuae, Nootchanat; Cheepsunthorn, Poonlarp

2018-04-01

Iron accumulation in activated microglia has been consistently reported in neurodegenerative diseases. Previous results suggest that these cells facilitate neuroinflammation leading to neuronal cell death. Therefore, chemical compounds that alleviate the activation of iron-rich microglia may result in neuroprotection. In the present study, the effect of valproic acid (VPA) on microglial activation under iron-rich conditions was investigated. BV-2 microglial cells were exposed to lipopolysaccharide (LPS; 1 µg/ml) and iron (300 µg/ml) with or without VPA (1.6 mM). The results demonstrated that VPA attenuated the activation of iron-rich BV2 cells induced by LPS by down-regulating the mRNA expression of inducible nitric oxide (NO) synthase and interleukin 1β (IL-1β; P<0.01), to ultimately reduce the production of NO and IL-1β (P<0.01). These events were accompanied by an attenuation in the nuclear translocation of nuclear factor-κB p65 subunit (P<0.01). These findings suggest that VPA may be therapeutically useful for attenuating the activation of iron-rich microglia.

Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Min-Ho; Kim, Mingoo; Lee, Byung-Hoon

2008-02-01

Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceridemore » concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P < 0.05) and fold change (> 1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid {beta}-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.« less

Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.

PubMed

Orr, J M; Abbott, F S; Farrell, K; Ferguson, S; Sheppard, I; Godolphin, W

1982-05-01

In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.

Protective effect of cinnamic acid in endotoxin-poisoned mice.

PubMed

Xu, Feng; Wang, Feng; Wen, Taoqun; Sang, Wentao; He, Xinyu; Li, Ling; Zeng, Nan

2017-12-01

In this work, we aimed to evaluate the protective effect of cinnamic acid (CD) on lipopolysaccharide (LPS; Escherichia coli 055:B5)-induced endotoxin-poisoned mice and clarify the underlying mechanisms. The mice were administrated CD 5 d before 15 mg/kg LPS challenge. 12 hr later, thymus was separated for determination of thymus indexes. Lung and spleen tissues were collected for histologic examination and the wet/dry weight ratio of lung was calculated, and serum was acquired for tumor necrosis factor-α (TNF-α), interleukin (IL)-18, and IL-1β measurement. Moreover, the expression of NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome was determined in lung. CD increased the thymus indexes and decreased lung wet/dry weight ratio. In addition, CD improved the lung and spleen histopathological changes induced by LPS and decreased the number of neutrophils in lung tissues. CD also inhibited the pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) production in serum. Furthermore, CD suppressed the LPS-induced NLRP3, Caspase-1, and IL-1β mRNA expression in lung, as well as the expression of NLRP3 and Caspase-1 (p20) protein. CD may have protective effects in endotoxin-poisoned mice via inhibiting the activation of NLRP3 inflammasome, and can be considered as a potential therapeutic candidate for diseases involved in endotoxin poisoning such as sepsis. Copyright © 2017 John Wiley & Sons, Ltd.

Investigation of "mysterious" disease in livestock: hydrocyanic acid poisoning.

PubMed

Krishna, L; Katoch, R C

1989-12-01

An investigation of "mysterious" disease due to hydrocyanic acid (HCN) poisoning in livestock in this state was carried out. Detailed clinicopathological and pathological studies were conducted. Characteristic signs of acute tympany followed with profuse frothing, convulsions and dyspnea were recorded. Cynosis of the mucosa with characteristic anoxemic tissue changes and a high concentration of HCN in rumen content, feed and skeletal muscles were recorded. These were sufficient to establish the diagnosis. Successful treatment with a specific antidote was achieved, and further morbidity and mortality was checked.

Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder.

PubMed

Anshu, Kumari; Nair, Ajay Kumar; Kumaresan, U D; Kutty, Bindu M; Srinath, Shoba; Laxmi, T Rao

2017-12-01

Attention is foundational to efficient perception and optimal goal driven behavior. Intact attentional processing is crucial for the development of social and communication skills. Deficits in attention are therefore likely contributors to the core pathophysiology of autism spectrum disorder (ASD). Clinical evidence in ASD is suggestive of impairments in attention and its control, but the underlying mechanisms remain elusive. We examined sustained, spatially divided attention in a prenatal valproic acid (VPA) model of ASD using the 5-choice serial reaction time task (5-CSRTT). As compared to controls, male and female VPA rats had progressively lower accuracy and higher omissions with increasing attentional demands during 5-CSRTT training, and showed further performance decrements when subjected to parametric task manipulations. It is noteworthy that although VPA exposure induced attentional deficits in both sexes, there were task parameter specific sex differences. Importantly, we did not find evidence of impulsivity or motivational deficits in VPA rats but we did find reduced social preference, as well as sensorimotor deficits that suggest pre-attentional information processing impairments. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. To the best of our knowledge, this is the first study examining attentional functions in a VPA model. Our work underscores the need for studying both sexes in ASD animal models and validates the use of the VPA model in the quest for mechanistic understanding of aberrant attentional functions and for evaluating suitable therapeutic targets. Autism Res 2017, 10: 1929-1944. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics

Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice.

PubMed

Yamaguchi, Hiroshi; Hara, Yuta; Ago, Yukio; Takano, Erika; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2017-08-30

We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function. Copyright © 2017 Elsevier B.V. All rights reserved.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

PubMed Central

Chiu, Chi-Tso; Wang, Zhifei; Hunsberger, Joshua G.

2013-01-01

The mood stabilizers lithium and valproic acid (VPA) are traditionally used to treat bipolar disorder (BD), a severe mental illness arising from complex interactions between genes and environment that drive deficits in cellular plasticity and resiliency. The therapeutic potential of these drugs in other central nervous system diseases is also gaining support. This article reviews the various mechanisms of action of lithium and VPA gleaned from cellular and animal models of neurologic, neurodegenerative, and neuropsychiatric disorders. Clinical evidence is included when available to provide a comprehensive perspective of the field and to acknowledge some of the limitations of these treatments. First, the review describes how action at these drugs’ primary targets—glycogen synthase kinase-3 for lithium and histone deacetylases for VPA—induces the transcription and expression of neurotrophic, angiogenic, and neuroprotective proteins. Cell survival signaling cascades, oxidative stress pathways, and protein quality control mechanisms may further underlie lithium and VPA’s beneficial actions. The ability of cotreatment to augment neuroprotection and enhance stem cell homing and migration is also discussed, as are microRNAs as new therapeutic targets. Finally, preclinical findings have shown that the neuroprotective benefits of these agents facilitate anti-inflammation, angiogenesis, neurogenesis, blood-brain barrier integrity, and disease-specific neuroprotection. These mechanisms can be compared with dysregulated disease mechanisms to suggest core cellular and molecular disturbances identifiable by specific risk biomarkers. Future clinical endeavors are warranted to determine the therapeutic potential of lithium and VPA across the spectrum of central nervous system diseases, with particular emphasis on a personalized medicine approach toward treating these disorders. PMID:23300133

Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid.

PubMed

Roullet, F I; Wollaston, L; Decatanzaro, D; Foster, J A

2010-10-13

Experiments in rodents have indicated that maternal valproic acid (VPA) exposure has permanent adverse effects upon neurological and behavioral development. In humans, prenatal exposure to VPA can induce fetal valproate syndrome, which has been associated with autism. The present study examined mouse pups exposed in utero to VPA, measuring physical development, olfactory discrimination, and social behavior as well as expression of plasticity-related genes, brain derived neurotrophic factor (BDNF) and NMDA receptor subunits NR2A and NR2B. VPA-exposed mice showed delayed physical development, impaired olfactory discrimination, and dysfunctional pre-weaning social behavior. In situ hybridization experiments revealed lower cortical expression of BDNF mRNA in VPA animals. These results support the validity of the VPA mouse model for human autism and suggest that alterations in plasticity-related genes may contribute to the behavioral phenotype. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

[Etiology of combined inhalational hydrocyanic acid and carbon monoxide poisoning].

PubMed

Sigrist, T; Dirnhofer, R

1979-01-01

A young man was found dead in a kitchen, that was partly burnt. Autopsy revealed, as cause of death, a combined intoxication following inhalation of carbon monoxide and hydrocyanic acid. Own investigations on the pyrolysis of pieces of furniture found in the kitchen (plastic plates containing melamine and plates containing formaldehyde) showed, that hydrocyanic acid was liberated through combustion of such substances and inhaled by the victim. The poisoning picture is discussed, and discussion includes especially considerations on the peculiar sensitivity of the brain toward the action of hydrocyanic acid and the relative insensitivity of the heart muscle. It is thought that the cause of such sensitivity difference lies in the physiological differences of the intracellular energy production. Finally the dangers of combustion gases developing from burning plastic materials are reemphasized.

Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling.

PubMed

Kautu, Bwarenaba B; Carrasquilla, Alejandro; Hicks, Matthew L; Caldwell, Kim A; Caldwell, Guy A

2013-04-29

Parkinson's disease (PD) is a currently incurable neurodegenerative disorder that affects the aging population. The loss of dopaminergic neurons in the substantia nigra is one of the pathological features of PD. The precise causes of PD remain unresolved but evidence supports both environmental and genetic contributions. Current efforts for the treatment of PD are directed toward the discovery of compounds that show promise in impeding age-dependent neurodegeneration in PD patients. Alpha-synuclein (α-Syn) is a human protein that is mutated in specific populations of patients with familial PD. Overexpression of α-Syn in animal models of PD replicates key symptoms of PD, including neurodegeneration. Here, we use the nematode Caenorhabditis elegans as a model system, whereby α-Syn toxicity causes dopaminergic neurodegeneration, to test the capacity of valproic acid (VA) to protect neurons. The results of our study showed that treatment of nematodes with moderate concentrations of VA significantly protects dopaminergic neurons against α-Syn toxicity. Consistent with previously established knowledge related to the mechanistic action of VA in the cell, we showed through genetic analysis that the neuroprotection conferred by VA is inhibited by cell-specific depletion of the C. elegans ortholog of the MAP extracellular signal-regulated kinase (ERK), MPK-1, in the dopaminergic neurons. These findings suggest that VA may exert its neuroprotective effect via ERK-MAPK, or alternately could act with MAPK signaling to additively provide dopaminergic neuroprotection. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.

PubMed

Kim, Ji-Woon; Seung, Hana; Kim, Ki Chan; Gonzales, Edson Luck T; Oh, Hyun Ah; Yang, Sung Min; Ko, Mee Jung; Han, Seol-Heui; Banerjee, Sourav; Shin, Chan Young

2017-02-01

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism.

PubMed

Silva, Guilherme Testa; Le Bé, Jean-Vincent; Riachi, Imad; Rinaldi, Tania; Markram, Kamila; Markram, Henry

2009-01-01

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 μm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12-15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

Enhanced Long-Term Microcircuit Plasticity in the Valproic Acid Animal Model of Autism

PubMed Central

Silva, Guilherme Testa; Le Bé, Jean-Vincent; Riachi, Imad; Rinaldi, Tania; Markram, Kamila; Markram, Henry

2009-01-01

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 μm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12–15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism. PMID:21423407

Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Debeb, Bisrat G.; Xu Wei; Mok, Henry

2010-03-01

Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cellmore » transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.« less

Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study.

PubMed

Rakic Ignjatovic, Anita; Miljkovic, Branislava; Todorovic, Dejan; Timotijevic, Ivana; Pokrajac, Milena

2009-02-01

Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders. VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior

Therapeutic review: is ascorbic acid of value in chromium poisoning and chromium dermatitis?

PubMed

Bradberry, S M; Vale, J A

1999-01-01

Repeated topical exposure to chromium(VI) may cause an allergic contact dermatitis or the formation of chrome ulcers. Systemic toxicity may occur following the ingestion of a chromium(VI) salt, from chromium(VI)-induced skin burns, or from inhalation of chromium(VI) occurring occupationally. Soluble chromium(VI) salts are usually absorbed more easily and cross cell membranes more readily than trivalent chromium salts, and, therefore chromium(VI) is more toxic than chromium(III). In experimental studies, endogenous ascorbic acid in rat lung, liver, and kidney and human plasma, effectively reduces chromium(VI) to chromium(III). The administration of exogenous ascorbic acid has been advocated therefore in the treatment of systemic chromium poisoning and chromium dermatitis to enhance the extracellular reduction of chromium(VI) to the less bioavailable chromium(III). In vitro experiments confirm that the addition of ascorbic acid to plasma containing chromium(VI) leads to a dose-dependent reduction of chromium(VI) to chromium(III). In animal studies, parenteral ascorbic acid 0.5-5 g/kg significantly reduced chromium-induced nephrotoxicity when administered 30 minutes before parenteral sodium dichromate and up to 1 hour after parenteral sodium chromate dosing. Parenteral ascorbic acid 0.5-5 g/kg also reduced mortality when given orally up to 2 hours after oral potassium dichromate dosing. However, the administration of parenteral ascorbic acid more than 2 hours after parenteral chromate in these experimental studies did not protect against renal damage, and parenteral ascorbic acid given 3 hours postparenteral chromate increased toxicity. In addition, there is no confirmed clinical evidence that the administration of ascorbic acid lessens morbidity or mortality in systemic chromium poisoning. A possible reason for the lack of benefit of ascorbic acid when administration is delayed, is that chromium(VI) cellular uptake has occurred prior to ascorbic acid administration

Valproic acid downregulates RBP4 and elicits hypervitaminosis A-teratogenesis--a kinetic analysis on retinol/retinoic acid homeostatic system.

PubMed

Chuang, Chao-Ming; Chang, Chi-Huang; Wang, Hui-Er; Chen, Kuan-Chou; Peng, Chiung-Chi; Hsieh, Chiu-Lan; Peng, Robert Y

2012-01-01

Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity. Proteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (-32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis.. This is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis.

Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

PubMed Central

Chuang, Chao-Ming; Chang, Chi-Huang; Wang, Hui-Er; Chen, Kuan-Chou; Peng, Chiung-Chi; Hsieh, Chiu-Lan; Peng, Robert Y.

2012-01-01

Background Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity. Methodology/Principal Findings Proteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (−32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis.. Conclusions/Significance This is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis. PMID:23028466

Valproic acid attenuates acute lung injury induced by ischemia-reperfusion in rats.

PubMed

Wu, Shu-Yu; Tang, Shih-En; Ko, Fu-Chang; Wu, Geng-Chin; Huang, Kun-Lun; Chu, Shi-Jye

2015-06-01

Evidence reveals that histone deacetylase (HDAC) inhibition has potential for the treatment of inflammatory diseases. The protective effect of HDAC inhibition involves multiple mechanisms. Heme oxygenase-1 (HO-1) is protective in lung injury as a key regulator of antioxidant response. The authors examined whether HDAC inhibition provided protection against ischemia-reperfusion (I/R) lung injury in rats by up-regulating HO-1 activity. Acute lung injury was induced by producing 40 min of ischemia followed by 60 min of reperfusion in isolated perfused rat lungs. The rats were randomly allotted to control group, I/R group, or I/R + valproic acid (VPA) group with or without an HO-1 activity inhibitor (zinc protoporphyrin IX) (n = 6 per group). I/R caused significant increases in the lung edema, pulmonary arterial pressure, lung injury scores, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 concentrations in bronchoalveolar lavage fluid. Malondialdehyde levels, carbonyl contents, and myeloperoxidase-positive cells in lung tissue were also significantly increased. I/R stimulated the degradation of inhibitor of nuclear factor-κB-α, nuclear translocation of nuclear factor-κB, and up-regulation of HO-1 activity. Furthermore, I/R decreased B-cell lymphoma-2, heat shock protein 70, acetylated histone H3 protein expression, and increased the caspase-3 activity in the rat lungs. In contrast, VPA treatment significantly attenuated all the parameters of lung injury, oxidative stress, apoptosis, and inflammation. In addition, VPA treatment also enhanced HO-1 activity. Treatment with zinc protoporphyrin IX blocked the protective effect of VPA. VPA protected against I/R-induced lung injury. The protective mechanism may be partly due to enhanced HO-1 activity following HDAC inhibition.

Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue.

PubMed

Shekh-Ahmad, Tawfeeq; Bialer, Meir; Yavin, Eylon

2012-02-01

Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds. New conjugation products between N,N'-dimethylethanolamine to VPA and TMCA to form N,N-dimethylethanolamine valproate (DEVA) and N,N-dimethylethanolamine 2,2,3,3-tetramethylcyclopropionate were synthesized and their anticonvulsant activity was assessed in the maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) seizure tests and the hippocampal kindling model in mice and/or rats. An amide analogue of DEVA (DEVAMIDE) was also synthesized and evaluated. The pharmacokinetics of DEVA and DEVAMIDE was comparatively evaluated in rats. In rats DEVA acted as a prodrug of VPA and had ED(50) values of 73 mg/kg and 158 mg/kg in the MES and the hippocampal kindling models, respectively. At these two anticonvulsant models DEVA was seven-times more potent than VPA. DEVAMIDE was active in the MES test at doses of 100 mg/kg (mice) and its rat-MES-ED(50)=38.6 mg/kg however, its protective index (PI=TD(50)/ED(50)) was twice lower than DEVA's PI. The TMCA analogues were inactive at the mice MES and scMet models. DEVA underwent rapid metabolic hydrolysis to VPA and consequently, in its pharmacokinetic analysis only VPA plasma levels were monitored. In contrast, DEVAMIDE was stable in whole blood. DEVA acts in rats as a prodrug of VPA yet shows a more potent anticonvulsant activity than VPA. DEVAMIDE acted as the drug on its own and was more potent than DEVA at the rat-MES test. Copyright © 2011 Elsevier B.V. All rights reserved.

Valproic Acid Increases Expression of Neuronal Stem/Progenitor Cell in Spinal Cord Injury

PubMed Central

Bang, Woo-Seok; Cho, Dae-Chul; Kim, Hye-Jeong; Sung, Joo-Kyung

2013-01-01

Objective This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model. Methods Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively. Results Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group. Conclusion Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI. PMID:24044073

Effects of developmental alcohol and valproic acid exposure on play behavior of ferrets

PubMed Central

Krahe, Thomas E.; Filgueiras, Claudio C.; Medina, Alexandre E.

2017-01-01

Exposure to alcohol and valproic acid (VPA) during pregnancy can lead to fetal alcohol spectrum disorders and fetal valproate syndrome, respectively. Altered social behavior is a hallmark of both these conditions and there is ample evidence showing that developmental exposure to alcohol and VPA affect social behavior in rodents. However, results from rodent models are somewhat difficult to translate to humans owing to the substantial differences in brain development, morphology, and connectivity. Since the cortex folding pattern is closely related to its specialization and that social behavior is strongly influenced by cortical structures, here we studied the effects of developmental alcohol and VPA exposure on the play behavior of the ferret, a gyrencephalic animal known for its playful nature. Animals were injected with alcohol (3.5 g/kg, i.p.), VPA (200 mg/kg, i.p.) or saline (i.p) every other day during the brain growth spurt period, between postnatal days 10 and 30. The play behavior of pairs of the same experimental group was evaluated 3 weeks later. Both treatments induced significant behavioral differences compared to controls. Alcohol and VPA exposed ferrets played less than saline treated ones, but while animals from the alcohol group displayed a delay in start playing with each other, VPA treated ones spent most of the time close to one another without playing. These findings not only extend previous results on the effects of developmental exposure to alcohol and VPA on social behavior, but make the ferret a great model to study the underlying mechanisms of social interaction. PMID:27208641

Valproic Acid Induces Hair Regeneration in Murine Model and Activates Alkaline Phosphatase Activity in Human Dermal Papilla Cells

PubMed Central

Lee, Soung-Hoon; Yoon, Juyong; Shin, Seung Ho; Zahoor, Muhamad; Kim, Hyoung Jun; Park, Phil June; Park, Won-Seok; Min, Do Sik; Kim, Hyun-Yi; Choi, Kang-Yell

2012-01-01

Background Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo. Methodology/ Principal Findings Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice. Conclusions/ Significance Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth. PMID:22506014

Late onset deficits in synaptic plasticity in the valproic acid rat model of autism.

PubMed

Martin, Henry G S; Manzoni, Olivier J

2014-01-01

Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barker, Christopher A., E-mail: barkerc@mskcc.org; Bishop, Andrew J.; Chang, Maria

2013-07-01

Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RTmore » were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.« less

Poison ivy/oak dermatitis. Use of polyamine salts of a linoleic acid dimer for topical prophylaxis.

PubMed

Orchard, S; Fellman, J H; Storrs, F J

1986-07-01

Closed patch tests were used to evaluate the ability of 156 different preparations (based on 22 different chemicals) to prevent poison ivy dermatitis. Several polyamine salts of a linoleic acid dimer were identified that were totally able to prevent the usual dermatitis in approximately 70% of subjects. The effectiveness of the preparations improved when the antigen and the protectant were washed off within eight to 12 hours, instead of remaining on the skin for 48 hours. When washed off, and depending on the protectant, concentration, and vehicle used, several of the preparations were totally able to prevent a dermatitis in a range of 56% to 100% of subjects tested. Further work with these compounds may greatly benefit the many people currently plagued by their allergy to poison ivy and poison oak.

Teratology study of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice.

PubMed

Okada, Akinobu; Onishi, Yuko; Aoki, Yoshinobu; Yagen, Boris; Sobol, Eyal; Bialer, Meir; Fujiwara, Michio

2006-06-01

Although valproic acid (VPA) is used extensively for treating various kinds of epilepsies, it is well known that it causes neural tube and skeletal defects in both humans and animals. The amide and urea derivatives of the tetramethylcylcopropyl VPA analogue, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (N-methoxy-TMCD) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMC-urea), were synthesized and shown to have a more potent anticonvulsant activity than VPA. The objective of this study was to investigate the teratogenic effects of these compounds in NMRI mice. Pregnant NMRI mice were given a single subcutaneous injection of either VPA, N-methoxy-TMCD, or TMC-urea at 1.8 and 3.6 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18. First, the live fetuses were examined to detect any external malformations, then their skeletons were double-stained for bone and cartilage and subsequently examined. Significant increases in fetal losses and neural tube defects were observed with administration of VPA at 3.6 mmol/kg when compared to the vehicle control. In contrast, upon cesarean section, there were no significant differences between either N-methoxy-TMCD or TMC-urea and the control groups for any parameter. Skeletal examination revealed that a number of the abnormalities were induced by VPA dose-dependently at high rates of incidence. These abnormalities were mainly at the axial skeletal level. However, lower frequencies of skeletal abnormality were observed with N-methoxy-TMCD and TMC-urea than with VPA. In addition to their more potent antiepileptic activity, these findings clearly indicate that N-methoxy-TMCD and TMC-urea are distinctly less teratogenic than VPA in NMRI mice.

Cytochrome P-450-catalyzed desaturation of valproic acid in vitro. Species differences, induction effects, and mechanistic studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rettie, A.E.; Boberg, M.; Rettenmeier, A.W.

1988-09-25

The cytochrome P-450-mediated desaturation of valproic acid (VPA) to its hepatotoxic metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), was examined in liver microsomes from rats, mice, rabbits and humans. The highest substrate turnover was found with microsomes from rabbits (44.2 +/- 2.7 pmol of product/nmol P-450/15 min), while lower activities were observed in preparations from human, mouse, and rat liver, in that order. Pretreatment of animals with phenobarbital led to enhanced rates of formation of 4-ene-VPA in vitro and yielded induction ratios for desaturation ranging from 2.5 to 8.4, depending upon the species. Comparative studies in the rat showed that phenobarbital is amore » more potent inducer of olefin formation than either phenytoin or carbamazepine. The mechanism of the desaturation reaction was studied by inter- and intramolecular deuterium isotope effect experiments, which demonstrated that removal of a hydrogen atom from the subterminal C-4 position of VPA is rate limiting in the formation of both 4-ene- and 4-hydroxy-VPA. Hydroxylation at the neighboring C-5 position, on the other hand, was highly sensitive to deuterium substitution at that site, but not to deuteration at C-4. Based on these findings, it is proposed that 4-ene- and 4-hydroxy-VPA are products of a common P-450-dependent metabolic pathway, in which a carbon-centered free radical at C-4 serves as the key intermediate. 5-Hydroxy-VPA, in contrast, derives from an independent hydroxylation reaction.« less

Sodium fluoroacetate poisoning.

PubMed

Proudfoot, Alex T; Bradberry, Sally M; Vale, J Allister

2006-01-01

Sodium fluoroacetate was introduced as a rodenticide in the US in 1946. However, its considerable efficacy against target species is offset by comparable toxicity to other mammals and, to a lesser extent, birds and its use as a general rodenticide was therefore severely curtailed by 1990. Currently, sodium fluoroacetate is licensed in the US for use against coyotes, which prey on sheep and goats, and in Australia and New Zealand to kill unwanted introduced species. The extreme toxicity of fluoroacetate to mammals and insects stems from its similarity to acetate, which has a pivotal role in cellular metabolism. Fluoroacetate combines with coenzyme A (CoA-SH) to form fluoroacetyl CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle and reacts with citrate synthase to produce fluorocitrate, a metabolite of which then binds very tightly to aconitase, thereby halting the cycle. Many of the features of fluoroacetate poisoning are, therefore, largely direct and indirect consequences of impaired oxidative metabolism. Energy production is reduced and intermediates of the tricarboxylic acid cycle subsequent to citrate are depleted. Among these is oxoglutarate, a precursor of glutamate, which is not only an excitatory neurotransmitter in the CNS but is also required for efficient removal of ammonia via the urea cycle. Increased ammonia concentrations may contribute to the incidence of seizures. Glutamate is also required for glutamine synthesis and glutamine depletion has been observed in the brain of fluoroacetate-poisoned rodents. Reduced cellular oxidative metabolism contributes to a lactic acidosis. Inability to oxidise fatty acids via the tricarboxylic acid cycle leads to ketone body accumulation and worsening acidosis. Adenosine triphosphate (ATP) depletion results in inhibition of high energy-consuming reactions such as gluconeogenesis. Fluoroacetate poisoning is associated with citrate accumulation in several tissues, including the brain. Fluoride

In utero exposure to valproic acid and autism--a current review of clinical and animal studies.

PubMed

Roullet, Florence I; Lai, Jonathan K Y; Foster, Jane A

2013-01-01

Valproic acid (VPA) is both an anti-convulsant and a mood stabilizer. Clinical studies over the past 40 years have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism. Two recent FDA warnings related to use of VPA in pregnancy emphasize the need to reevaluate its use clinically during child-bearing years. The emerging clinical evidence showing a link between VPA exposure and both cognitive function and risk of autism brings to the forefront the importance of understanding how VPA exposure influences neurodevelopment. In the past 10 years, animal studies have investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure. Behavioral studies show that VPA exposure in both rats and mice leads to autistic-like behaviors in the offspring, including social behavior deficits, increased repetitive behaviors, and deficits in communication. Based on this work VPA maternal challenge in rodents has been proposed as an animal model to study autism. This model has both face and construct validity; however, like all animal models there are limitations to its translation to the clinical setting. Here we provide a review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid.

PubMed

Bhalla, Sheena; Joshi, Deval; Bhullar, Shaminder; Kasuga, Daniel; Park, Yeonhee; Kay, Christine N

2013-07-01

The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies. A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated. Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm(2) (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use. VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.

Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA.

PubMed

Hirsch, Mauro Mozael; Deckmann, Iohanna; Fontes-Dutra, Mellanie; Bauer-Negrini, Guilherme; Della-Flora Nunes, Gustavo; Nunes, Walquiria; Rabelo, Bruna; Riesgo, Rudimar; Margis, Rogerio; Bambini-Junior, Victorio; Gottfried, Carmem

2018-05-01

Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication and language, and restricted repertoire of activities and interests. The etiology of ASD remains unknown and no clinical markers for diagnosis were identified. Environmental factors, including prenatal exposure to valproic acid (VPA), may contribute to increased risk of developing ASD. MicroRNA (miRNA) are small noncoding RNA that regulate gene expression and are frequently linked to biological processes affected in neurodevelopmental disorders. In this work, we analyzed the effects of resveratrol (an antioxidant and anti-inflammatory molecule) on behavioral alterations of the VPA model of autism, as well as the levels of circulating miRNA. We also evaluated the same set of miRNA in autistic patients. Rats of the VPA model of autism showed reduced total reciprocal social interaction, prevented by prenatal treatment with resveratrol (RSV). The levels of miR134-5p and miR138-5p increased in autistic patients. Interestingly, miR134-5p is also upregulated in animals of the VPA model, which is prevented by RSV. In conclusion, our findings revealed important preventive actions of RSV in the VPA model, ranging from behavior to molecular alterations. Further evaluation of preventive mechanisms of RSV can shed light in important biomarkers and etiological triggers of ASD. Copyright © 2018 Elsevier Ltd. All rights reserved.

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

PubMed

Zhang, Xi; He, Xiaosong; Li, Qingqing; Kong, Xuejian; Ou, Zhenri; Zhang, Le; Gong, Zhuo; Long, Dahong; Li, Jianhua; Zhang, Meng; Ji, Weidong; Zhang, Wenjuan; Xu, Liping; Xuan, Aiguo

2017-05-09

Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood. Here we investigated if and how mammalian target of rapamycin (mTOR) signaling is involved in the neuronal differentiation of VPA-induced NSCs. Our data demonstrated that mTOR activation not only promoted but also was necessary for the neuronal differentiation of NSCs induced by VPA. We further found that inhibition of mTOR signaling blocked demethylation of neuron-specific gene neurogenin 1 (Ngn1) regulatory element in induced cells. These are correlated with the significant alterations of passive DNA demethylation and the active DNA demethylation pathway in the Ngn1 promoter, but not the suppression of lysine-specific histone methylation and acetylation in the promoter region of Ngn1. These findings highlight a potentially important role for mTOR signaling, by working together with DNA demethylation, to influence the fate of NSCs via regulating the expression of Ngn1 in VPA-induced neuronal differentiation of NSCs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas

PubMed Central

Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

2013-01-01

The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. PMID:24092664

Determination of formic acid tissue and fluid concentrations in three fatalities due to methanol poisoning.

PubMed

Hantson, P; Haufroid, V; Mahieu, P

2000-12-01

Three fatalities caused by methanol ingestion are reported. Admission blood methanol concentrations ranged from 0.28 to 4.6 g/L. Two patients had been admitted after a significant delay (>20 hours), and one patient was observed within 90 minutes following ingestion. Formic acid levels were determined in blood samples at admission and ranged from 302 to 680 mg/L. The patients died 44, 55, and 82 hours after poisoning. Formic acid determinations in postmortem tissues were performed by a gas chromatograph method. The authors found great variability in formic acid distribution among the patients and among organs.

Histamine poisoning (scombroid fish poisoning): an allergy-like intoxication.

PubMed

Taylor, S L; Stratton, J E; Nordlee, J A

1989-01-01

Histamine poisoning results from the consumption of foods, typically certain types of fish and cheeses, that contain unusually high levels of histamine. Spoiled fish of the families, Scombridae and Scomberesocidae (e.g. tuna, mackerel, bonito), are commonly implicated in incidents of histamine poisoning, which leads to the common usage of the term, "scombroid fish poisoning", to describe this illness. However, certain non-scombroid fish, most notably mahi-mahi, bluefish, and sardines, when spoiled are also commonly implicated in histamine poisoning. Also, on rare occasions, cheeses especially Swiss cheese, can be implicated in histamine poisoning. The symptoms of histamine poisoning generally resemble the symptoms encountered with IgE-mediated food allergies. The symptoms include nausea, vomiting, diarrhea, an oral burning sensation or peppery taste, hives, itching, red rash, and hypotension. The onset of the symptoms usually occurs within a few minutes after ingestion of the implicated food, and the duration of symptoms ranges from a few hours to 24 h. Antihistamines can be used effectively to treat this intoxication. Histamine is formed in foods by certain bacteria that are able to decarboxylate the amino acid, histidine. However, foods containing unusually high levels of histamine may not appear to be outwardly spoiled. Foods with histamine concentrations exceeding 50 mg per 100 g of food are generally considered to be hazardous. Histamine formation in fish can be prevented by proper handling and refrigerated storage while the control of histamine formation in cheese seems dependent on insuring that histamine-producing bacteria are not present in significant numbers in the raw milk.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid.

PubMed

Bertelsen, Freja; Folloni, Davide; Møller, Arne; Landau, Anne M; Scheel-Krüger, Jørgen; Winterdahl, Michael

2017-09-01

To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29-34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

PubMed Central

Gorlia, T.; Cairncross, J.G.; van den Bent, M.J.; Mason, W.; Belanger, K.; Brandes, A.A.; Bogdahn, U.; Macdonald, D.R.; Forsyth, P.; Rossetti, A.O.; Lacombe, D.; Mirimanoff, R.-O.; Vecht, C.J.; Stupp, R.

2011-01-01

Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981–22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24–0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53–0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49–0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo. PMID:21880994

Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma.

PubMed

Mascaro-Cordeiro, Bruna; Oliveira, Indhira Dias; Tesser-Gamba, Francine; Pavon, Lorena Favaro; Saba-Silva, Nasjla; Cavalheiro, Sergio; Dastoli, Patrícia; Toledo, Silvia Regina Caminada

2018-05-22

Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines. Dose-response curve determined IC 50 values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes. The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p < 0.0001). TERT, GLI1, and AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation. MB tumors belonging to SHH molecular subgroup, with TP53 MUT , would be the ones that present high risk in relation to VA use during the treatment, while TP53 WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.

Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead.

PubMed

van Eijkeren, Jan C H; Olie, J Daniël N; Bradberry, Sally M; Vale, J Allister; de Vries, Irma; Clewell, Harvey J; Meulenbelt, Jan; Hunault, Claudine C

2017-02-01

Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model's predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. Pre-chelation blood lead concentrations ranged between 99 and 150 μg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.

Spinal Muscular Atrophy Biomarker Measurements from Blood Samples in a Clinical Trial of Valproic Acid in Ambulatory Adults

PubMed Central

Renusch, Samantha R.; Harshman, Sean; Pi, Hongyang; Workman, Eileen; Wehr, Allison; Li, Xiaobai; Prior, Thomas W.; Elsheikh, Bakri H.; Swoboda, Kathryn J.; Simard, Louise R.; Kissel, John T.; Battle, Daniel; Parthun, Mark R.; Freitas, Michael A.; Kolb, Stephen J.

2015-01-01

Abstract Background: Clinical trials of therapies for spinal muscular atrophy (SMA) that are designed to increase the expression the SMN protein ideally include careful assessment of relevant SMN biomarkers. Objective: In the SMA VALIANT trial, a recent double-blind placebo-controlled crossover study of valproic acid (VPA) in ambulatory adult subjects with SMA, we investigated relevant pharmacodynamic biomarkers in blood samples from SMA subjects by direct longitudinal measurement of histone acetylation and SMN mRNA and protein levels in the presence and absence of VPA treatment. Methods: Thirty-three subjects were randomized to either VPA or placebo for the first 6 months followed by crossover to the opposite arm for an additional 6 months. Outcome measures were compared between the two treatments (VPA and placebo) using a standard crossover analysis. Results: A significant increase in histone H4 acetylation was observed with VPA treatment (p = 0.005). There was insufficient evidence to suggest a treatment effect with either full length or truncated SMN mRNA transcript levels or SMN protein levels. Conclusions: These measures were consistent with the observed lack of change in the primary clinical outcome measure in the VALIANT trial. These results also highlight the added benefit of molecular and pharmacodynamic biomarker measurements in the interpretation of clinical trial outcomes. PMID:27858735

Valproic Acid Promotes Survival of Facial Motor Neurons in Adult Rats After Facial Nerve Transection: a Pilot Study.

PubMed

Zhang, Lili; Fan, Zhaomin; Han, Yuechen; Xu, Lei; Liu, Wenwen; Bai, Xiaohui; Zhou, Meijuan; Li, Jianfeng; Wang, Haibo

2018-04-01

Valproic acid (VPA), a medication primarily used to treat epilepsy and bipolar disorder, has been applied to the repair of central and peripheral nervous system injury. The present study investigated the effect of VPA on functional recovery, survival of facial motor neurons (FMNs), and expression of proteins in rats after facial nerve trunk transection by functional measurement, Nissl staining, TUNEL, immunofluorescence, and Western blot. Following facial nerve injury, all rats in group VPA showed a better functional recovery, which was significant at the given time, compared with group NS. The Nissl staining results demonstrated that the number of FMNs survival in group VPA was higher than that in group normal saline (NS). TUNEL staining showed that axonal injury of facial nerve could lead to neuronal apoptosis of FMNs. But treatment of VPA significantly reduced cell apoptosis by decreasing the expression of Bax protein and increased neuronal survival by upregulating the level of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) expression in injured FMNs compared with group NS. Overall, our findings suggest that VPA may advance functional recovery, reduce lesion-induced apoptosis, and promote neuron survival after facial nerve transection in rats. This study provides an experimental evidence for better understanding the mechanism of injury and repair of peripheral facial paralysis.

Valproic acid inhibits epithelial‑mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression.

PubMed

Mao, Shaowei; Lu, Guoliang; Lan, Xiaopeng; Yuan, Chuanwei; Jiang, Wei; Chen, Yougen; Jin, Xunbo; Xia, Qinghua

2017-11-01

Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial‑mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786‑O and Caki‑1 treated with VPA, the neural (N)‑cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)‑cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N‑cadherin and simultaneously upregulated E‑cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA‑mediated EMT‑inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor‑β (TGF‑β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1‑γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT‑associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF‑β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.

Recognizing the Toxicodendrons (poison ivy, poison oak, and poison sumac).

PubMed

Guin, J D; Gillis, W T; Beaman, J H

1981-01-01

Poison ivy, poison oak, and poison sumac are now classified in the genus Toxicodendron which is readily distinguished from Rhus. In the United States, there are two species of poison oak, Toxicodendron diversilobum (western poison oak) and Toxicodendron toxicarium (eastern poison oak). There are also two species of poison ivy, Toxicodendron rydbergii, a nonclimbing subshrub, and Toxicodendron radicans, which may be either a shrub or a climbing vine. There are nine subspecies of T. radicans, six of which are found in the United States. One species of poison sumac, Toxicodendron vernix, occurs in the United States. Distinguishing features of these plants and characteristics that separate Toxicodendron from Rhus are outlined in the text and illustrated in color plates.

The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

PubMed Central

Riebeling, Christian; Pirow, Ralph; Becker, Klaus; Buesen, Roland; Eikel, Daniel; Kaltenhäuser, Johanna; Meyer, Frauke; Nau, Heinz; Slawik, Birgitta; Visan, Anke; Volland, Jutta; Spielmann, Horst; Luch, Andreas; Seiler, Andrea

2011-01-01

Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition. PMID:21227905

Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1α/VEGF signals.

PubMed

Zhao, Y; You, W; Zheng, J; Chi, Y; Tang, W; Du, R

2016-11-01

Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer. The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated. Our present study reveals that 1 mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1α (HIF-1α), and not HIF-1β, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1α can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time-dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1α and VEGF expression. Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF-1α and VEGF suppression of cervical cancer cells.

Severe valproic acid intoxication: case study on the unbound fraction and the applicability of extracorporeal elimination.

PubMed

van den Broek, Marcel P H; Sikma, Maaike A; Ververs, Tessa F; Meulenbelt, Jan

2009-12-01

Among anticonvulsants, valproic acid (VPA) is cited as the most frequent cause of unintentional and intentional intoxications. Symptoms of VPA intoxication are diverse and are related to VPA plasma concentration. Although total plasma concentrations of less than 450 mg/l produce limited toxicity, severe intoxications (>850 mg/l) can induce coma and are ultimately life threatening. A 32-year-old comatose woman was admitted to the ICU at our hospital; she suffered from hypotension, respiratory depression, hypoglycaemia, sinus bradycardia, hyperammonaemia, metabolic acidosis, and her core body temperature was 33.7 degrees C. The total VPA plasma concentration was 1244 mg/l with an increased unbound fraction of 85%. After we administered multiple doses of activated charcoal, she underwent continuous veno-venous haemofiltration to reduce the plasma VPA concentration. As the total concentration decreased, the unbound fraction also decreased. Within 20 h of admission, the patient made a full recovery. In cases of VPA intoxication, protein-binding saturation and drug characteristics render extracorporeal elimination, an effective technique for eliminating the unbound drug. Its application should be considered, depending on clinical symptoms, VPA concentration (>300 mg/l), albumin concentration and ammonia concentration (>400 micromol/l). The application of this technique should be weighed against its risks. This case illustrates the clinical significance of applying continuous veno-venous haemofiltration in VPA intoxication because of protein-binding saturation, and suggests when extracorporeal elimination should be considered.

The application of multiple analyte adduct formation in the LC-MS3 analysis of valproic acid in human serum.

PubMed

Dziadosz, Marek

2017-01-01

LC-MS using electrospray ionisation (negative ion mode) and low-energy collision-induced dissociation tandem mass spectrometric (CID-MS/MS) analysis, together with the multiple analyte adduct formation with the components of the mobile phase, were applied to analyse valproic acid in human serum with LC-MS 3 . The CID-fragmentation of the precursor analyte adduct [M+2CH 3 COONa-H] - was applied in the method validation (307.1/225.1/143.0). Chromatographic separation was performed with a Luna 5μm C18 (2) 100A, 150mm×2mm column and the elution with a mobile phase consisting of A (H 2 O/methanol=95/5, v/v) and B (H 2 O/methanol=3/97, v/v), both with 10mM ammonium acetate and 0.1% acetic acid. A binary flow pumping mode with a total flow rate of 0.400mL/min was used. The calculated limit of detection/quantification of the method calibrated in the range of 10-200μg/mL was 0.31/1.0μg/mL. The sample preparation based on protein precipitation with 1mL of H 2 O/methanol solution (3/97, v/v) with 10mM sodium acetate and 100mM acetic acid. On the basis of the experiments performed could be demonstrated, that multiple analyte adduct formation can be applied to generate MS 3 quantitation of analytes with problematic fragmentation. The presented new strategy makes the analysis of small drugs, which do not produce any stable product ions at all, on the basis of LC-MS 3 possible. Copyright © 2016 Elsevier B.V. All rights reserved.

Unintentional ingestion of Cordyceps fungus-infected cicada nymphs causing ibotenic acid poisoning in Southern Vietnam.

PubMed

Doan, Uyen Vy; Mendez Rojas, Bomar; Kirby, Ralph

2017-09-01

Cordyceps fungus found in infected cicada nymphs ("cicada flowers") is utilized in traditional Chinese medicine. Cordyceps fungus toxicity in humans has not been previously reported. We report 60 cases of apparent Cordyceps poisoning in Southern Vietnam. We retrospectively collected demographic and clinical data from the medical records (21 cases) and by telephone interview (39 cases) of patients admitted to seven hospitals in Southern Vietnam following ingestion of cicada flowers between 2008 and 2015. We also determined the species of Cordyceps present in the cicada flowers and performed a partial chemical analysis of the fungus. Sixty cases of toxic effects following ingestion of cicada flowers were documented. Symptom onset occurred within 60 minutes following ingestion. Symptoms included dizziness, vomiting, salivation, mydriasis, jaw stiffness, urinary retention, seizures, agitated delirium, hallucinations, somnolence and coma. None of the patients suffered liver or kidney injury. There was one fatality. The Cordyceps fungus involved in these poisoning was identified as Ophiocordyceps heteropoda. The presence of ibotenic acid was confirmed, but musimol and muscarine were absent. Cicada infected with Ophiocordyceps heteropoda in Vietnam contain ibotenic acid and are associated with a clinical syndrome consistent with its effects.

Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

PubMed

Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

2013-10-01

The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid.

PubMed

Gao, Jingquan; Wu, Hongmei; Cao, Yonggang; Liang, Shuang; Sun, Caihong; Wang, Peng; Wang, Ji; Sun, Hongli; Wu, Lijie

2016-09-01

Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA-induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p-CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Swimming pool cleaner poisoning

MedlinePlus

Swimming pool cleaner poisoning occurs when someone swallows this type of cleaner, touches it, or breathes in ... The harmful substances in swimming pool cleaner are: Bromine ... copper Chlorine Soda ash Sodium bicarbonate Various mild acids

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats.

PubMed

Chu, Weihua; Yuan, Jichao; Huang, Lei; Xiang, Xin; Zhu, Haitao; Chen, Fei; Chen, Yanyan; Lin, Jiangkai; Feng, Hua

2015-07-01

Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.

Chronic valproic acid administration impairs contextual memory and dysregulates hippocampal GSK-3β in rats.

PubMed

Sintoni, Silvia; Kurtys, Ewelina; Scandaglia, Marilyn; Contestabile, Antonio; Monti, Barbara

2013-05-01

Valproic acid (VPA), a long-standing anti-epileptic and anti-manic drug, exerts multiple actions in the nervous system through various molecular mechanisms. Neuroprotective properties have been attributed to VPA in different models of neurodegeneration, but contrasting results on its improvement of learning and memory have been reported in non-pathologic conditions. In the present study, we have tested on a hippocampal-dependent learning test, the contextual fear conditioning, the effect of chronic VPA administration through alimentary supplementation that allows relatively steady concentrations to be reached by a drug otherwise very rapidly eliminated in rodents. Contextual fear memory was significantly impaired in rats chronically treated with VPA for 4 weeks. To understand the cellular and molecular correlates of this amnesic effect with particular regard to hippocampus, we addressed three putatively memory-related targets of VPA action in this brain area, obtaining the following main results: i) chronic VPA promoted an increase of post-translational modifications of histone H3 (acetylation and phosphorylation) known to favor gene transcription; ii) adult neurogenesis in the dentate gyrus, which has been controversially reported to be affected by VPA, was unchanged; and iii) GSK-3β, a kinase playing a key role in hippocampal plasticity, as well as in learning and memory, was dysregulated by VPA treatment. These results point at GSK-3β dysregulation in the hippocampus as an important parameter in the amnesic effect of VPA. The VPA amnesic effect in the animal model here reported is also supported by some observations in patients and, therefore, it should be taken into account and monitored in VPA-based therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

Thrombospondin-1 peptide ABT-510 combined with valproic acid is an effective antiangiogenesis strategy in neuroblastoma.

PubMed

Yang, Qiwei; Tian, Yufeng; Liu, Shuqing; Zeine, Rana; Chlenski, Alexandre; Salwen, Helen R; Henkin, Jack; Cohn, Susan L

2007-02-15

In the pediatric cancer neuroblastoma, clinically aggressive disease is associated with increased levels of angiogenesis stimulators and high vascular index. We and others have hypothesized that blocking angiogenesis may be effective treatment for this pediatric malignancy. However, little is known about the efficacy of antiangiogenic agents in pediatric malignancies. Recently, promising results have been reported in an adult phase I study of ABT-510, a peptide derivative of the natural angiogenic inhibitor thrombospondin-1. Histone deacetylase inhibitors, such as valproic acid (VPA), have also been shown to have antiangiogenic activity in several cancer models. In this study, we evaluated the effects of ABT-510 and VPA on neuroblastoma tumor growth and angiogenesis. Although only VPA was capable of blocking the proliferation of neuroblastoma cells and inducing neuroblastoma cell apoptosis in vitro, treatment with VPA or ABT-510 alone significantly suppressed the growth of neuroblastoma xenografts established from two different MYCN-amplified cell lines. Combination therapy more effectively inhibited the growth of small neuroblastoma xenografts than single-agent treatment, and in animals with large xenografts, total cessation of tumor growth was achieved with this treatment approach. The microvascular density was significantly reduced in the xenografts treated with combination therapy compared with controls or tumors treated with single agents. In addition, the number of structurally abnormal vessels was reduced, suggesting that these agents may "normalize" the tumor vasculature. Our results indicate that ABT-510 combined with VPA may be an effective antiangiogenic treatment strategy for children with high-risk neuroblastoma.

Comparative Network-Based Recovery Analysis and Proteomic Profiling of Neurological Changes in Valproic Acid-Treated Mice

PubMed Central

2013-01-01

Despite its prominence for characterization of complex mixtures, LC–MS/MS frequently fails to identify many proteins. Network-based analysis methods, based on protein–protein interaction networks (PPINs), biological pathways, and protein complexes, are useful for recovering non-detected proteins, thereby enhancing analytical resolution. However, network-based analysis methods do come in varied flavors for which the respective efficacies are largely unknown. We compare the recovery performance and functional insights from three distinct instances of PPIN-based approaches, viz., Proteomics Expansion Pipeline (PEP), Functional Class Scoring (FCS), and Maxlink, in a test scenario of valproic acid (VPA)-treated mice. We find that the most comprehensive functional insights, as well as best non-detected protein recovery performance, are derived from FCS utilizing real biological complexes. This outstrips other network-based methods such as Maxlink or Proteomics Expansion Pipeline (PEP). From FCS, we identified known biological complexes involved in epigenetic modifications, neuronal system development, and cytoskeletal rearrangements. This is congruent with the observed phenotype where adult mice showed an increase in dendritic branching to allow the rewiring of visual cortical circuitry and an improvement in their visual acuity when tested behaviorally. In addition, PEP also identified a novel complex, comprising YWHAB, NR1, NR2B, ACTB, and TJP1, which is functionally related to the observed phenotype. Although our results suggest different network analysis methods can produce different results, on the whole, the findings are mutually supportive. More critically, the non-overlapping information each provides can provide greater holistic understanding of complex phenotypes. PMID:23557376

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

PubMed Central

Saha, Subbroto Kumar; Yin, Yingfu; Kim, Kyeongseok; Yang, Gwang-Mo; Abdal Dayem, Ahmed; Choi, Hye Yeon; Cho, Ssang-Goo

2017-01-01

Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC. PMID:28498322

Effects of valproic acid and magnesium sulphate on rocuronium requirement in patients undergoing craniotomy for cerebrovascular surgery.

PubMed

Kim, M-H; Hwang, J-W; Jeon, Y-T; Do, S-H

2012-09-01

Many anti-epileptics cause resistance to non-depolarizing neuromuscular blocking agents, but this has not been reported for valproic acid (VPA). We hypothesized that VPA would increase the rocuronium requirement and that magnesium sulphate (MgSO(4)) may reduce this increase. Fifty-five patients undergoing cerebrovascular surgeries were studied. Subjects were allocated into three groups at a 1:1:1 ratio: Groups VM, VC, and C. Groups VM and VC were given VPA premedication; Group C was not. A rocuronium injection (0.6 mg kg(-1) i.v.) was administered to Group VM, followed by MgSO(4) as a 50 mg kg(-1) i.v. bolus and 15 mg kg(-1) h(-1) infusion. The same volume of 0.9% saline was administered to the other groups. Supplementary rocuronium (0.15 mg kg(-1)) was given whenever the train-of-four count reached 2. Rocuronium requirements (primary outcome), mean arterial pressure (MAP), heart rate (HR), nausea, vomiting, shivering, and use of anti-emetics and nicardipine were compared. Group VC showed the highest rocuronium requirement [mg kg(-1) h(-1): 0.47 (0.08) vs 0.33 (0.12) (Group C), 0.31 (0.07) (Group VM); P<0.001]. MAP, intraoperative HR, nausea, vomiting, shivering, and use of anti-emetics and nicardipine were not significantly different among the groups. Postoperative HR was lower in Group VM than in Group VC. VPA increased the rocuronium requirement, and MgSO(4) infusion attenuated this increase.

Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiang, Tony K.L.; Teng Xiaowei; Surendradoss, Jayakumar

2011-05-01

The present study was conducted in sandwich-cultured rat hepatocytes to investigate the chemical basis of glutathione (GSH) depletion by valproic acid (VPA) and evaluate the role of GSH depletion in VPA toxicity. Among the synthetic metabolites of VPA investigated, 4-ene-VPA and (E)-2,4-diene-VPA decreased cellular levels of total GSH, but only (E)-2,4-diene-VPA was more effective and more potent than the parent drug. The in situ generated, cytochrome P450-dependent 4-ene-VPA did not contribute to GSH depletion by VPA, as suggested by the experiment with a cytochrome P450 inhibitor, 1-aminobenzotriazole, to decrease the formation of this metabolite. In support of a role formore » metabolites, alpha-F-VPA and octanoic acid, which do not undergo biotransformation to form a 2,4-diene metabolite, CoA ester, or glucuronide, did not deplete GSH. A time course experiment showed that GSH depletion did not occur prior to the increase in 2',7'-dichlorofluorescein (a marker of oxidative stress), the decrease in [2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] (WST-1) product formation (a marker of cell viability), or the increase in lactate dehydrogenase (LDH) release (a marker of necrosis) in VPA-treated hepatocytes. In conclusion, the cytochrome P450-mediated 4-ene-VPA pathway does not play a role in the in situ depletion of GSH by VPA, and GSH depletion is not an initiating event in VPA toxicity in sandwich-cultured rat hepatocytes.« less

N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells.

PubMed

Prestegui-Martel, Berenice; Bermúdez-Lugo, Jorge Antonio; Chávez-Blanco, Alma; Dueñas-González, Alfonso; García-Sánchez, José Rubén; Pérez-González, Oscar Alberto; Padilla-Martínez, Itzia Irene; Fragoso-Vázquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Correa-Basurto, Ana María; Méndez-Luna, David; Trujillo-Ferrara, José; Correa-Basurto, José

2016-01-01

Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC 50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

Morphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies.

PubMed

Tashiro, Yasura; Oyabu, Akiko; Imura, Yoshio; Uchida, Atsuko; Narita, Naoko; Narita, Masaaki

2011-06-01

Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

PubMed Central

Banerjee, Anwesha; Engineer, Crystal T.; Sauls, Bethany L.; Morales, Anna A.; Kilgard, Michael P.; Ploski, Jonathan E.

2014-01-01

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning. PMID:25429264

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally.

PubMed

Barrett, Catherine E; Hennessey, Thomas M; Gordon, Katelyn M; Ryan, Steve J; McNair, Morgan L; Ressler, Kerry J; Rainnie, Donald G

2017-01-01

The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.

Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme

PubMed Central

Kerkhof, Melissa; Dielemans, Janneke C. M.; van Breemen, Melanie S.; Zwinkels, Hanneke; Walchenbach, Robert; Taphoorn, Martin J.; Vecht, Charles J.

2013-01-01

Background To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation. Methods A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months. Results Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7–67.3) compared with 61 weeks (95% CI: 52.5–69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43–0.92; P = .016), adjusting for age, extent of resection, and O6-DNA methylguanine-methyltransferase promoter methylation status. Conclusions Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months’ longer survival of patients with GBM. PMID:23680820

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development.

PubMed

Podgorac, Jelena; Pešić, Vesna; Pavković, Željko; Martać, Ljiljana; Kanazir, Selma; Filipović, Ljupka; Sekulić, Slobodan

2016-09-15

Clinical research has identified developmental delay and physical malformations in children prenatally exposed to the antiepileptic drug (AED) valproic acid (VPA). However, the early signs of neurodevelopmental deficits, their evolution during postnatal development and growth, and the dose effects of VPA are not well understood. The present study aimed to examine the influence of maternal exposure to a wide dose range (50, 100, 200 and 400mg/kg/day) of VPA during breeding and gestation on early physical and neuromotor development in mice offspring. Body weight gain, eye opening, the surface righting reflex (SRR) and tail suspension test (TST) were examined in the offspring at postnatal days 5, 10 and 15. We observed that: (1) all tested doses of VPA reduced the body weight of the offspring and the timing of eye opening; (2) offspring exposed to VPA displayed immature forms of righting and required more time to complete the SRR; (3) latency for the first immobilization in the TST is shorter in offspring exposed to higher doses of VPA; however, mice in all groups exposed to VPA exhibited atypical changes in this parameter during the examined period of maturation; (4) irregularities in swinging and curling activities were observed in animals exposed to higher doses of VPA. This study points to delayed somatic development and postponed maturation of the motor system in all of the offspring prenatally exposed to VPA, with stronger effects observed at higher doses. The results implicate that the strategy of continuous monitoring of general health and achievements in motor milestones during the early postnatal development in prenatally VPA-exposed offspring, irrespectively of the dose applied, could help to recognize early developmental irregularities. Copyright © 2016 Elsevier B.V. All rights reserved.

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism.

PubMed

Hara, Yuta; Ago, Yukio; Higuchi, Momoko; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2017-11-01

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model. Copyright © 2017 Elsevier Inc. All rights reserved.

Outsmarting Poison Ivy and Other Poisonous Plants

MedlinePlus

... Consumer Updates Outsmarting Poison Ivy and Other Poisonous Plants Share Tweet Linkedin Pin it More sharing options ... whitish-green fruits hang in loose clusters. Poison Plant Rashes Aren’t Contagious Poison ivy and other ...

L-Arginine in the treatment of valproate overdose - five clinical cases.

PubMed

Schrettl, Verena; Felgenhauer, Norbert; Rabe, Christian; Fernando, Malkanthi; Eyer, Florian

2017-04-01

Valproic acid and its metabolites - particularly valproyl-CoA - are inhibitors of the enzyme N-acetylglutamate synthetase. The amino acid l-arginine can stimulate N-acetylglutamate synthetase activity and could be potentially used therapeutically to correct hyperammonemia caused by valproate therapy or overdose. Severely valproic-acid-poisoned patients are usually treated with l-carnitine or hemodialysis in order to decrease hyperammonemia. We herein report of five cases, in which l-arginine was administered. Observational study on five cases. Patients with hyperammonemia (i.e., ammonia 80 > μg/dL) and symptoms consistent with valproate overdose (i.e., drowsiness, coma) were selected for treatment with l-arginine. Data was collected retrospectively. l-Arginine decreased ammonia levels in a close temporal relation (case I ammonia in EDTA-plasma [μg/dL] decreased from 381 to 39; case II from 281 to 50; case III from 669 to 74; case IV from 447 to 56; case V from 202 to 60). In cases I and II, hemodialysis was performed and l-carnitine was given before the administration of l-arginine. In case III, hemodialysis was performed after the administration of l-arginine was already started. In cases IV and V, treatment with l-arginine was the sole measure to decrease ammonia levels in plasma. The results suggest that l-arginine may be beneficial in selected cases of valproate overdose complicated by hyperammonemia. l-Arginine could extend our conventional treatment options for valproic acid overdose.

Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons.

PubMed

Zdraljevic, Stefan; Strand, Christine; Seidel, Hannah S; Cook, Daniel E; Doench, John G; Andersen, Erik C

2017-07-01

Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.

Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis.

PubMed

Zimmermann, Fernanda Francine; Gaspary, Karina Vidarte; Leite, Carlos Eduardo; De Paula Cognato, Giana; Bonan, Carla Denise

2015-01-01

Changes in social behavior are associated with brain disorders, including mood disorders, stress, schizophrenia, Alzheimer's disease, and autism spectrum disorders (ASD). Autism is a complex neurodevelopmental disorder characterized by deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Zebrafish is one of the most social vertebrates used as a model in biomedical research, contributing to an understanding of the mechanisms that underlie social behavior. Valproic acid (VPA) is used as an anti-epileptic drug and mood stabilizer; however, prenatal VPA exposure in humans has been associated with an increased incidence of autism and it can also affect fetal brain development. Therefore, we conducted a behavioral screening at different periods of zebrafish development at 6, 30, 70, and 120dpf (days postfertilization) after VPA exposure in the early development stage to investigate social behavior, locomotion, aggression, and anxiety. VPA (48μM) exposure during the first 48hpf (hours postfertilization) did not promote changes on survival, morphology, and hatching rate at 24hpf, 48hpf, and 72hpf. The behavioral patterns suggest that VPA exposure induces changes in locomotor activity and anxiety at different developmental periods in zebrafish. Furthermore, a social interaction deficit is present at 70dpf and 120dpf. VPA exposure did not affect aggression in the adult stage at 70dpf and 120dpf. This is the first study that demonstrated zebrafish exposed to VPA during the first 48h of development exhibit deficits in social interaction, anxiety, and hyperactivity at different developmental periods. Copyright © 2015 Elsevier Inc. All rights reserved.

Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice.

PubMed

Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Hasebe, Shigeru; Kawase, Haruki; Tanabe, Wataru; Tsukada, Shinji; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2017-11-01

Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.

Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice.

PubMed

Kolozsi, E; Mackenzie, R N; Roullet, F I; deCatanzaro, D; Foster, J A

2009-11-10

In rodents, a single administration of valproic acid (VPA) in utero leads to developmental delays and lifelong deficits in motor performance, social behavior, and anxiety-like behavior in the offspring. Recently, we have demonstrated that VPA mice show alterations in postnatal growth and development, and deficits in olfactory discrimination and social behavior early in development. Based on behavioral and molecular parallels between VPA rodents and individuals with autism, maternal challenge with VPA has been suggested to be a good animal model of autism. Neuroligins (NLGN) are a family of postsynaptic cell-adhesion molecules that play a role in synaptic maturation through association with their presynaptic partners, the neurexins (NRXN). Both NLGNs and NRXN members have been implicated in genetic studies of autism. In the present study, we examined changes at the level of expression of NLGN and NRXN mRNAs in the adult brain from mice exposed in utero to VPA. Mouse brain tissue was processed using in situ hybridization and analyzed with densitometry to examine expression of three NLGN genes (NLGN1, NLGN2, and NLGN3) and three NRXN genes (NRXN1, NRXN2, and NRXN3). Expression levels of NLGN1, NLGN2, NRXN1, NRXN2, and NRXN3 were observed to be similar in VPA and control mice. NLGN3 mRNA expression was found to be significantly lower in the VPA mice relative to control animals in hippocampal subregions, cornu ammonis (CA1) and dentate gyrus, and somatosensory cortex. This lowered expression may be linked to autistic-like behavioral phenotype observed in the VPA mice.

Influence of tube type, storage time, and temperature on the total and free concentration of valproic acid.

PubMed

Tarasidis, C G; Garnett, W R; Kline, B J; Pellock, J M

1986-01-01

The influence of storage conditions on the total and free concentration of valproic acid (VPA) was studied in six normal male subjects who ingested 750 mg of VPA (3 X 250 mg Depakene capsules; Abbott Laboratories). Blood samples were collected in various types of Vacutainer tubes (red top, no additives; green top, sodium heparin; blue top, sodium citrate; and purple top, EDTA) 2 h post administration of VPA. Either these samples were centrifuged immediately or stored for various periods of time at room temperature or refrigerated, or the supernate was frozen prior to analysis. Free VPA samples were obtained utilizing the Amicon ultrafiltration system. All VPA samples were analyzed by gas-liquid chromatography. Total VPA concentrations obtained from plasma collected with sodium citrate were lower (p less than 0.05) than either serum or plasma collected with other anticoagulants. There were no differences (p greater than 0.05) in total or free VPA concentrations between samples collected in serum or in plasma collected with heparin or EDTA. Storing samples for 96 h at room temperature did not alter the total VPA concentrations but was found to increase the free fraction of VPA (p less than 0.05). The refrigeration or freezing of the supernate from the blood samples for 7 days did not alter (p greater than 0.05) the total or the free fraction of VPA. The results of this study demonstrate that total and/or free VPA may be collected from either serum or plasma, provided sodium citrate is not used to collect plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Valproic acid (VPA) inhibits the epithelial-mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4.

PubMed

Lan, Xiaopeng; Lu, Guoliang; Yuan, Chuanwei; Mao, Shaowei; Jiang, Wei; Chen, Yougen; Jin, Xunbo; Xia, Qinghua

2016-01-01

The epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. Previous studies have reported that valproic acid (VPA) suppresses prostate carcinoma (PCa) cell metastasis and down-regulates SMAD4 protein levels, which is the key molecule in TGF-β-induced EMT. However, the correlation between VPA and the EMT in PCa remains uncertain. Markers of the EMT in PCa cells and xenografts were molecularly assessed after VPA treatment. The expression and mono-ubiquitination of SMAD4 were also analyzed. After transfection with plasmids that express SMAD4 or short hairpin RNA for SMAD4 down-regulation, markers of EMT were examined to confirm whether VPA inhibits the EMT of PCa cells through the suppression of SMAD4. VPA induced the increase in E-cadherin (p < 0.05), and the decrease in N-cadherin (p < 0.05) and Vimentin (p < 0.05), in PCa cells and xenografts. SMAD4 mRNA and protein levels were repressed by VPA (p < 0.05), whereas the level of mono-ubiquitinated SMAD4 was increased (p < 0.05). SMAD4 knockdown significantly increased E-cadherin expression in PC3 cells, but SMAD4 over-expression abolished the VPA-mediated EMT-inhibitory effect. VPA inhibits the EMT in PCa cells via the inhibition of SMAD4 expression and the mono-ubiquitination of SMAD4. VPA could serve as a promising agent in PCa treatment, with new strategies based on its diverse effects on posttranscriptional regulation.

Cadmium poisoning of oxygen reduction on platinum electrode in potassium hydroxide

NASA Technical Reports Server (NTRS)

Miller, R. O.

1972-01-01

Experiment with a rotating disk and ring apparatus showed no poisoning by cadmium in 8.5 M KOH, alone or with Cl(-) or CO3(=). Poisoning does not occur either in 0.1 M KOH supernatant at CdO, but a partially reversible poisoning results from .0001 M CdCl2 and traces of fatty acid are present. Evidence indicates that the catastrophic poisoning affects the four-electron O2 reduction more than it does the one-electron H3O(+) discharge.

Lead poisoning in captive wild animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zook, B.C.; Sauer, R.M.; Garner, F.M.

1972-07-01

Lead poisoning was diagnosed post-mortem in 34 simian primates, 11 parrots, and 3 Australian fruit bats at the National Zoological Park. Diagnoses were made by the finding of acid-fast intranuclear inclusion bodies in renal epithelia or hepatocytes and, in most cases, by finding excess lead in samples of liver. The estimated prevalence of lead intoxication among autopsied primates and parrots was 44% and 50% respectively. Leaded paint was found in many animal enclosures at this zoo and it was available to all the lead-poisoned animals in this study. The finding of renal intranuclear inclusion bodies in animals at several zoos,more » scattered reports of lead intoxication of animals dwelling in various zoos, the occurrence of leaded paint in many zoos and the high incidence of lead poisoning at this zoo, indicated that lead poisoning of zoo animals is much more common than was previously thought.« less

Acute hydrofluoric acid exposure reported to Taiwan Poison Control Center, 1991-2010.

PubMed

Wu, M-L; Yang, C-C; Ger, J; Tsai, W-J; Deng, J-F

2014-05-01

Hydrofluoric acid (HF) is a dangerous chemical that can cause severe cutaneous burns as well as possible systemic toxicity. We retrospectively analyzed all human HF exposure cases reported to the National Poison Control Center of Taiwan between 1991 and 2010. In this 20-year survey, 324 calls were identified, with a majority of dermal exposure (84%). Occupational exposure accounted for 80% of all cases, with workers in semiconductor industry (61%), cleaning industry (15%), chemical or metal industry (13%), and other industries (11%). Electrolyte imbalances were uncommon, hypocalcemia, hypomagnesemia, and hypokalemia were recorded in 8.6%, 1.2%, and 1.5% of all cases, respectively. Most cases (64%) of dermal exposure received antidotal treatment. Treatment modalities of dermal exposure included calcium gluconate soaking, 49.8%; intravenous calcium, 20.6%; and topical use of calcium gluconate gel, 13.9%. Twenty patients (7%) received surgery. Following HF exposure, the majority of patients presented with mild (56.5%) or moderate (36.7%) toxic effects. However, four patients were severely intoxicated; two patients died of HF-related dysrhythmia and shock. Significant symptomology may occur following HF exposure, and most of the HF exposure required hospitals evaluation. Calcium gluconate soaks appear to be effective in reducing local pain and tissue damage. Hyperkalemia should not be overemphasized as a common finding in HF exposure, hypokalemia tends to occur in cases of severe HF poisoning.

Encapsulation of valproic acid and sodic phenytoin in ordered mesoporous SiO 2 solids for the treatment of temporal lobe epilepsy

NASA Astrophysics Data System (ADS)

López, T.; Basaldella, E. I.; Ojeda, M. L.; Manjarrez, J.; Alexander-Katz, R.

2006-10-01

Temporal lobe epilepsy is one of the most frequent types of human neurological diseases, and a variety of surgical procedures have been developed for the treatment of intractable cases. An alternative is the use of drug-containing reservoirs based on nanostructured materials of controlled pore sizes in order to deliver the drug without causing secondary effects. Ordered SiO 2 nanostructures were developed as drug reservoirs. The latter were prepared by the sol-gel process using tetraethyl orthosilicate TEOS as precursor to form the "sol" and P123 surfactant as the organic structure-directing agent. In addition to the nontoxic nature of amorphous silica, uniform and tunable pore sizes between 2.5 and 30 nm can be obtained in this way. The aim of this study is to investigate the potential of these materials for the storage and release of drugs in the brain. For that, we loaded valproic acid (VH) and sodic phenytoin (PH) molecules into an ordered mesoporous SiO 2 by impregnation and characterized the drug impregnated SiO 2 by standard physical and spectroscopic techniques to identify the parameters necessary to improve the capacity and quality of the reservoirs. Finally, a study of neurohistopathology of the effects of these reservoirs on brain tissue is presented.

Identification of 19-epi-okadaic acid, a new diarrhetic shellfish poisoning toxin, by liquid chromatography with mass spectrometry detection.

PubMed

Paz, Beatriz; Daranas, Antonio H; Cruz, Patricia G; Franco, José M; Norte, Manuel; Fernández, José J

2008-01-01

Okadaic acid (1) (OA) and its congeners are mainly responsible for diarrhetic shellfish poisoning (DSP) syndrome. The presence of several OA derivatives have already been confirmed in Prorocentrum and Dinophysis spp. In this paper, we report on the detection and identification of a new DSP toxin, the OA isomer 19-epi-okadaic acid (2) (19-epi-OA), isolated from cultures of Prorocentrum belizeanum, by determining its retention time (RT) and fragmentation pattern using liquid chromatography coupled with mass spectrometry (LC-MS/MS).

Real-Time Quantitative Analysis of Valproic Acid in Exhaled Breath by Low Temperature Plasma Ionization Mass Spectrometry

NASA Astrophysics Data System (ADS)

Gong, Xiaoxia; Shi, Songyue; Gamez, Gerardo

2017-04-01

Real-time analysis of exhaled human breath is a rapidly growing field in analytical science and has great potential for rapid and noninvasive clinical diagnosis and drug monitoring. In the present study, an LTP-MS method was developed for real-time, in-vivo and quantitative analysis of γ-valprolactone, a metabolite of valproic acid (VPA), in exhaled breath without any sample pretreatment. In particular, the effect of working conditions and geometry of the LTP source on the ions of interest, protonated molecular ion at m/z 143 and ammonium adduct ion at m/z 160, were systematically characterized. Tandem mass spectrometry (MS/MS) with collision-induced dissociation (CID) was carried out in order to identify γ-valprolactone molecular ions ( m/z 143), and the key fragment ion ( m/z 97) was used for quantitation. In addition, the fragmentation of ammonium adduct ions to protonated molecular ions was performed in-source to improve the signal-to-noise ratio. At optimum conditions, signal reproducibility with an RSD of 8% was achieved. The concentration of γ-valprolactone in exhaled breath was determined for the first time to be 4.83 (±0.32) ng/L by using standard addition method. Also, a calibration curve was obtained with a linear range from 0.7 to 22.5 ng/L, and the limit of detection was 0.18 ng/L for γ-valprolactone in standard gas samples. Our results show that LTP-MS is a powerful analytical platform with high sensitivity for quantitative analysis of volatile organic compounds in human breath, and can have potential applications in pharmacokinetics or for patient monitoring and treatment.

Neurofibromatosis 2 tumor suppressor, the gene induced by valproic acid, mediates neurite outgrowth through interaction with paxillin.

PubMed

Yamauchi, Junji; Miyamoto, Yuki; Kusakawa, Shinji; Torii, Tomohiro; Mizutani, Reiko; Sanbe, Atsushi; Nakajima, Hideki; Kiyokawa, Nobutaka; Tanoue, Akito

2008-07-01

Valproic acid (VPA), the drug for bipolar disorder and epilepsy, has a potent ability to induce neuronal differentiation, yet comparatively little is presently known about the underlying mechanism. We previously demonstrated that c-Jun N-terminal kinase (JNK) phosphorylation of the focal adhesion protein paxillin mediates differentiation in N1E-115 neuroblastoma cells. Here, we show that VPA up-regulates the neurofibromatosis type 2 (NF2) tumor suppressor, merlin, to regulate neurite outgrowth through the interaction with paxillin. The inhibition of merlin function by its knockdown or expression of merlin harboring the Gln-538-to-Pro mutation, a naturally occurring NF2 missense mutation deficient in linking merlin to the actin cytoskeleton, decreases VPA-induced neurite outgrowth. Importantly, the expression of merlin by itself is not sufficient to induce neurite outgrowth, which requires co-expression with paxillin, the binding partner of merlin. In fact, the missense mutation Trp-60-to-Cys or Phe-62-to-Ser, that is deficient in binding to paxillin, reduces neurite outgrowth induced by VPA. In addition, co-expression of a paxillin construct harboring the mutation at the JNK phosphorylation site with merlin results in blunted induction of the outgrowth. We also find that the first LIM domain of paxillin is a major binding region with merlin and that expression of the isolated first LIM domain blocks the effects of VPA. Furthermore, similar findings that merlin regulates neurite outgrowth through the interaction with paxillin have been observed in several kinds of neuronal cells. These results suggest that merlin is an as yet unknown regulator of neurite outgrowth through the interaction with paxillin, providing a possibly common mechanism regulating neurite formation.

Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat.

PubMed

Khan, Sabbir; Kumar, Sandeep; Jena, Gopabandhu

2016-06-01

Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia.

PubMed

Sun, Rulin; Zhang, Santao; Hu, Wenjun; Lu, Xing; Lou, Ning; Yang, Zhende; Chen, Shaoyong; Zhang, Xiaoping; Yang, Hongmei

2016-07-01

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. Copyright © 2016 the American Physiological Society.

Germination Conditions For Poison Ivy

Treesearch

Nathan M. Schiff; Kristina F. Connor; Margaret S. Devall

2004-01-01

Several scarification and stratification treatments were tested to optimize germination conditions for poison ivy [Toxicodendron radicans (L.) Kunst]. Fall-collected seeds soaked for 1 hour in water showed increasing germination with increasing stratification. Scarification with concentrated sulphuric acid for 30 minutes resulted in approximately 65...

Identification of 19-epi-okadaic Acid, a New Diarrhetic Shellfish Poisoning Toxin, by Liquid Chromatography with Mass Spectrometry Detection

PubMed Central

Paz, Beatriz; Daranas, Antonio H.; Cruz, Patricia G.; Franco, José M.; Norte, Manuel; Fernández, José J.

2008-01-01

Okadaic acid (1) (OA) and its congeners are mainly responsible for diarrhetic shellfish poisoning (DSP) syndrome. The presence of several OA derivatives have already been confirmed in Prorocentrum and Dinophysis spp. In this paper, we report on the detection and identification of a new DSP toxin, the OA isomer 19-epi-okadaic acid (2) (19-epi-OA), isolated from cultures of Prorocentrum belizeanum, by determining its retention time (RT) and fragmentation pattern using liquid chromatography coupled with mass spectrometry (LC–MS/MS). PMID:19005581

The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid.

PubMed

Castro, Kamila; Baronio, Diego; Perry, Ingrid Schweigert; Riesgo, Rudimar Dos Santos; Gottfried, Carmem

2017-07-01

Autism spectrum disorder (ASD) is characterized by impairments in social interaction and communication, and by restricted repetitive behaviors and interests. Its etiology is still unknown, but different environmental factors during pregnancy, such as exposure to valproic acid (VPA), are associated with high incidence of ASD in children. In this context, prenatal exposure to VPA in rodents has been used as a reliable model of ASD. Ketogenic diet (KD) is an alternative therapeutic option for refractory epilepsy; however, the effects of this approach in ASD-like behavior need to be evaluated. We conducted a behavioral assessment of the effects of KD in the VPA model of autism. Pregnant animals received a single-intraperitoneal injection of 600 mg/kg VPA, and their offspring were separated into four groups: (1) control group with standard diet (C-SD), (2) control group with ketogenic diet (C-KD), (3) VPA group with standard diet (VPA-SD), and (4) VPA group with ketogenic diet (VPA-KD). When compared with the control group, VPA animals presented increased social impairment, repetitive behavior and higher nociceptive threshold. Interestingly, the VPA group fed with KD presented improvements in social behavior. These mice displayed higher scores in sociability index and social novelty index when compared with the SD-fed VPA mice. VPA mice chronically exposed to a KD presented behavioral improvements; however, the mechanism by which KD improves ASD-like features needs to be further investigated. In conclusion, the present study reinforces the potential use of KD as a treatment for the core deficits of ASD.

A rapid and highly sensitive UPLC-MS/MS method using pre-column derivatization with 2-picolylamine for intravenous and percutaneous pharmacokinetics of valproic acid in rats.

PubMed

Joo, Kyung-Mi; Choi, Dalwoong; Park, Yang-Hui; Yi, Chang-Geun; Jeong, Hye-Jin; Cho, Jun-Cheol; Lim, Kyung-Min

2013-11-01

A rapid, highly sensitive and specific ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for the detection of valproic acid (VPA) in rat plasma following the topical application was developed and validated. This method was carried out with pre-column derivatization using 2-picolylamine (PA) which reacts with the carboxylic acid group of VPA. The derivatization was completed in 10min and the resulting PA-VPA derivative enabled the sensitive detection of VPA in selected reaction monitoring (SRM) mode. Sample preparation was done with simple liquid-liquid extraction and chromatographic separation was achieved within 5min on a C18 column using a gradient elution with the mobile phase of 2mM ammonium formate containing 0.1% formic acid and methanol. The standard curves were linear over the concentration range of 0.07-200μg/mL with a correlation coefficient higher than 0.99. The limit of detection (LOD) and the lower limit of quantification (LLOQ) was 0.03 and 0.07μg/mL, respectively with 100μL of plasma sample. The intra- and inter-day precisions were measured to be below 10.7% and accuracies were within the range of 94.1-115.9%. The validated method was successfully applied to the pharmacokinetics of VPA in the rat following topical and intravenous applications. Copyright © 2013 Elsevier B.V. All rights reserved.

A new model of the mechanism underlying lead poisoning: SNPs in miRNA target region influence the δ-aminolevulinic acid dehydratase expression level.

PubMed

Li, Chunping; Wang, Miaomiao; Wang, Yiqing; Zhang, Jinlong; Sun, Na

2017-11-01

To determine if SNPs located within the 3'-UTR of δ-aminolevulinic acid dehydratase (ALAD) can alter the risk of lead poisoning and the ALAD gene expression. A case-control study was carried out to find the SNPs in miRNA target region. Luciferase reporter gene assay, qRT-PCR and Western blot was used to determine the relationship between miRNA and SNPs. We found a significant association between rs818708 and the risk of lead poisoning. miR-545-5p was influenced by rs818708 variant and might result in a significant change in ALAD expression. rs818708 T > C can weaken the binding capability between miR-545-5p and 3'-UTR of ALAD and thus may alter the risk of lead poisoning.

The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine.

PubMed

Serin, Hepsen Mine; Koç, Zehra Pınar; Temelli, Berfin; Esen, İhsan

2015-10-01

The negative effect of antiepileptic drugs on bone health has been previously documented. However, which antiepileptic drug is safer in regard to bone health is still questionable. Our aims were to investigate the bone mineral density alterations in pediatric patients who receive antiepileptic medication for a minimum of two years and to compare the results of these drugs. Fifty-nine patients (32 males, 27 females; mean age: 8.6±4.6years) and a control group (13 males, 7 females; mean age: 7.6±3.3years) were included in the study. The patients were receiving necessarily the same antiepileptic drugs (AEDs) for at least two years, and none of the patients had mental retardation or cerebral palsy. The patients were divided into three groups: group 1 (patients receiving levetiracetam (LEV), n=20), group 2 (patients receiving carbamazepine (CBZ), n=11), and group 3 (patients receiving valproic acid (VPA), n=28). Plasma calcium (Ca), phosphorus (P), parathyroid hormone (PTH), alkaline phosphatase (ALP), vitamin D levels, and bone mineral density (BMD) values of femur and vertebras (L1-4) and z-scores (comparative results of BMD values of the patients with the age- and gender-matched controls in device database) of the groups were compared. The differences between P, PTH, ALP and age, Ca and BMD results, and vitamin D levels of the patients in all four groups was not statistically significant according to Kruskal-Wallis test (p>0.05). The z-score levels of all the patient and control groups were also not statistically significantly different compared with each other. In contrast to previous reports in pediatric patients, our study has documented that there is not a considerable bone loss in patients receiving long-term AED medication. Although levetiracetam has been proposed as bone-protecting medication, we did not observe any difference between AEDs regarding bone mineral density after two years of treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Fluoxetine prevents the memory deficits and reduction in hippocampal cell proliferation caused by valproic acid.

PubMed

Welbat, Jariya Umka; Sangrich, Preeyanuch; Sirichoat, Apiwat; Chaisawang, Pornthip; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanun; Wigmore, Peter

2016-12-01

Valproic acid (VPA), a commonly used antiepileptic drug, has been reported to cause cognitive impairments in patients. In a previous study, using a rodent model, we showed that VPA treatment impaired cognition which was associated with a reduction in the cell proliferation required for hippocampal neurogenesis. The antidepressant fluoxetine has been shown to increase hippocampal neurogenesis and to reverse the memory deficits found in a number of pathological conditions. In the present study we investigated the protective effects of fluoxetine treatment against the impairments in memory and hippocampal cell proliferation produced by VPA. Male Sprague Dawley rats received daily treatment with fluoxetine (10mg/kg) by oral gavage for 21days. Some rats were co-administered with VPA (300mg/kg, twice daily i.p. injections) for 14days from day 8 to day 21 of the fluoxetine treatment. Spatial memory was tested using the novel object location (NOL) test. The number of proliferating cells present in the sub granular zone of the dentate gyrus was quantified using Ki67 immunohistochemistry at the end of the experiment. Levels of the receptor Notch1, the neurotrophic factor BDNF and the neural differentiation marker DCX were determined by Western blotting. VPA-treated rats showed memory deficits, a decrease in the number of proliferating cells in the sub granular zone and decreases in the levels of Notch1 and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notch1 and BDNF were prevented in animals which had received both VPA and fluoxetine. Rats receiving fluoxetine alone did not show a significant difference in the number of proliferating cells or behavior compared to controls. These results demonstrated that the spatial memory deficits and reduction of cell proliferation produced by VPA can be ameliorated by the simultaneous administration of the antidepressant fluoxetine. Crown Copyright © 2016. Published by Elsevier B

Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid.

PubMed

Kim, Pitna; Park, Jin Hee; Kwon, Kyoung Ja; Kim, Ki Chan; Kim, Hee Jin; Lee, Jong Min; Kim, Hahn Young; Han, Seol-Heui; Shin, Chan Young

2013-01-01

Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Photographic fixative poisoning

MedlinePlus

Photographic developer poisoning; Hydroquinone poisoning; Quinone poisoning; Sulfite poisoning ... Poisonous ingredients include: Hydroquinones Quinones Sodium ... fixative can also break down (decompose) to form sulfur dioxide ...

Scombroid poisoning.

PubMed

McInerney, J; Sahgal, P; Vogel, M; Rahn, E; Jonas, E

1996-08-01

Scombroid poisoning is described in the literature as a toxic poisoning caused by ingestion of certain dark meat fish undergoing bacterial decomposition. Poisoning results from the ingestion of a heat-stable toxin. We describe the case of a man who presented to the emergency department several hours after eating tuna steak with evidence of scombroid poisoning that was associated with loss of vision and atrial tachycardia with block. All signs and symptoms resolved after treatment for scombroid poisoning.

A review of pitfalls and progress in chelation treatment of metal poisonings.

PubMed

Andersen, Ole; Aaseth, Jan

2016-12-01

Most acute and chronic human metal poisonings are due to oral or inhalation exposure. Almost 80% of published animal experiments on chelation in metal poisoning used single or repeated intraperitoneal, intramuscular or intravenous administration of metal and chelator, impeding extrapolation to clinical settings. Intramuscular administration of dimercaptopropanol (BAL) has until now been used in acute arsenic, lead, and mercury poisonings, but repeated BAL administration increased the brain uptake of As, Pb and Hg in experimental animals. Also, diethyl dithiocarbamate (DDC) has been used as antidote in acute experimental animal parenteral Cd poisoning, and both DDC and tetraethylthiuram disulfide (TTD, disulfiram, Antabuse) have been used in nickel allergic patients. However, even one dose of DDC given immediately after oral Cd or Ni increased their brain uptake considerably. The calcium salt of ethylenediamminetetraacetic acid (CaEDTA) but not dimercaptosuccinic acid (DMSA) increased the brain uptake of Pb. In oral Cd or Hg poisoning, early oral administration of DMSA or dimercaptopropane sulfonate (DMPS) increased survival and reduced intestinal metal uptake. Oral administration of Prussian Blue or resins with fixed chelating groups that are not absorbed offer chelation approaches for decorporation after oral exposure to various metals. Diethylenetriaminepentaacetic acid (DTPA) nebulizers for pulmonary chelation after inhalation exposure need further development. Also, combined chelation with more than one compound may offer extensive advances. Solid knowledge on the chemistry of metal chelates together with relevant animal experiments should guide development of chelation procedures to alleviate and not aggravate the clinical status of poisoned patients. Copyright © 2016 Elsevier GmbH. All rights reserved.

Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study

PubMed Central

Ignjatovic, Anita Rakic; Miljkovic, Branislava; Todorovic, Dejan; Timotijevic, Ivana; Pokrajac, Milena

2009-01-01

AIM To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. METHODS Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. RESULTS CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l−1; 95% confidence interval (CI) −4.84863, −0.66194; P = 0.01] and Cmax by 28% (from 1.911 to 1.383 mg l−1; 95% CI −0.98197, −0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h−1 kg−1; 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l−1; 95% CI −0.77479, −0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good. CONCLUSIONS VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB–CBZ PK interaction needs to be further evaluated in a more comprehensive study. PMID:19076986

House of Poison: Poisons in the Home.

ERIC Educational Resources Information Center

Keller, Rosanne

One of a series of instructional materials produced by the Literacy Council of Alaska, this booklet provides information about common household poisons. Using a simplified vocabulary and shorter sentences, it provides statistics concerning accidental poisonings; a list of the places poisons are usually found in the home; steps to make the home…

Valproic acid treatment attenuates caspase-3 activation and improves survival after lethal burn injury in a rodent model.

PubMed

Luo, Hong-Min; Hu, Sen; Bai, Hui-Ying; Wang, Hai-Bin; Du, Ming-Hua; Lin, Zhi-Long; Ma, Li; Wang, Huan; Lv, Yi; Sheng, Zhi-Yong

2014-01-01

Burn injury may result in multiple organ dysfunction partially because of apoptotic cell death. The authors have previously shown that valproic acid (VPA) improves survival in a dog burn model. The aim of this study is to examine whether a VPA improves survival in a rodent burn model and whether this was because of inhibition of cell apoptosis. Rats were subjected to third-degree 55% TBSA burns and randomized to treatment with a VPA (300 mg/kg) or normal saline. One group of animals was monitored for 12 hours for survival analysis; another group was killed at 6 hours after injury, and brains, hearts, and blood samples were harvested for examination. Plasma creatine kinase (CK)-MB activities and neuron-specific enolase (NSE) levels were measured to evaluate the cardiac and brain damages. The effects of a VPA on acetylation of histone H3 and caspase-3 activation were also evaluated. Major burn injury resulted in a significant decrease in the acetylation of histone H3, and there was an increase in plasma CK-MB activities, NSE concentrations, and tissue levels of activated caspase-3. A VPA treatment significantly increased the acetylation of histone H3 and survival of the animals after major burn injury. In addition, a VPA treatment significantly attenuated the plasma CK-MB activities, an NSE concentrations, and inhibited caspase-3 activation after major burn injury. These results indicate that a VPA can attenuate cardiac and brain injury, and can improve survival in a rodent model of lethal burn injury. These protective effects may be mediated in part through the inhibition of caspase-3 activation.

S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice.

PubMed

Ornoy, Asher; Weinstein-Fudim, Liza; Tfilin, Matanel; Ergaz, Zivanit; Yanai, Joseph; Szyf, Moshe; Turgeman, Gadi

2018-01-16

A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary. Copyright © 2018. Published by Elsevier Inc.

[The prevalence of obesity and metabolic syndrome in paediatric patients with epilepsy treated in monotherapy with valproic acid].

PubMed

Carmona-Vazquez, C R; Ruiz-Garcia, M; Pena-Landin, D M; Diaz-Garcia, L; Greenawalt, S R

2015-09-01

Valproic acid (VPA) is a useful antiepileptic drug for controlling different types of epilepsy. It has several side effects and is associated to increased body weight, as well as metabolic and endocrine disorders, including metabolic syndrome. To determine the prevalence of obesity and metabolic syndrome among paediatric patients with epilepsy treated in monotherapy with VPA. The study was cross-sectional, observational and analytical. A sample of patients treated with VPA between 2010-2014 were studied and the body mass index (BMI), abdominal perimeter, arterial blood pressure, glucose, triglycerides and high density lipoproteins (HDL) were studied in search of obesity and metabolic syndrome. Obesity was defined as a BMI above the 95th percentile, and metabolic syndrome was considered if at least three of the following criteria were fulfilled: abdominal perimeter above the 90th percentile, systolic arterial pressure above the 90th percentile, triglycerides above 110 mg/dL and HDL below 40 mg/dL. A total of 47 patients with a mean age of 10.1 ± 4 years were studied; 51.06% were males. Eight (17%) of them developed obesity and, of those, two (25%) had metabolic syndrome. Three patients went on to become overweight (6%). Statistically significant differences were observed in the mean age in comparison to the BMI groups, where the obese patients were adolescents (ANOVA, p = 0.0001) and those who took more VPA per day were the obese (ANOVA, p = 0.024). Patients treated with VPA who become obese may go on to develop metabolic syndrome. They require careful monitoring and, if they are seen to put on weight, withdrawal of the drug should be considered.

Determination of valproic acid in human plasma using dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection

PubMed Central

Fazeli-Bakhtiyari, Rana; Panahi-Azar, Vahid; Sorouraddin, Mohammad Hossein; Jouyban, Abolghasem

2015-01-01

Objective(s): Dispersive liquid-liquid microextraction coupled with gas chromatography (GC)-flame ionization detector was developed for the determination of valproic acid (VPA) in human plasma. Materials and Methods: Using a syringe, a mixture of suitable extraction solvent (40 µl chloroform) and disperser (1 ml acetone) was quickly added to 10 ml of diluted plasma sample containing VPA (pH, 1.0; concentration of NaCl, 4% (w/v)), resulting in a cloudy solution. After centrifugation (6000 rpm for 6 min), an aliquot (1 µl) of the sedimented organic phase was removed using a 1-µl GC microsyringe and injected into the GC system for analysis. One variable at a time optimization method was used to study various parameters affecting the extraction efficiency of target analyte. Then, the developed method was fully validated for its accuracy, precision, recovery, stability, and robustness. Results: Under the optimum extraction conditions, good linearity range was obtained for the calibration graph, with correlation coefficient higher than 0.998. Limit of detection and lower limit of quantitation were 3.2 and 6 μg/ml, respectively. The relative standard deviations of intra and inter-day analysis of examined compound were less than 11.5%. The relative recoveries were found in the range of 97 to 107.5%. Finally, the validated method was successfully applied to the analysis of VPA in patient sample. Conclusion: The presented method has acceptable levels of precision, accuracy and relative recovery and could be used for therapeutic drug monitoring of VPA in human plasma. PMID:26730332

Lead poisoning in six captive avian species

USGS Publications Warehouse

Beyer, W. Nelson; Spann, James W.; Sileo, Louis; Franson, J. Christian

1988-01-01

Red-winged blackbirds (Agelaius phoeniceus), brown-headed cowbirds (Molothrus ater), common grackles (Quiscalus quiscula), mallards (Anas platyrhynchos), northern bobwhites (Colinus virginianus), and eastern screech-owls (Otus asio) were poisoned with a concentration of lead (Pb) acetate in the diet which was increased by 60% each week until half of the birds in each treatment group died; surviving birds and all control birds except screech-owis were then killed by euthanasia. An additional group of mallards was poisoned with Pb shot. The gizzards of mallards poisoned either way usually were stained with bile; some of these birds also had proventricular impaction. Most poisoned birds of the other species were emaciated but lacked other gross lesions caused by Pb poisoning. In birds other than mallards, Pb poisoning could not be diagnosed without histological or hematological examinations or analysis of tissues. Poisoned birds of all six species could be reliably separated from control birds by an increase in the protoporphyrin concentrations in the blood and by a decrease in the activity of delta-aminolevulinic acid dehydratase (ALAD) in red blood cells. Hepatic iron (Fe) concentrations varied so much among individual birds that even though median hepatic Fe concentrations increased in poisoned birds, hepatic Fe concentrations were not useful in identifying poisoned birds. Renal intranuclear inclusion bodies occurred in 83% of all birds dying from Pb poisoning. Nephrosis, myocardial necrosis, and arterial fibrinoid necrosis were occasionally present. Median hepatic Pb concentrations varied from 20 ppm (wet wt) in male red-winged blackbirds to 111 ppm in female northern bobwhites. Median renal Pb concentrations varied from 22 ppm in redwinged blackbirds to 190 ppm in female northern bobwhites. Hepatic and renal Pb concentrations varied substantially among birds within each species. Median hepatic and renal Pb concentrations of birds that died were not statistically

Tetrahydrozoline poisoning

MedlinePlus

... help if this information is not immediately available. Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Kerosene poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Dieffenbachia poisoning

MedlinePlus

... were eaten, if known Time swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Detergent poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Pokeweed poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002874.htm Pokeweed poisoning To use the sharing features on this page, please enable JavaScript. Pokeweed is a flowering plant. Pokeweed poisoning occurs ...

Philodendron poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002872.htm Philodendron poisoning To use the sharing features on this page, please enable JavaScript. Philodendron is a flowering houseplant. Philodendron poisoning occurs ...

[Analysis of characteristics of acute poisoning caused by various poisons in Guangxi, China].

PubMed

Hu, De-hong; Zhang, Zhen-ming; Liu, Qing-hua; Jiang, Dong-fang

2013-11-01

To investigate the characteristics of acute poisonings caused by various poisons in Guangxi, China. A retrospective investigation was performed in 5859 cases of acute poisonings who were admitted to 63 hospitals in 11 cities, as well as 531 types of poisons involved. The poisons were categorized into 6 groups; each group of cases was stratified by the rural or urban settings, frequency of poisoning, and cause of poisoning to analyze the numbers of cases and constituent ratios. Most types of poisons (68.74%) belonged to drugs (217 types) and pesticides (148 types). Most cases of poisonings (61.63%) were caused by pesticides (n = 2547) and chemicals (n = 1064). Pesticides, poisons of plant origins, and poisons of animal origins were responsible for most of the cases in rural settings; 88.46%, 79.10%, and 66.74% of the cases of these poison categories happened in rural settings. Chemicals, drugs, and other poisons were responsible for most of the cases in urban settings; 70.20%, 61.74%, and 63.73% of the cases of these poison categories happened in urban settings. The numbers of cases in 5-year-poisoning groups were the highest in all categories of poisons, accounting for 85.24%, 88.57%, 55.16%, 70.79%, 68.36%, and 66.44%of cases of respective categories. Most cases of poisonings by chemicals, poisons of animal origin, and other poisons were accident-related (86.24%, 72.66%, and 46.71%of the poison categories). Most cases of poisonings by pesticides and drugs were suicide-related (59.39% and 33.52% of the poison categories). Most cases by poisons of plant origin were caused by accidental ingestion (70.36% of the poison category). Most of the acute poisonings in Guangxi area are caused by pesticides and chemicals; the most common causes of poisoning are accidents, accidental ingestion, and suicide. There are significant differences in the causes of acute poisonings between the urban and rural settings.

Experimental lead poisoning in bald eagles

USGS Publications Warehouse

Pattee, H.; Wiemeyer, S.; Hoffman, P.; Carpenter, J.; Sileo, L.

1979-01-01

Captive, crippled bald eagles unsuitable for release were fed lead shot to determine diagnostic criteria for lead poisoning. The eagles were fluoroscoped and bled periodically to determine shot retention and blood delta--aminolevulinic acid dehydratase activity. Microscopic examination revealed renal tubular degeneration, arterial fibrinoid necrosis and myocardial necrosis. Acid-fast intra-nuclear inclusion bodies were not found in proximal convoluted tubule cells. Analyses of blood and toxicological data are not yet complete.

The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations.

PubMed

Wu, Chien-Chih; Pai, Tsung-Yu; Hsiao, Fei-Yuan; Shen, Li-Jiuan; Wu, Fe-Lin Lin

2016-10-01

Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem. A 5-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded, and differences among various CBPMs were analyzed. Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were subtherapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (P < 0.001) in VPA serum concentrations during the use of CBPMs: 72% ± 17%, 42% ± 22%, and 67% ± 19% in the ertapenem (N = 9), imipenem/cilastatin (N = 17), and meropenem (N = 26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (P < 0.005). The onset of this drug interaction occurred within 24 hours of CBPMs' administration, and VPA serum concentrations returned to 90% of baseline within 7 days of CBPMs' discontinuation along with a 20% increase in VPA dose. Increasing VPA dose during the use of ertapenem or meropenem did not result in elevating VPA serum concentrations to therapeutic levels during the combined therapy period. CBPMs reduced VPA serum concentration within 24 hours of administration by approximately 60%. Ertapenem and meropenem had a greater effect on VPA serum concentration than imipenem/cilastatin. Because of the dramatic reduction of VPA serum

A "pennurth of arsenic for rat poison": the Arsenic Act, 1851 and the prevention of secret poisoning.

PubMed Central

Bartrip, P

1992-01-01

In this country any chemist or druggist can furnish the means of self-destruction or murder for a few pence, and in too many instances have done so with the utmost indifference. The sale of a poison is regarded as a mere act of commercial intercourse; tant pis for the unfortunate victim of error or passion; he has the benefit of a coroner's inquest; the vendor of the poison receives a reprimand, and things resume their natural course--that is, arsenic and oxalic acid are retailed without compunction, and men are hurried from time to time into eternity. Images p56-a PMID:1542234

Influence of uridine diphosphate glucuronosyltransferase 2B7 -161C>T polymorphism on the concentration of valproic acid in pediatric epilepsy patients.

PubMed

Inoue, Kazuyuki; Suzuki, Eri; Yazawa, Rei; Yamamoto, Yoshiaki; Takahashi, Toshiki; Takahashi, Yukitoshi; Imai, Katsumi; Koyama, Seiichi; Inoue, Yushi; Tsuji, Daiki; Hayashi, Hideki; Itoh, Kunihiko

2014-06-01

Valproic acid (VPA) is widely used to treat various types of epilepsy. Interindividual variability in VPA pharmacokinetics may arise from genetic polymorphisms of VPA-metabolizing enzymes. This study aimed to examine the relationships between plasma VPA concentrations and the -161C>T single nucleotide polymorphism in uridine diphosphate glucuronosyltransferase (UGT) 2B7 genes in pediatric epilepsy patients. This study included 78 pediatric epilepsy patients carrying the cytochrome P450 (CYP) 2C9*1/*1 genotype and who were not treated with the enzyme inducers (phenytoin, phenobarbital, and carbamazepine), lamotrigine, and/or topiramate. CYP2C9*3 and UGT2B7 -161C>T polymorphisms were identified using methods based on polymerase chain reaction-restriction fragment length polymorphism. Blood samples were drawn from each patient under steady-state conditions, and plasma VPA concentrations were measured. Significant differences in adjusted plasma VPA concentrations were observed between carriers of CC, CT, and TT genotypes in the UGT2B7 -161C>T polymorphism (P = 0.039). Patients with the CC genotype had lower adjusted plasma VPA concentrations than those with CT or TT genotype (P = 0.028). These data suggest that the UGT2B7 -161C>T polymorphism in pediatric epilepsy patients carrying the CYP2C9*1/*1 genotype affects VPA concentration.

Upward gaze-evoked nystagmus with organoarsenic poisoning.

PubMed

Nakamagoe, Kiyotaka; Ishii, Kazuhiro; Tamaoka, Akira; Shoji, Shin'ichi

2006-01-10

The authors report assessment of abnormal ocular movements in three patients after organoarsenic poisoning from diphenylarsinic acid. The characteristic and principal sign is upward gaze-evoked nystagmus. Moreover, vertical gaze holding impairment was shown by electronystagmography on direct current recording.

Fast targeted analysis of 132 acidic and neutral drugs and poisons in whole blood using LC-MS/MS.

PubMed

Di Rago, Matthew; Saar, Eva; Rodda, Luke N; Turfus, Sophie; Kotsos, Alex; Gerostamoulos, Dimitri; Drummer, Olaf H

2014-10-01

The aim of this study was to develop an LC-MS/MS based screening technique that covers a broad range of acidic and neutral drugs and poisons by combining a small sample volume and efficient extraction technique with simple automated data processing. After protein precipitation of 100μL of whole blood, 132 common acidic and neutral drugs and poisons including non-steroidal anti-inflammatory drugs, barbiturates, anticonvulsants, antidiabetics, muscle relaxants, diuretics and superwarfarin rodenticides (47 quantitated, 85 reported as detected) were separated using a Shimadzu Prominence HPLC system with a C18 separation column (Kinetex XB-C18, 4.6mm×150mm, 5μm), using gradient elution with a mobile phase of 25mM ammonium acetate buffer (pH 7.5)/acetonitrile. The drugs were detected using an ABSciex(®) API 2000 LC-MS/MS system (ESI+ and -, MRM mode, two transitions per analyte). The method was fully validated in accordance with international guidelines. Quantification data obtained using one-point calibration compared favorably to that using multiple calibrants. The presented LC-MS/MS assay has proven to be applicable for determination of the analytes in blood. The fast and reliable extraction method combined with automated processing gives the opportunity for high throughput and fast turnaround times for forensic and clinical toxicology. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Reversal of pentylenetetrazole-altered swimming and neural activity-regulated gene expression in zebrafish larvae by valproic acid and valerian extract.

PubMed

Torres-Hernández, Bianca A; Colón, Luis R; Rosa-Falero, Coral; Torrado, Aranza; Miscalichi, Nahira; Ortíz, José G; González-Sepúlveda, Lorena; Pérez-Ríos, Naydi; Suárez-Pérez, Erick; Bradsher, John N; Behra, Martine

2016-07-01

Ethnopharmacology has documented hundreds of psychoactive plants awaiting exploitation for drug discovery. A robust and inexpensive in vivo system allowing systematic screening would be critical to exploiting this knowledge. The objective of this study was to establish a cheap and accurate screening method which can be used for testing psychoactive efficacy of complex mixtures of unknown composition, like plant crude extracts. We used automated recording of zebrafish larval swimming behavior during light vs. dark periods which we reproducibly altered with an anxiogenic compound, pentylenetetrazole (PTZ). First, we reversed this PTZ-altered swimming by co-treatment with a well-defined synthetic anxiolytic drug, valproic acid (VPA). Next, we aimed at reversing it by adding crude root extracts of Valeriana officinalis (Val) from which VPA was originally derived. Finally, we assessed how expression of neural activity-regulated genes (c-fos, npas4a, and bdnf) known to be upregulated by PTZ treatment was affected in the presence of Val. Both VPA and Val significantly reversed the PTZ-altered swimming behaviors. Noticeably, Val at higher doses was affecting swimming independently of the presence of PTZ. A strong regulation of all three neural-activity genes was observed in Val-treated larvae which fully supported the behavioral results. We demonstrated in a combined behavioral-molecular approach the strong psychoactivity of a natural extract of unknown composition made from V. officinalis. Our results highlight the efficacy and sensitivity of such an approach, therefore offering a novel in vivo screening system amenable to high-throughput testing of promising ethnobotanical candidates.

The interplay between ventro striatal BDNF levels and the effects of valproic acid on the acquisition of ethanol-induced conditioned place preference in mice.

PubMed

Dos Santos, Manuel Alves; Escudeiro, Sarah Sousa; Vasconcelos, Germana Silva; Matos, Natália Castelo Branco; de Souza, Marcos Romário Matos; Patrocínio, Manoel Cláudio Azevedo; Dantas, Leonardo Pimentel; Macêdo, Danielle; Vasconcelos, Silvânia Maria Mendes

2017-11-01

Alcohol addiction is a chronic, relapsing and progressive brain disease with serious consequences for health. Compulsive use of alcohol is associated with the capacity to change brain structures involved with the reward pathway, such as ventral striatum. Recent evidence suggests a role of chromatin remodeling in the pathophysiology of alcohol dependence and addictive-like behaviors. In addition, neuroadaptive changes mediated by the brain-derived neurotrophic factor (BDNF) seems to be an interesting pharmacological target for alcoholism treatment. In the present study, we evaluated the effects of the deacetylase inhibitor valproic acid (VPA) (300mg/kg) on the conditioned rewarding effects of ethanol using conditioned place preference (CPP) (15% v/v; 2g/kg). Ethanol rewarding effect was investigated using a biased protocol of CPP. BDNF levels were measured in the ventral striatum. Ethanol administration induced CPP. VPA pretreatment did not reduce ethanol-CPP acquisition. VPA pretreatment increased BDNF levels when compared to ethanol induced-CPP. VPA pretreatment increased BDNF levels even in saline conditioned mice. Taken together, our results indicate a modulatory effect of VPA on the BDNF levels in the ventral striatum. Overall, this study brings initial insights into the involvement of neurotrophic mechanisms in the ventral striatum in ethanol-induced addictive-like behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

Gadd45a, the gene induced by the mood stabilizer valproic acid, regulates neurite outgrowth through JNK and the substrate paxillin in N1E-115 neuroblastoma cells.

PubMed

Yamauchi, Junji; Miyamoto, Yuki; Murabe, Mayu; Fujiwara, Yoko; Sanbe, Atsushi; Fujita, Yuko; Murase, Shoko; Tanoue, Akito

2007-05-15

Valproic acid (VPA), a mood stabilizer and anticonvulsant, has a variety of neurotrophic functions; however, less is known about how VPA regulates neurite outgrowth. Here, using N1E-115 neuroblastoma cells as the model, we show that VPA upregulates Gadd45a to trigger activation of the downstream JNK cascade controlling neurite outgrowth. VPA induces the phosphorylation of c-Jun N-terminal kinase (JNK) and the substrate paxillin, while VPA induction of neurite outgrowth is inhibited by JNK inhibitors (SP600125 and the small JNK-binding peptide) or a paxillin construct harboring a Ser 178-to-Ala mutation at the JNK phosphorylation. Transfection of Gadd45a, acting through the effector MEKK4, leads to the phosphorylation of the JNK cascade. Conversely, knockdown of Gadd45a with siRNA reduces the effect of VPA. Taken together, these results suggest that upregulation of Gadd45a explains one of the mechanisms whereby VPA induces the neurotrophic effect, providing a new role of Gadd45a in neurite outgrowth.

Scombroid fish poisoning: an overlooked marine food poisoning.

PubMed

Wu, M L; Yang, C C; Yang, G Y; Ger, J; Deng, J F

1997-08-01

Scombroid fish poisoning is a food-borne chemical intoxication caused by certain spoiled fish that contain a large amount of histamine and some biogenic diamines. It has gradually become a world-wide medical problem and probably is the most common cause of fish poisoning. As the data on the incidents of scombroid fish poisoning in Taiwan remains scarce, we report 2 incidents of scombroid fish poisoning in Northern Taiwan. We collected data of the 2 outbreaks of suspected fish poisoning which were reported to us in 1996. An epidemiological investigation was undertaken. Questionnaire interviews were given to persons who ate lunch in the same cafeteria in outbreak 2. The leftover fish were sent for species identification and toxin analysis. The first incident involving 4 women occurred in March 1996. All cases experienced flush, dizziness, blurred vision and skin rashes after eating lunch. A non-scombroid fish of Makaira with histamine levels as high as 84.13 mg/100 g flesh was implicated in this incident. In August 1996, another incident involving some cases who ate lunch at the same cafeteria were investigated. A total of 146 questionnaires were distributed with a return of 132 questionnaires (90.4%). Fifty-five employees reported positive signs or symptoms; 48 persons who ate fish and 7 women who did not eat fish were ill. Fish was the only food associated with the illness with an attack rate of 73.8% (p < 0.001). The incriminated fish was later identified as a scombroid fish of Euthynnus with a histamine content of 271.9 mg/100 g flesh in 1 leftover piece and 118.5 mg/100 g flesh in another piece. Most cases in these 2 outbreaks received treatment with antihistamines and had rapid and complete recovery. The diagnosis of scombroid fish poisoning could be misdiagnosed as food allergy or bacterial food poisoning if physicians are not aware of such poisoning. The nonspecific but characteristic symptomatology of histamine food poisoning and previous consumption of fish

The power of poison: pesticide poisoning of Africa's wildlife.

PubMed

Ogada, Darcy L

2014-08-01

Poisons have long been used to kill wildlife throughout the world. An evolution has occurred from the use of plant- and animal-based toxins to synthetic pesticides to kill wildlife, a method that is silent, cheap, easy, and effective. The use of pesticides to poison wildlife began in southern Africa, and predator populations were widely targeted and eliminated. A steep increase has recently been observed in the intensity of wildlife poisonings, with corresponding population declines. However, the majority of poisonings go unreported. Under national laws, it is illegal to hunt wildlife using poisons in 83% of African countries. Pesticide regulations are inadequate, and enforcement of existing legislation is poor. Few countries have forensic field protocols, and most lack storage and testing facilities. Methods used to poison wildlife include baiting carcasses, soaking grains in pesticide solution, mixing pesticides to form salt licks, and tainting waterholes. Carbofuran is the most widely abused pesticide in Africa. Common reasons for poisoning are control of damage-causing animals, harvesting fish and bushmeat, harvesting animals for traditional medicine, poaching for wildlife products, and killing wildlife sentinels (e.g., vultures because their aerial circling alerts authorities to poachers' activities). Populations of scavengers, particularly vultures, have been decimated by poisoning. Recommendations include banning pesticides, improving pesticide regulations and controlling distribution, better enforcement and stiffer penalties for offenders, increasing international support and awareness, and developing regional pesticide centers. © 2014 New York Academy of Sciences.

Experimental lead-shot poisoning in bald eagles

USGS Publications Warehouse

Pattee, O.H.; Wiemeyer, Stanley N.; Mulhern, B.M.; Sileo, L.; Carpenter, J.W.

1981-01-01

Captive, crippled bald eagles unsuitable for release were fed lead shot to determine diagnostic criteria for lead poisoning. The eagles were fluoroscoped and bled periodically to determine shot retention and blood delta--aminolevulinic acid dehydratase activity. Microscopic examination revealed renal tubular degeneration, arterial fibrinoid necrosis and myocardial necrosis. Acid-fast intra-nuclear inclusion bodies were not found in proximal convoluted tubule cells. Analyses of blood and toxicological data are not yet complete.

Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Renzo, Francesca; Cappelletti, Graziella; Broccia, Maria L.

2007-04-15

Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice weremore » treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 h after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor {alpha} = 0.51 and maximum velocity by a factor {beta} = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations.« less

Ciguatera fish poisoning

PubMed Central

Crump, J.; McLay, C.; Chambers, S.

1999-01-01

Ciguatera fish poisoning is one of a variety of non-bacterial forms of human seafood poisoning. Consuming large predatory fish from tropical reef ecosystems may be hazardous. We describe a case that is typical of the disease, and illustrates the persistence of neurological symptoms that occur in some patients.


Keywords: ciguatera fish poisoning; ichthyosarcotoxaemia; poisoning; biotoxins PMID:10621882

Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism.

PubMed

Schneider, Tomasz; Ziòłkowska, Barbara; Gieryk, Agnieszka; Tyminska, Anna; Przewłocki, Ryszard

2007-09-01

It has been suggested that behavioral aberrations observed in autism could be the result of dysfunction of the neuroregulatory role performed by the endogenous opioid peptides. Many of those aberrations have been recently modeled in rats exposed to valproic acid (VPA) on the 12th day of gestation (VPA rats). The aim of the present study was to elucidate functioning of the enkephalinergic system, one of the endogenous opioid peptide systems strongly involved in emotional responses, in VPA rats using both biochemical and behavioral methods. In situ hybridization was used to measure proenkephalin mRNA expression in adult VPA rats' central nucleus of the amygdala, the dorsal striatum, and the nucleus accumbens. Additional groups of animals were examined in a conditioned place aversion to naloxone, the elevated plus maze, and object recognition tests to assess their basal hedonic tone, anxiety, learning and memory, respectively. Prenatal exposure to VPA decreased proenkephalin mRNA expression in the dorsal striatum and the nucleus accumbens but not in the central nucleus of the amygdala. It also increased anxiety and attenuated conditioned place aversion to naloxone but had no impact on learning and memory. The present results suggest that prenatal exposure to VPA may lead to the decreased activity of the striatal enkephalinergic system and in consequence to increased anxiety and disregulated basal hedonic tone observed in VPA rats. Presented results are discussed in light of interactions between enkephalinergic, GABAergic, and dopaminergic systems in the striatum and mesolimbic areas of the brain.

Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis.

PubMed

Jo, Seong Jin; Shin, Hyoseung; Park, Young Woon; Paik, Seung Hwan; Park, Won Seok; Jeong, Yeon Su; Shin, Hong Ju; Kwon, Ohsang

2014-04-01

Valproic acid (VPA), a widely used anticonvulsant, inhibits glycogen synthase kinase 3β and activates the Wnt/β-catenin pathway, which is associated with hair growth cycle and anagen induction. To assess the efficacy of topical VPA for treating androgenetic alopecia (AGA), we performed a randomized, double-blind, placebo-controlled clinical trial. Male patients with moderate AGA underwent treatment with either VPA (sodium valproate, 8.3%) or placebo spray for 24 weeks. The primary end-point for efficacy was the change in hair count during treatment, which was assessed by phototrichogram analysis. Of the 40 patients enrolled in the study, 27 (n = 15, VPA group; n = 12, placebo group) completed the entire protocol with good compliance. No statistical differences in age, hair loss duration and total hair count at baseline were found between the groups. The mean change in total hair count was significantly higher in the VPA group than in the placebo group (P = 0.047). Both groups experienced mostly mild and self-limited adverse events, but their differences in prevalence rates were similar between the two groups (P = 0.72). A subject treated with topical VPA developed ventricular tachycardia, but it did not seem to be related to the VPA spray. Topical VPA increased the total hair counts of our patients; therefore, it is a potential treatment option for AGA. © 2014 Japanese Dermatological Association.

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

PubMed

Caponigro, Francesco; Di Gennaro, Elena; Ionna, Franco; Longo, Francesco; Aversa, Corrado; Pavone, Ettore; Maglione, Maria Grazia; Di Marzo, Massimiliano; Muto, Paolo; Cavalcanti, Ernesta; Petrillo, Antonella; Sandomenico, Fabio; Maiolino, Piera; D'Aniello, Roberta; Botti, Gerardo; De Cecio, Rossella; Losito, Nunzia Simona; Scala, Stefania; Trotta, Annamaria; Zotti, Andrea Ilaria; Bruzzese, Francesca; Daponte, Antonio; Calogero, Ester; Montano, Massimo; Pontone, Monica; De Feo, Gianfranco; Perri, Francesco; Budillon, Alfredo

2016-11-25

Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR. V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response

Shaving cream poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Oven cleaner poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Lighter fluid poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Lip moisturizer poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002723.htm Lip moisturizer poisoning To use the sharing features on this page, please enable JavaScript. This poisoning results from eating or swallowing lip ...

Face powder poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002700.htm Face powder poisoning To use the sharing features on this page, please enable JavaScript. Face powder poisoning occurs when someone swallows or ...

Rhubarb leaves poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002876.htm Rhubarb leaves poisoning To use the sharing features on this page, please enable JavaScript. Rhubarb leaves poisoning occurs when someone eats pieces ...

Nail polish poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002722.htm Nail polish poisoning To use the sharing features on this page, please enable JavaScript. This poisoning is from swallowing or breathing in ( ...

Effects of Humic Acids in Chronic Lead Poisoning.

PubMed

Vašková, Janka; Krempaská, Klára; Žatko, Daniel; Mudroň, Pavol; Glinská, Gabriela; Vaško, Ladislav

2018-05-10

Chronic exposure to lead causes disruption to energy production mechanisms and tissue damage, in particular through its binding to thiol groups and competition for zinc binding sites. We investigated the possibility of preventing the consequences of chronic lead poisoning by administration of three different doses of humic acids (HAs) into feed with the aim of establishing an effective HA dose. During the 10-week experiment, a sub-lethal dose of lead acetate was given to rats during the first 5 weeks, with continuous administration of HA over 10 weeks. Measurements were taken to determine the content of the metals Pb, Mn, Cu, Fe and Zn; the metalloid Se; and selected antioxidant markers in the heart, liver, kidney and plasma after the first, fifth and tenth weeks of experiment. The administration of lead and HAs clearly affects the redistribution of the elements and the activity of the antioxidant enzymes. This fact was particularly highlighted in the lead-only group as, within the experiment, significantly higher Pb concentrations were found only in the plasma of this group. However, in the group with 1% HA administered with lead, we observed a rise in Zn concentrations in the organs and the deposition of Fe into the liver. Decreased glutathione reductase activity in the plasma and balanced reduced glutathione concentrations indicated sufficient efficiency of redox reactions. SOD activities were among those affected most strongly, with only the 1% HA group showing no effect on heavy metal redistribution as a result of HA administration.

Poison Control Centers

MedlinePlus

... 1222 immediately. Name State American Association of Poison Control Centers Address AAPCC Central Office NOT A POISON ... not for emergency use. Arkansas ASPCA Animal Poison Control Center Address 1717 S. Philo Road, Suite 36 Urbana, ...

Haematological toxicity of Valproic acid compared to Levetiracetam in patients with glioblastoma multiforme undergoing concomitant radio-chemotherapy: a retrospective cohort study.

PubMed

Tinchon, Alexander; Oberndorfer, Stefan; Marosi, Christine; Gleiss, Andreas; Geroldinger, Angelika; Sax, Cornelia; Sherif, Camillo; Moser, Walter; Grisold, Wolfgang

2015-01-01

Patients with glioblastoma multiforme (GBM) and symptomatic seizures are in need of a sufficient antiepileptic treatment. Haematological toxicity is a limiting side effect of both, first line radio-chemotherapy with temozolomide (TMZ) and co-medication with antiepileptic drugs. Valproic acid (VPA) and levetiracetam (LEV) are considered favourable agents in brain tumor patients with seizures, but are commonly reported to induce haematological side effects on their own. We hypothesized, that antiepileptic treatment with these agents has no increased impact on haematological side effects during radio-chemotherapy in the first line setting. We included 104 patients from two neuro-oncologic centres with GBM and standard radio-chemotherapy in a retrospective cohort study. Patients were divided according to their antiepileptic treatment with either VPA, LEV or without antiepileptic drug therapy (control group). Declines in haemoglobin levels and absolute blood cell counts for neutrophil granulocytes, lymphocytes and thrombocytes were analyzed twice during concomitant and once during adjuvant phase. A comparison between the examined groups was performed, using a linear mixed model. Neutrophil granulocytes, lymphocytes and thrombocytes significantly decreased over time in all three groups (all p < 0.012), but there was no significant difference between the compared groups. A significant decline in haemoglobin was observed in the LEV treated group (p = 0.044), but did not differ between the compared groups. As a novel finding, this study demonstrates that co-medication either with VPA or LEV in GBM patients undergoing first line radio-chemotherapy with TMZ has no additional impact on medium-term haematological toxicity.

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

PubMed Central

He, Yingzi; Cai, Chengfu; Tang, Dongmei; Sun, Shan; Li, Huawei

2014-01-01

In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID:25431550

Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans.

PubMed

Kumar, K Prem; Kumar, Sreeletha Prem; Nair, G Achuthan

2009-05-01

Risk assessment of the amnesic shellfish poison, domoic acid, a potent neurotoxin, is evaluated based on its current knowledge and its harmful effects, and is presented under four headings, viz., (1) hazard identification, (2) dose response assessment, (3) exposure assessment and (4) risk characterization. Domoic acid binds the glutamate receptor site of the central nervous system (CNS) of humans and causes depolarization of neurons and an increase in cellularcalcium. In nature, domoic acid is produced by the algae, Pseudonitzschia spp. and they enter into the body of shellfish through their consumption. This toxin is reported to cause gastroenteritis, renal insufficiency confusion and memory loss in humans, since it affects the hippocampus of the brain. In rats, intraperitonial and oral administration of domoic acid result in scratching, tremor and convulsions, and in monkeys, the toxic symptoms like mastication, salivation, projectile vomiting, weakness, teeth grinding and lethargy are apparent. The no-observed-adverse-effect-level (NOAEL) in animals reveals that pure toxin is more effective than those isolated from shellfish. Based on LD50 values, it is found that intraperitonial administration of this toxin in animals is 31 fold more effective than oral administration. Low levels of domoic acid (0.20-0.75 ppm) show no toxic symptoms in non-human primates, but clinical effects are apparent in them and in humans, at a concentration of 1.0 ppm. The tolerable daily intake (TDI) of domoic acid for humans is calculated as 0.075 ppm, whereas for razor clams and crabs, the TDI are 19.4 and 31.5 ppm respectively. The hazard quotient (HQ) is found to be 2. Being an irreversible neurotoxin, domoic acid has severe public health implications. Death occurs in those above 68 years old. In order to ensure adequate protection to public health, the concentration of domoic acid in shellfish and shellfish parts at point of sale shall not exceed the current permissible limit of 20

Acid soldering flux poisoning

MedlinePlus

Acid soldering flux is a chemical used to clean and protect the area where two pieces of metal are ... The harmful substances in soldering fluxes are called hydrocarbons. They include: Ammonium chloride Rosin Hydrochloric acid Zinc chloride

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

PubMed

Avallone, Antonio; Piccirillo, Maria Carmela; Delrio, Paolo; Pecori, Biagio; Di Gennaro, Elena; Aloj, Luigi; Tatangelo, Fabiana; D'Angelo, Valentina; Granata, Cinzia; Cavalcanti, Ernesta; Maurea, Nicola; Maiolino, Piera; Bianco, Franco; Montano, Massimo; Silvestro, Lucrezia; Terranova Barberio, Manuela; Roca, Maria Serena; Di Maio, Massimo; Marone, Pietro; Botti, Gerardo; Petrillo, Antonella; Daniele, Gennaro; Lastoria, Secondo; Iaffaioli, Vincenzo R; Romano, Giovanni; Caracò, Corradina; Muto, Paolo; Gallo, Ciro; Perrone, Francesco; Budillon, Alfredo

2014-11-24

Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15�

Starch poisoning

MedlinePlus

Cooking starch poisoning; Laundry starch poisoning ... Cooking and laundry starch are both made from vegetable products, most commonly: Corn Potatoes Rice Wheat Both are usually considered nonpoisonous (nontoxic), but ...

Prevention of Food Poisoning.

ERIC Educational Resources Information Center

Army Quartermaster School, Ft. Lee, VA.

The programed text provides a single lesson, four-hour, correspondence subcourse on the prevention of food poisoning. It covers the following areas: a definition of food poisoning; chemical food poisoning; biological food poisoning; causes and prevention of trichinosis; six factors controlling bacteria growth; bacterial infection; prevention of…

Protecting Yourself from Poisonous Plants

MedlinePlus

... NIOSH NIOSH Fast Facts: Protecting Yourself from Poisonous Plants Language: English (US) Español (Spanish) Kreyol Haitien (Hatian ... outdoors is at risk of exposure to poisonous plants, such as poison ivy, poison oak, and poison ...

Can poison control data be used for pharmaceutical poisoning surveillance?

PubMed

Naun, Christopher A; Olsen, Cody S; Dean, J Michael; Olson, Lenora M; Cook, Lawrence J; Keenan, Heather T

2011-05-01

To determine the association between the frequencies of pharmaceutical exposures reported to a poison control center (PCC) and those seen in the emergency department (ED). A statewide population-based retrospective comparison of frequencies of ED pharmaceutical poisonings with frequencies of pharmaceutical exposures reported to a regional PCC. ED poisonings, identified by International Classification of Diseases, Version 9 (ICD-9) codes, were grouped into substance categories. Using a reproducible algorithm facilitated by probabilistic linkage, codes from the PCC classification system were mapped into the same categories. A readily identifiable subset of PCC calls was selected for comparison. Correlations between frequencies of quarterly exposures by substance categories were calculated using Pearson correlation coefficients and partial correlation coefficients with adjustment for seasonality. PCC reported exposures correlated with ED poisonings in nine of 10 categories. Partial correlation coefficients (r(p)) indicated strong associations (r(p)>0.8) for three substance categories that underwent large changes in their incidences (opiates, benzodiazepines, and muscle relaxants). Six substance categories were moderately correlated (r(p)>0.6). One category, salicylates, showed no association. Limitations Imperfect overlap between ICD-9 and PCC codes may have led to miscategorization. Substances without changes in exposure frequency have inadequate variability to detect association using this method. PCC data are able to effectively identify trends in poisonings seen in EDs and may be useful as part of a pharmaceutical poisoning surveillance system. The authors developed an algorithm-driven technique for mapping American Association of Poison Control Centers codes to ICD-9 codes and identified a useful subset of poison control exposures for analysis.

Postmortem computed tomography and magnetic resonance imaging facilitates forensic autopsy in a fatal case of poisoning with formic acid, diphenhydramine, and ethanol.

PubMed

Berger, Florian; Steuer, Andrea E; Rentsch, Katharina; Gascho, Dominic; Stamou, Stamatios; Schärli, Sarah; Thali, Michael J; Krämer, Thomas; Flach, Patricia M

2016-09-01

A case of fatal poisoning by ingesting formic acid, diphenhydramine, and ethanol by a 25-year-old woman who committed suicide is presented. Prior to autopsy, postmortem computed tomography and postmortem magnetic resonance tomography were performed and revealed severe damage to the stomach, the left thoracic wall, and parts of the liver. Imaging detected acid-induced fluid-fluid level within the thoracic cavity (fat-equivalent fluid and necrotic pleural effusion). This case report illustrates that postmortem cross-sectional imaging may facilitate dissection of severely damaged or complex regions, and may provide additional information compared to autopsy and toxicological examinations alone.

Scombroid poisoning: a review.

PubMed

Hungerford, James M

2010-08-15

Scombroid poisoning, also called histamine fish poisoning, is an allergy-like form of food poisoning that continues to be a major problem in seafood safety. The exact role of histamine in scombroid poisoning is not straightforward. Deviations from the expected dose-response have led to the advancement of various possible mechanisms of toxicity, none of them proven. Histamine action levels are used in regulation until more is known about the mechanism of scombroid poisoning. Scombroid poisoning and histamine are correlated but complicated. Victims of scombroid poisoning respond well to antihistamines, and chemical analyses of fish implicated in scombroid poisoning generally reveal elevated levels of histamine. Scombroid poisoning is unique among the seafood toxins since it results from product mishandling rather than contamination from other trophic levels. Inadequate cooling following harvest promotes bacterial histamine production, and can result in outbreaks of scombroid poisoning. Fish with high levels of free histidine, the enzyme substrate converted to histamine by bacterial histidine decarboxylase, are those most often implicated in scombroid poisoning. Laboratory methods and screening methods for detecting histamine are available in abundance, but need to be compared and validated to harmonize testing. Successful field testing, including dockside or on-board testing needed to augment HACCP efforts will have to integrate rapid and simplified detection methods with simplified and rapid sampling and extraction. Otherwise, time-consuming sample preparation reduces the impact of gains in detection speed on the overall analysis time. Published by Elsevier Ltd.

Ethanol poisoning

MedlinePlus

... this page: //medlineplus.gov/ency/article/002644.htm Ethanol poisoning To use the sharing features on this page, please enable JavaScript. Ethanol poisoning is caused by drinking too much alcohol. ...

Boric acid poisoning

MedlinePlus

... effectively treat (adsorb) boric acid. For skin exposure, treatment may include: Surgical removal of burned skin (debridement) Transfer to a hospital that specializes in burn care Washing of the skin (irrigation), possibly every ...

Nitric acid poisoning

MedlinePlus

... Board on Environmental Studies and Toxicology; Division on Earth and Life Studies; National Research Council. Nitric acid: ... Board on Environmental Studies and Toxicology; Division on Earth and Life Studies; National Research Council. Acute Exposure ...

Hydrochloric acid poisoning

MedlinePlus

... measure and monitor the person's vital signs, including temperature, pulse, breathing rate, and blood pressure. The person ... into the stomach to suction (aspirate) any remaining acid if the victim is seen shortly after ingesting ...

Managing aluminum phosphide poisonings

PubMed Central

Gurjar, Mohan; Baronia, Arvind K; Azim, Afzal; Sharma, Kalpana

2011-01-01

Aluminum phosphide (AlP) is a cheap, effective and commonly used pesticide. However, unfortunately, it is now one of the most common causes of poisoning among agricultural pesticides. It liberates lethal phosphine gas when it comes in contact either with atmospheric moisture or with hydrochloric acid in the stomach. The mechanism of toxicity includes cellular hypoxia due to the effect on mitochondria, inhibition of cytochrome C oxidase and formation of highly reactive hydroxyl radicals. The signs and symptoms are nonspecific and instantaneous. The toxicity of AlP particularly affects the cardiac and vascular tissues, which manifest as profound and refractory hypotension, congestive heart failure and electrocardiographic abnormalities. The diagnosis of AlP usually depends on clinical suspicion or history, but can be made easily by the simple silver nitrate test on gastric content or on breath. Due to no known specific antidote, management remains primarily supportive care. Early arrival, resuscitation, diagnosis, decrease the exposure of poison (by gastric lavage with KMnO4, coconut oil), intensive monitoring and supportive therapy may result in good outcome. Prompt and adequate cardiovascular support is important and core in the management to attain adequate tissue perfusion, oxygenation and physiologic metabolic milieu compatible with life until the tissue poison levels are reduced and spontaneous circulation is restored. In most of the studies, poor prognostic factors were presence of acidosis and shock. The overall outcome improved in the last decade due to better and advanced intensive care management. PMID:21887030

Paradichlorobenzene poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002902.htm Paradichlorobenzene poisoning To use the sharing features on this page, please enable JavaScript. Paradichlorobenzene is a white, solid chemical with a ...

Yew poisoning

MedlinePlus

... poisoning URL of this page: //medlineplus.gov/ency/article/002877.htm Yew poisoning To use the sharing features on this page, please enable JavaScript. The yew plant is a shrub with evergreen- ...

Using Poison Center Exposure Calls to Predict Methadone Poisoning Deaths

PubMed Central

Dasgupta, Nabarun; Davis, Jonathan; Jonsson Funk, Michele; Dart, Richard

2012-01-01

Purpose There are more drug overdose deaths in the Untied States than motor vehicle fatalities. Yet the US vital statistics reporting system is of limited value because the data are delayed by four years. Poison centers report data within an hour of the event, but previous studies suggested a small proportion of poisoning deaths are reported to poison centers (PC). In an era of improved electronic surveillance capabilities, exposure calls to PCs may be an alternate indicator of trends in overdose mortality. Methods We used PC call counts for methadone that were reported to the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System in 2006 and 2007. US death certificate data were used to identify deaths due to methadone. Linear regression was used to quantify the relationship of deaths and poison center calls. Results Compared to decedents, poison center callers tended to be younger, more often female, at home and less likely to require medical attention. A strong association was found with PC calls and methadone mortality (b = 0.88, se = 0.42, t = 9.5, df = 1, p<0.0001, R2 = 0.77). These findings were robust to large changes in a sensitivity analysis assessing the impact of underreporting of methadone overdose deaths. Conclusions Our results suggest that calls to poison centers for methadone are correlated with poisoning mortality as identified on death certificates. Calls received by poison centers may be used for timely surveillance of mortality due to methadone. In the midst of the prescription opioid overdose epidemic, electronic surveillance tools that report in real-time are powerful public health tools. PMID:22829925

Poison Ivy

MedlinePlus

... leaves of the plants. Look Out for Poison Plants These plants can be anywhere — from the woods ... pill or liquid form. Preventing Rashes From Poison Plants The best approach is to avoid getting the ...

Poisonous Plants

MedlinePlus

... Publications and Products Programs Contact NIOSH NIOSH POISONOUS PLANTS Recommend on Facebook Tweet Share Compartir Photo courtesy ... U.S. Department of Agriculture Many native and exotic plants are poisonous to humans when ingested or if ...

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

PubMed

Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Katashiba, Keisuke; Hasebe, Shigeru; Takano, Erika; Onaka, Yusuke; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2016-09-01

Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Foxglove poisoning

MedlinePlus

Foxglove poisoning most often occurs from sucking the flowers or eating the seeds, stems, or leaves of ... The poisonous substances are found in: Flowers, leaves, stems, and seeds of the foxglove plant Heart medicine (digitalis glycoside)

Cologne poisoning

MedlinePlus

... Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 100. ... Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 32. ...

Fish and shellfish poisoning.

PubMed

Trevino, S

1998-01-01

To review history, biology, and medical aspects associated with fish and shellfish poisoning. Current literature, various Web sites, and Halstead's Volume II of Poisonous and Venomous Marine Animals. Determined by author. Determined by author. Fish and shellfish poisoning occur through the natural event of the food chain. Fish and shellfish consume algae that contain toxin-producing dinoflagellates. As a result they become contaminated and the toxin is concentrated as it moves up the food chain. Fish and shellfish can tolerate high levels of toxins, thereby appearing healthy while posing a significant danger to man. The toxin cannot be detected by sight, smell, or taste and is not destroyed by cooking or freezing. Thus man becomes an unsuspecting victim. There are several types of poisoning that occur through fish and shellfish consumption. They are ciguatera and scombroid fish poisoning; and paralytic, diarrheic, neurotoxic, and amnesic shellfish poisoning. A different toxin produces each of these poisonings; however, sources and symptoms may be similar among these poisonings making them difficult to diagnose. These intoxications can vary in severity from mild to fatal depending on the type and amount of toxin ingested. Age and underlying illnesses may also contribute to the outcome of these poisonings. Though people are aware of health warnings and may think they are important, it is human nature to think that "this could not possibly happen to me". Therefore, they fail to make the necessary changes required to reduce the incidence of fish and shellfish poisoning.

Lithium Poisoning.

PubMed

Baird-Gunning, Jonathan; Lea-Henry, Tom; Hoegberg, Lotte C G; Gosselin, Sophie; Roberts, Darren M

2017-05-01

Lithium is a commonly prescribed treatment for bipolar affective disorder. However, treatment is complicated by lithium's narrow therapeutic index and the influence of kidney function, both of which increase the risk of toxicity. Therefore, careful attention to dosing, monitoring, and titration is required. The cause of lithium poisoning influences treatment and 3 patterns are described: acute, acute-on-chronic, and chronic. Chronic poisoning is the most common etiology, is usually unintentional, and results from lithium intake exceeding elimination. This is most commonly due to impaired kidney function caused by volume depletion from lithium-induced nephrogenic diabetes insipidus or intercurrent illnesses and is also drug-induced. Lithium poisoning can affect multiple organs; however, the primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Lithium poisoning has a low mortality rate; however, chronic lithium poisoning can require a prolonged hospital length of stay from impaired mobility and cognition and associated nosocomial complications. Persistent neurological deficits, in particular cerebellar, are described and the incidence and risk factors for its development are poorly understood, but it appears to be uncommon in uncomplicated acute poisoning. Lithium is readily dialyzable, and rationale support extracorporeal treatments to reduce the risk or the duration of toxicity in high-risk exposures. There is disagreement in the literature regarding factors that define patients most likely to benefit from treatments that enhance lithium elimination, including specific plasma lithium concentration thresholds. In the case of extracorporeal treatments, there are observational data in its favor, without evidence from randomized controlled trials (none have been performed), which may lead to conservative practices and

Oral hyposensitization to poison ivy and poison oak.

PubMed

Marks, J G; Trautlein, J J; Epstein, W L; Laws, D M; Sicard, G R

1987-04-01

We evaluated the safety and efficacy of a 1:1 mixture of pentadecylcatechol (PDC) and heptadecylcatechol (HDC) diacetate in reducing hypersensitivity to poison ivy and poison oak. The study was double-blind, parallel, randomized, and placebo controlled. The 44 subjects receiving the active drug ingested a cumulative dose of 306.5 mg over a five-week period. Subsequently, 14 patients were continued on a maintenance phase, ingesting an additional 960 mg of drug. The PDC-HDC diacetate was well tolerated, with no significant side effects. Evaluation of efficacy compared poststudy and prestudy reactions to patch tests using urushiol in doses of 0.025, 0.05, 0.125, 0.25, and 0.5 micrograms applied to the forearm. The results indicated that the induction phase as well as the maintenance phase did not induce a statistically significant hyposensitivity to urushiol, and we were thus unable to decrease sensitivity to poison ivy and poison oak in humans using orally ingested PDC-HDC diacetate.

[Development and application of poison databank and poisonous animal and plants sample databank].

PubMed

Yin, Yu; Jiang, Shao-Feng; Cai, Jun; Luo, Tao; Xie, Li-Jing; Zhou, Jing; Sun, Cheng-Ye

2008-03-01

To establish a comprehensive,easily approached, operated, and searched internet poison databank as to providing professional poison data and knowledge of effective treatment for those consented such as medical staff, and emergency response team in the shortest time. We established a computer poison databank, by adopting B/S structure, using SQL Server databank, and explore technology, in which all information may easily be explored and obtained by users. The database integrated the information in relating to the substances identifiers, physical and chemical properties, toxicology data, clinical manifestation while intoxication, emergency response guides, effective treatment, anything related to the special antidotes, preventive measures, poison analysis, and manufacturers of chemicals, pharmaceuticals, herbs, pesticides, animal, plant, bacteria, fungi, productions and toxins. Otherwise some information about poison control organizations and experts, literatures about poison case reports, poison incidents, were also involved in the system, which can also provide a shortcut, convenient, and exact search. The databank might be easily used on several fields, providing important information with acute poison incidents disposal and clinic treatment.

Valproic acid-inducible Arl4D and cytohesin-2/ARNO, acting through the downstream Arf6, regulate neurite outgrowth in N1E-115 cells.

PubMed

Yamauchi, Junji; Miyamoto, Yuki; Torii, Tomohiro; Mizutani, Reiko; Nakamura, Kazuaki; Sanbe, Atsushi; Koide, Hiroshi; Kusakawa, Shinji; Tanoue, Akito

2009-07-15

The mood-stabilizing agent valproic acid (VPA) potently promotes neuronal differentiation. As yet, however, little is known about the underlying molecular mechanism. Here, we show that VPA upregulates cytohesin-2 and mediates neurite outgrowth in N1E-115 neuroblastoma cells. Cytohesin-2 is the guanine-nucleotide exchange factor (GEF) for small GTPases of the Arf family; it regulates many aspects of cellular functions including morphological changes. Treatment with the specific cytohesin family inhibitor SecinH3 or knockdown of cytohesin-2 with its siRNA results in blunted induction of neurite outgrowth in N1E-115 cells. The outgrowth is specifically inhibited by siRNA knockdown of Arf6, but not by that of Arf1. Furthermore, VPA upregulates Arl4D, an Arf-like small GTPase that has recently been identified as the regulator that binds to cytohesin-2. Arl4D knockdown displays an inhibitory effect on neurite outgrowth resulting from VPA, while expression of constitutively active Arl4D induces outgrowth. We also demonstrate that the addition of cell-permeable peptide, coupling the cytohesin-2-binding region of Arl4D into cells, reduces the effect of VPA. Thus, Arl4D is a previously unknown regulator of neurite formation through cytohesin-2 and Arf6, providing another example that the functional interaction of two different small GTPases controls an important cellular function.

Valproic acid exposure decreases Cbp/p300 protein expression and histone acetyltransferase activity in P19 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamparter, Christina L.

The teratogenicity of the antiepileptic drug valproic acid (VPA) is well established and its inhibition of histone deacetylases (HDAC) is proposed as an initiating factor. Recently, VPA-mediated HDAC inhibition was demonstrated to involve transcriptional downregulation of histone acetyltransferases (HATs), which was proposed to compensate for the increased acetylation resulting from HDAC inhibition. Cbp and p300 are HATs required for embryonic development and deficiencies in either are associated with congenital malformations and embryolethality. The objective of the present study was to characterize Cbp/p300 following VPA exposure in P19 cells. Consistent with previous studies, exposure to 5 mM VPA over 24 hmore » induced a moderate decrease in Cbp/p300 mRNA, which preceded a strong decrease in total cellular protein mediated by ubiquitin-proteasome degradation. Nuclear Cbp/p300 protein was also decreased following VPA exposure, although to a lesser extent. Total cellular and nuclear p300 HAT activity was reduced proportionately to p300 protein levels, however while total cellular HAT activity also decreased, nuclear HAT activity was unaffected. Using the Cbp/p300 HAT inhibitor C646, we demonstrated that HAT inhibition similarly affected many of the same endpoints as VPA, including increased reactive oxygen species and caspase-3 cleavage, the latter of which could be attenuated by pre-treatment with the antioxidant catalase. C646 exposure also decreased NF-κB/p65 protein, which was not due to reduced mRNA and was not attenuated with catalase pre-treatment. This study provides support for an adaptive HAT response following VPA exposure and suggests that reduced Cbp/p300 HAT activity could contribute to VPA-mediated alterations. - Highlights: • VPA exposure in vitro downregulates Cbp/p300 mRNA and induces protein degradation. • Cbp/p300 histone acetyltransferase activity is similarly reduced with VPA exposure. • Inhibition of Cbp/p300 acetyltransferase

Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite.

PubMed

Marks, J G; Fowler, J F; Sheretz, E F; Rietschel, R L

1995-08-01

Poison ivy and poison oak are the most common causes of allergic contact dermatitis in North America. We investigated whether a new topical lotion containing 5% quaternium-18 bentonite prevents experimentally induced poison ivy and poison oak allergic contact dermatitis. A single-blind, paired comparison, randomized, multicenter investigation was used to evaluate the effectiveness and safety of quaternium-18 bentonite lotion in preventing experimentally induced poison ivy and poison oak allergic contact dermatitis in susceptible volunteers. One hour before both forearms were patch tested with urushiol, the allergenic resin from poison ivy and poison oak, 5% quaternium-18 bentonite lotion was applied on one forearm. The test patches were removed after 4 hours and the sites interpreted for reaction 2, 5, and 8 days later. The difference in reactions between treated and untreated patch test sites was statistically analyzed. Two hundred eleven subjects with a history of allergic contact dermatitis to poison ivy and poison oak were studied. One hundred forty-four subjects had positive reactions to urushiol. The test sites pretreated with quaternium-18 bentonite lotion had absent or significantly reduced reactions to the urushiol compared with untreated control sites (p < 0.0001) on all test days. When it occurred, the reaction consistently appeared later on treated than on control sites (p < 0.0001). One occurrence of mild, transient erythema at the application site was the only side effect from the quaternium-18 bentonite lotion. Quaternium-18 bentonite lotion was effective in preventing or diminishing experimentally produced poison ivy and poison oak allergic contact dermatitis.

Cold wave lotion poisoning

MedlinePlus

... if known) Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Poison Ivy

MedlinePlus

... way to get rid of it? Resources U.S. Food and Drug Administration, Outsmarting Poison Ivy and Other Poisonous Plants Last Updated: June 21, 2017 This article was contributed by: familydoctor.org editorial staff Categories: Family Health, Kids and TeensTags: allergic reaction, Dermatologic, ...

Look Out! It's Poison Ivy!

ERIC Educational Resources Information Center

Darlington, Elizabeth, Day

1986-01-01

Provides background information on poison ivy and offers suggestions for instructional activities. Includes illustrations of the varieties of poison ivy leaf forms and poison ivy look-alikes. Highlights interesting facts and cases associated with poison ivy and its relatives. (ML)

Evaluation of poison information services provided by a new poison information center.

PubMed

Churi, Shobha; Abraham, Lovin; Ramesh, M; Narahari, M G

2013-01-01

The aim of this study is to assess the nature and quality of services provided by poison information center established at a tertiary-care teaching hospital, Mysore. This was a prospective observational study. The poison information center was officially established in September 2010 and began its functioning thereafter. The center is equipped with required resources and facility (e.g., text books, Poisindex, Drugdex, toll free telephone service, internet and online services) to provide poison information services. The poison information services provided by the center were recorded in documentation forms. The documentation form consists of numerous sections to collect information on: (a) Type of population (children, adult, elderly or pregnant) (b) poisoning agents (c) route of exposure (d) type of poisoning (intentional, accidental or environmental) (e) demographic details of patient (age, gender and bodyweight) (f) enquirer details (background, place of call and mode of request) (g) category and purpose of query and (h) details of provided service (information provided, mode of provision, time taken to provide information and references consulted). The nature and quality of poison information services provided was assessed using a quality assessment checklist developed in accordance with DSE/World Health Organization guidelines. Chi-Square test (χ(2)). A total of 419 queries were received by the center. A majority (n = 333; 79.5%) of the queries were asked by the doctors to provide optimal care (n = 400; 95.5%). Most of the queries were received during ward rounds (n = 201; 48.0%), followed by direct access (n = 147; 35.1%). The poison information services were predominantly provided through verbal communication (n = 352; 84.0%). Upon receipt of queries, the required service was provided immediately (n = 103; 24.6%) or within 10-20 min (n = 296; 70.6%). The queries were mainly related to intentional poisoning (n = 258; 64.5%), followed by accidental poisoning

Imported occupational lead poisoning: report of four cases.

PubMed

Petracca, M; Scafa, F; Boeri, R; Flachi, Daniela; Candura, S M

2013-01-01

In most industrialized countries, occupational lead poisoning has become increasingly rare, however this metal remains a serious health hazard in the rest of the world. We observedfour male patients (aged 35 / 54 years) who had suffered recurrent abdominal pain due to recent lead exposure (for 7 to 13 months) in two Chinese battery recycling plants. On their return to Italy, three of them presented normocytic, normochromic anaemia. The diagnosis was confirmed by high lead levels in the blood and urine, decreased erythrocyte delta-aminolevulinic acid dehydratase (ALA-D), raised erythrocyte zinc protoporphyrin (ZP), and elevated urinary excretion of b-aminolevulinic acid (ALA-U) and porphyrins. Chelation with EDTA resulted in increased urinary lead excretion, improvement of the clinical picture, decreased ZP, and progressive normalization of the other lead biomarkers (Pb-B, ALA-D, ALA-U, urinary porphyrins). Temporary work in developing countries may result in imported lead poisoning. Differential diagnosis of this unusual condition requires careful medical history collection and specific toxicological analysis. Preventive measures for workers going abroad are needed.

Tropical fish poisoning in temperate climates: food poisoning from ciguatera toxin presenting in Avonmouth.

PubMed

Kipping, Ruth; Eastcott, Howard; Sarangi, Joyshri

2006-12-01

Ciguatera toxin causes a range of gastrointestinal, cardiovascular and neurological symptoms that occur within 1-6 h of ingesting fish with the toxin and can last for days, months or years. It is a well-recognized problem in the tropics. Avon Health Protection Team investigated food poisoning on a ship at Avonmouth, which was thought by the crew to be related to a white snapper fish from the Caribbean. The symptoms were initially thought to be scombroid fish poisoning but were consistent with ciguatera fish poisoning. Cases of fish poisoning from fish imported from the Caribbean and Pacific or travellers returning from tropical countries may be ciguatera fish poisoning, but mistakenly diagnosed as scombroid fish poisoning.

Something fishy: six patients with an unusual cause of food poisoning!

PubMed

Hall, Michael

2003-06-01

Scombroid fish poisoning is a clinical syndrome attributed to the ingestion of contaminated fish. A toxin or toxins, known as scombrotoxin, result from decomposition by endogenous flora of the amino acid histidine liberating bioactive amines, predominantly histamine. The presentation has features of histamine toxicity, typically with urticaria, flushing, headache, abdominal cramps, diarrhoea and vomiting. The course is usually mild and self-limiting. The author describes six cases of scombroid poisoning after ingestion of fish from the same Canberra restaurant. One case resulted in significant hypotension necessitating a prolonged stay in the ED.

Acute amaurotic epilepsy caused by lead poisoning in non-human primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zook, B.C.; Sauer, R.M.; Garner, F.M.

1972-09-15

Lead poisoning was diagnosed in all of 14 simian primates that died of acute amaurotic epilepsy at the National Zoological Park. Two primates from the Antwerp Zoo included in the original description of acute amaurotic epilepsy were also retrospectively found to have lead poisoning. Diagnosis was based on history, clinical signs, histologic brain lesions, available source of lead, acid-fast intranuclear inclusion bodies in renal and hepatic cells, and excess lead in liver specimens. It was concluded that acute amaurotic epilepsy should be considered a clinical syndrome of lead intoxication.

Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells

PubMed Central

FORTSON, WENDELL S.; KAYARTHODI, SHUBHALAXMI; FUJIMURA, YASUO; XU, HUALI; MATTHEWS, ROLAND; GRIZZLE, WILLIAM E.; RAO, VEENA N.; BHAT, GANAPATHY K.; REDDY, E. SHYAM P.

2012-01-01

An ETS family member, ETS Related Gene (ERG) is involved in the Ewing family of tumors as well as leukemias. Rearrangement of the ERG gene with the TMPRSS2 gene has been identified in the majority of prostate cancer patients. Additionally, overexpression of ERG is associated with un- favorable prognosis in prostate cancer patients similar to leukemia patients. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate transcription as well as epigenetic status of genes through acetylation of both histones and transcription factors. Deregulation of HATs and HDACs is frequently seen in various cancers, including prostate cancer. Many cellular oncogenes as well as tumor viral proteins are known to target either or both HATs and HDACs. Several studies have demonstrated that there are alterations of HDAC activity in prostate cancer cells. Recently, we found that ERG binds and inhibits HATs, which suggests that ERG is involved in deregulation of protein acetylation. Additionally, it has been shown that ERG is associated with a higher expression of HDACs. In this study, we tested the effect of the HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) on ERG-positive prostate cancer cells (VCaP). We found that VPA and TSA induce apoptosis, upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression and affect acetylation status of p53 in VCaP cells. These results suggest that HDAC inhibitors might restore HAT activity through two different ways: by inhibiting HDAC activity and by repressing HAT targeting oncoproteins such as ERG. PMID:21519790

Fermented corn flour poisoning in rural areas of China. III. Isolation and identification of main toxin produced by causal microorganisms.

PubMed

Hu, W J; Chen, X M; Meng, H D; Meng, Z H

1989-03-01

Flavotoxin A was isolated from Pseudomonas cocovenenans subsp. farinofermentans culture in semisolid potato-dextrose-agar medium, which was isolated from fermented corn meal that had caused food poisoning outbreaks in China. The isolation, purification, and chemical structure of this toxin were studied. The NMR spectra, the uv spectra, and molar extinction coefficients, and the mass spectra of Flavotoxin A are in good agreement with those reported for bongkrekic acid. Therefore, Flavotoxin A and bongkrekic acid are the same organic chemical compound; the molecular formula is C28H38O7. The oral LD50 of the purified Flavotoxin A in mice was 3.16 mg/kg (1.53-6.15 mg/kg). The existence of bongkrekic acid in toxic fermented corn samples collected during food poisoning outbreaks was also confirmed. It is concluded that bongkrekic acid has played an important role in the outbreaks of fermented corn poisoning.

Chemical poisoning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binns, W.

1956-01-01

The toxicity of a number of chemicals are discussed in relation to their effects on farm animals. Arsenic has been a common cause of accidental poisoning of animals because it often is used to kill insects, parasites, weeds and rodents. It may be acute or chronic, depending on the amount consumed. The common symptoms are loss of flesh; a bright-red coloration of the mucous membranes; digestive disturbance, irregular pulse, and depression. Livestock may be affected by excess amounts of fluorides. An excessive amount of F interferes with the normal calcification of the bones and teeth. Animals may get lead poisoningmore » by chewing or licking lead-painted objects, lead storage batteries, and discarded painting materials. Orchard sprays also contain lead compounds. Symptoms include inflammation of the mucous membranes, loss of appetite, diarrhea, grinding of teeth, and salivation. Lead may also affect the nervous system causing animals to walk in circles and run into objects because of blindness. Molybdenum poisoning may occur in animals that graze on forage plants containing excessive amounts of the element. Some of the symptoms of chronic molybdenum poisoning are profuse diarrhea, and general weakness. Nitrate poisoning may be produced by a number of plants and fertilizer. The symptoms include staggering gait, tremors, rapid breathing and marked dilation of pupils. Salt poisoning may occur from the excessive consumption of sodium chloride. Symptoms include hypersensitivity to touch, loss of appetite and loss of coordination. Selenium poisoning is caused by the ingestion of plants that have absorbed selenium from the soils. Symptoms include loss of hair and rough horns, long and deformed hoofs, and sloughing of hoofs.« less

Clinical Validation and Implications of Dried Blood Spot Sampling of Carbamazepine, Valproic Acid and Phenytoin in Patients with Epilepsy

PubMed Central

Kong, Sing Teang; Lim, Shih-Hui; Lee, Wee Beng; Kumar, Pasikanthi Kishore; Wang, Hwee Yi Stella; Ng, Yan Lam Shannon; Wong, Pei Shieen; Ho, Paul C.

2014-01-01

To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r = 0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT−1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs. PMID:25255292

Acute poisonings treated in hospitals in Oslo: a one-year prospective study (I): pattern of poisoning.

PubMed

Hovda, K E; Bjornaas, M A; Skog, K; Opdahl, A; Drottning, P; Ekeberg, O; Jacobsen, D

2008-01-01

Prospective design is mandatory to study pattern of poisoning and suicidal intention of patients. Prospective cross-sectional multi-center study of all patients contacting health care services because of acute poisoning during one year in Oslo, irrespective of intention. Data on the adult hospitalized patients (> or = 16 years) are presented here. Of a total of 3,775 such adult contacts (3,025 episodes), there were 947 (31 %) hospitalizations; annual incidence 1.9 (per 1,000) in males and 2.1 in females. Median age was 36 years (range 16-89); 54% females. Benzodiazepines (18%), ethanol (17%), paracetamol (12%), opioids (7%), and gamma hydroxybutyric acid (GHB) (7%) were most frequently taken. Patients stated suicidal intention in 29% of the admissions; physicians in 10%. Benzodiazepines and ethanol were the most common agents, but newer illicit drugs were frequent, especially GHB. Males often took ethanol and drugs of abuse; females often used prescription drugs with suicidal intention.

EPIDEMIOLOGY OF ACCIDENTAL POISONING

PubMed Central

Bissell, D. M.; McInnes, Robert S.

1960-01-01

In San Jose, California, studies of cases of accidental poisoning showed that the greatest hazard was to children 1 through 3 years of age. Drugs accounted for half the cases, household products for another third, and insecticides and rodenticides and others for the remainder. Most often poison material was within easy reach of the children. An analysis of families in which an accident occurred indicated that accidental poisoning might happen to any family. Since there was little after-effect of poisoning in cases in which treatment was obtained promptly, education directed toward getting prompt treatment seems most advisable. Community agencies interested in poison control need to focus their attention on parents of pre-school children. PMID:13801023

Advanced biotherapy for the treatment of sulfur mustard poisoning.

PubMed

Sun, Mingxue; Yang, Yuyan; Meng, Wenqi; Xu, Qingqiang; Lin, Fengwu; Chen, Yongchun; Zhao, Jie; Xiao, Kai

2018-04-25

Sulfur mustard (SM), a bifunctional alkylating agent, can react with a variety of biochemical molecules (DNA, RNA, proteins and other cell components) to cause a series of serious health issues or even death. Although a plethora of research has been done, the pathogenesis of SM poisoning has yet to be fully understood due to its high complexity. As a consequence, a specific antidote has not yet been developed and the treatment of SM poisoning remains a medical challenge. In recent years, various biological products and cell transplantation in the treatment of SM poisoning offered a significant clinical treatment progress. By highlighting these and other research studies, we hereby summarize the progress in this field in an effort to provide useful information on the clinical treatment of SM poisoning. This review summarizes the major advances of SM poisoning therapy by means of biological products (peptide and protein drugs, polysaccharides drugs, nucleic acid drugs, etc.), and cell transplantation (e.g., bone marrow, limbal stem cells, mesenchymal stem cells), as well as other relevant biotherapeutic approaches. We searched the database PubMed for published domestic and international articles using web based resources for information on histological, immunochemical, ultrastructural, and treatment features of SM-induced manifestations in both animal models and human tissues. To this end, we applied keywords containing mustard gas, chemical warfare, SM, eye, lung and skin. Our review provides a comprehensive understanding of the advances of available biotherapies in SM poisoning, and its potential for the treatment of SM-induced injuries. Potentially, our review will provide new insights for future research studies in this field. Copyright © 2018. Published by Elsevier B.V.

Pick your poison: what's new in poison control for the preschooler.

PubMed

Glenn, Lauren

2015-01-01

Accidental childhood poisonings are a major public health concern despite many efforts to alleviate this problem. While the rate of pediatric fatalities due to poisonings have decreased over the last two decades, poison control centers around the US have collectively fielded over one million calls with regard to toxic exposures in the preschool age group. According to the American Association of Poison Control Centers nearly half of all human exposures reported last year involved children under six. By focusing poison prevention efforts on the preschooler, we can attempt to decrease morbidity and mortality in the most vulnerable age group affected. Although the subject is still prevalent, current discussion on this topic is limited. Newer literature discusses past initiatives such as child resistant packaging and sticker deterrent programs and addresses their efficacy. This article revisits older mechanisms of prevention as well as the science behind the human motivation to change one's own practice and behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Plant poisons: their occurrence, biochemistry and physiological properties.

PubMed

Vickery, Margaret

2010-01-01

Plants produce poisons as a defence against predators. Many of these substances are biosynthesised from non-protein amino acids by biosynthetic pathways which have been deduced from the results of isotopic tracer analysis. These secondary metabolites have been used by humans over thousands of years, both as drugs and as agents to kill animals and commit homicide.

Mildew remover poisoning

MedlinePlus

Poisonous ingredients include: Detergents Hydrogen peroxide Sodium hypochlorite Sodium perborate Sodium percarbonate ... for recovery. Swallowing such poisons can have severe effects on many parts of the body. The ultimate ...

Plant fertilizer poisoning

MedlinePlus

Plant fertilizers and household plant foods are used to improve plant growth. Poisoning can occur if someone swallows these products. Plant fertilizers are mildly poisonous if small amounts are swallowed. ...

Lead Poisoning in Childhood.

ERIC Educational Resources Information Center

Pueschel, Siegfried M., Ed.; Linakis, James G., Ed.; Anderson, Angela C., Ed.

The magnitude of childhood lead poisoning has been inexplicably neglected by modern medicine and by legislators. However, since the 1970s, increased attention has been focused on lead poisoning, and advances have been made in several areas, including understanding of the neurodevelopmental and behavioral ramifications of lead poisoning, and…

[Plant poisoning cases in Turkey].

PubMed

Oztekin-Mat, A

1994-01-01

In Turkey, the majority of the population live in rural areas where they use wild plants as food and medicine. The confusion of an edible plant with a poisonous one give rise to serious poisoning which may even result in death. The incidence of plant poisoning in Turkey is about 6% and especially high among children between ages of 2 and 11 living in rural areas. The number of species that cause poisoning is around twenty and Hyoscyamus niger (Solanaceae), Colchicum species (Liliaceae), Conium maculatum (Umbelliferae) and Prunus species (Rosaceae) are the most important. Mushroom poisoning is more frequent in spring and fall. The main reasons are their widespread usage as food and the inexperience of the gatherers in distinguishing the edibles from the poisonous. Amanita phalloides, A. verna, A. muscaria, A. pantherina are responsible for severe cases of poisoning.

Outpatient treatment of acute poisonings in Oslo: poisoning pattern, factors associated with hospitalization, and mortality

PubMed Central

2012-01-01

Background Most patients with acute poisoning are treated as outpatients worldwide. In Oslo, these patients are treated in a physician-led outpatient clinic with limited diagnostic and treatment resources, which reduces both the costs and emergency department overcrowding. We describe the poisoning patterns, treatment, mortality, factors associated with hospitalization and follow-up at this Emergency Medical Agency (EMA, "Oslo Legevakt"), and we evaluate the safety of this current practice. Methods All acute poisonings in adults (> or = 16 years) treated at the EMA during one year (April 2008 to April 2009) were included consecutively in an observational study design. The treating physicians completed a standardized form comprising information needed to address the study's aims. Multivariate logistic regression analysis was used to identify the factors associated with hospitalization. Results There were 2348 contacts for 1856 individuals; 1157 (62%) were male, and the median age was 34 years. The most frequent main toxic agents were ethanol (43%), opioids (22%) and CO or fire smoke (10%). The physicians classified 73% as accidental overdoses with substances of abuse taken for recreational purposes, 15% as other accidents (self-inflicted or other) and 11% as suicide attempts. Most (91%) patients were treated with observation only. The median observation time until discharge was 3.8 hours. No patient developed sequelae or died at the EMA. Seventeen per cent were hospitalized. Gamma-hydroxybutyric acid, respiratory depression, paracetamol, reduced consciousness and suicidal intention were factors associated with hospitalization. Forty-eight per cent were discharged without referral to follow-up. The one-month mortality was 0.6%. Of the nine deaths, five were by new accidental overdose with substances of abuse. Conclusions More than twice as many patients were treated at the EMA compared with all hospitals in Oslo. Despite more than a doubling of the annual number of

Hair straightener poisoning

MedlinePlus

... this page: //medlineplus.gov/ency/article/002706.htm Hair straightener poisoning To use the sharing features on this page, please enable JavaScript. Hair straightener poisoning occurs when someone swallows products that ...

Hair spray poisoning

MedlinePlus

... this page: //medlineplus.gov/ency/article/002705.htm Hair spray poisoning To use the sharing features on this page, please enable JavaScript. Hair spray poisoning occurs when someone breathes in (inhales) ...

Mercuric chloride poisoning

MedlinePlus

... page: //medlineplus.gov/ency/article/002474.htm Mercuric chloride poisoning To use the sharing features on this page, please enable JavaScript. Mercuric chloride is a very poisonous form of mercury. It ...

Self-Protection Mechanism of Hexagonal WO3-Based DeNOx Catalysts against Alkali Poisoning.

PubMed

Zheng, Li; Zhou, Meijuan; Huang, Zhiwei; Chen, Yaxin; Gao, Jiayi; Ma, Zhen; Chen, Jianmin; Tang, Xingfu

2016-11-01

A good catalyst for efficiently controlling NO x emissions often demands strong resistance against alkali poisoning. Although the traditional ion-exchange model, based on acid-base reactions of alkalis with Brønsted acid sites, has been established over the past two decades, it is difficult to be used as a guideline to develop such an alkali-resistant catalyst. Here we establish a self-protection mechanism of deNO x catalysts against alkali poisoning by systematically studying the intrinsic nature of alkali resistance of V 2 O 5 /HWO (HWO = hexagonal WO 3 ) that shows excellent resistance to alkali poisoning in selective catalytic reduction of NO x with NH 3 (SCR). Synchrotron X-ray diffraction and absorption spectroscopies demonstrate that V 2 O 5 /HWO has spatially separated catalytically active sites (CASs) and alkali-trapping sites (ATSs). During the SCR process, ATSs spontaneously trap alkali ions such as K + , even if alkali ions initially block CASs, thus releasing CASs to realize the self-protection against alkali poisoning. X-ray photoelectron spectra coupled with theoretical calculations indicate that the electronic interaction between the alkali ions and ATSs with an energy saving is the driving force of the self-protection. This work provides a strategy to design alkali-resistant deNO x catalysts.

Black-spot poison ivy.

PubMed

Schram, Sarah E; Willey, Andrea; Lee, Peter K; Bohjanen, Kimberly A; Warshaw, Erin M

2008-01-01

In black-spot poison ivy dermatitis, a black lacquerlike substance forms on the skin when poison ivy resin is exposed to air. Although the Toxicodendron group of plants is estimated to be the most common cause of allergic contact dermatitis in the United States, black-spot poison ivy dermatitis is relatively rare.

Lead poisoning: An overview

NASA Technical Reports Server (NTRS)

Gendel, Neil

1993-01-01

A problem that should be of great concern to all of us is the lead poisoning of children. First, I would like to present a short overview concerning the reasons everyone should care about lead poisoning, then discuss the history of lead poisoning, what is happening today across the country, and the future.

Poison Ivy Dermatitis

MedlinePlus

... Favorite Name: Category: Share: Yes No, Keep Private Poison Ivy Dermatitis Share | "Leaves of three - let it ... has a longer stem than the other two. Poison ivy clings to tree trunks and other vertical ...

Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

PubMed

Wei, Muyun; Mao, Shaowei; Lu, Guoliang; Li, Liang; Lan, Xiaopeng; Huang, Zhongxian; Chen, Yougen; Zhao, Miaoqing; Zhao, Yueran; Xia, Qinghua

2018-04-17

Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways. 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. VPA not only exhibits

Current approaches of the management of mercury poisoning: need of the hour

PubMed Central

2014-01-01

Mercury poisoning cases have been reported in many parts of the world, resulting in many deaths every year. Mercury compounds are classified in different chemical types such as elemental, inorganic and organic forms. Long term exposure to mercury compounds from different sources e.g. water, food, soil and air lead to toxic effects on cardiovascular, pulmonary, urinary, gastrointestinal, neurological systems and skin. Mercury level can be measured in plasma, urine, feces and hair samples. Urinary concentration is a good indicator of poisoning of elemental and inorganic mercury, but organic mercury (e.g. methyl mercury) can be detected easily in feces. Gold nanoparticles (AuNPs) are a rapid, cheap and sensitive method for detection of thymine bound mercuric ions. Silver nanoparticles are used as a sensitive detector of low concentration Hg2+ ions in homogeneous aqueous solutions. Besides supportive therapy, British anti lewisite, dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA. succimer) and dimercaptopropanesulfoxid acid (DMPS) are currently used as chelating agents in mercury poisoning. Natural biologic scavengers such as algae, azolla and other aquatic plants possess the ability to uptake mercury traces from the environment. PMID:24888360

Experience in estimating neutron poison worths

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiang, R.T.; Congdon, S.P.

1989-01-01

Gadolinia, {sup 135}Xe, {sup 149}Sm, control rod, and soluble boron are five neutron poisons that may appear in light water reactor assemblies. Reliable neutron poison worth estimation is useful for evaluating core operating strategies, fuel cycle economics, and reactor safety design. Based on physical presence, neutron poisons can be divided into two categories: local poisons and global poisons. Gadolinia and control rod are local poisons, and {sup 135}Xe, {sup 149}Sm, and soluble boron are global poisons. The first-order perturbation method is commonly used to estimate nuclide worths in fuel assemblies. It is well known, however, that the first-order perturbation methodmore » was developed for small perturbations, such as the perturbation due to weak absorbers, and that neutron poisons are not weak absorbers. The authors have developed an improved method to replace the first-order perturbation method, which yields very poor results, for estimating local poison worths. It has also been shown that the first-order perturbation method seems adequate to estimate worths for global poisons caused by flux compensation.« less

Cardiovascular Abnormalities in Carbon Monoxide Poisoning.

PubMed

Garg, Jalaj; Krishnamoorthy, Parasuram; Palaniswamy, Chandrasekar; Khera, Sahil; Ahmad, Hasan; Jain, Diwakar; Aronow, Wilbert S; Frishman, William H

Acute carbon monoxide (CO) poisoning is the most common cause of poisoning and poisoning-related death in the United States. It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death. Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias. Acute myocardial ischemia has also been reported from increased thrombogenicity due to CO poisoning. Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality. Carboxyhemoglobin (COHb) levels do not correlate well with the clinical severity of CO poisoning. Supplemental oxygen remains the cornerstone of therapy for CO poisoning. Hyperbaric oxygen therapy increases CO elimination and has been used with wide variability in patients with evidence of neurological and myocardial injury from CO poisoning, but its benefit in limiting or reversing cardiac injury is unknown. We present a comprehensive review of literature on cardiovascular manifestations of CO poisoning and propose a diagnostic algorithm for managing patients with CO poisoning.

Recreational phenethylamine poisonings reported to a French poison control center.

PubMed

Le Roux, Gaël; Bruneau, Chloé; Lelièvre, Bénédicte; Bretaudeau Deguigne, Marie; Turcant, Alain; Harry, Patrick; Boels, David

2015-09-01

Over the last decade, use of phenethylamines has become increasingly prevalent. This study aimed to describe typical aspects of phenethylamine poisoning in order to better inform patient care. Phenethylamine poisoning cases reported to the Poison Control Center of Angers, France, from January, 2007 to December, 2013 were examined. Clinical findings were examined in 105 patients, including phenethylamine used, symptoms and final outcome. Patients were predominantly male (80%), with mean age 26±8 years. MDMA (38%), amphetamine (18%) and methamphetamine (14%) were the most commonly reported. Synthetic cathinones (10%) and the 2C series (7%) were also found. Substances most commonly associated with phenethylamine poisoning were cannabis (27%), ethanol (20%) and cocaine (9%). The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. Of the cases, the Poison Severity Score was: null or low, 66%, moderate, 21%, severe or fatal, 13%. Of the patients, 77% received hospital care and 12.4% were admitted to an intensive care unit. Analytical confirmations were obtained for all severe cases. While 93% of patients recovered, there were 5 deaths and 2 patients presented with neurological sequelae. Phenethylamine poisonings may be severe in young and healthy individuals. Physicians, toxicologists and analysts should be aware of new phenethylamine consumption trends in order to inform management of patient care and to contribute to a more responsive drug policy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Suicide by poisoning in the Souss-Massa-Drâa region of Morocco].

PubMed

Mahir, Siham; Soulaymani, Abdelmajid; Hami, Hind; Mokhtari, Abdelrhani; Benali, Doha; Ouammi, Lahcen; Windy, Maria; Benchekh, Rachida Soulaymani

2013-01-01

Deliberate self-poisoning is a serious problem in Morocco, including in the Souss-Massa-Drâa region. However, our understanding of the problem of suicidal poisoning remains limited. This paper aims to describe the characteristics of patients, toxic substances and poisoning and to identify the risk factors influencing patient outcomes. A retrospective study was conducted of all cases of deliberate self-poisoning recorded between 1981 and 2007 by the Centre Anti-Poison et de Pharmacovigilance du Maroc. 1,130 cases of self-poisoning were identified. The mean age was 25 ± 10.1 years and the sex ratio was 0.4. Paraphenylenediamine was the most common cause of death (48 deaths), followed by hydrochloric acid (15 deaths). A close relationship was found between progression to healing and female adolescents and between progression to death and men in other age groups. The study also found that patients who used paraphenylenediamine were twelve times more likely to die (CI95%: 7.4%-19.2%) than those who used other substances. Patients with respiratory and cardiovascular conditions had a relative risk of 9.8 (CI95%: 6.3%-16%) and 3.6 (CI95%: 2.3%-5.7%). Of the 937 cases with known outcome, 89 died (9.5%).

Parathion poisoning of Mississippi kites in Oklahoma

USGS Publications Warehouse

Franson, J. Christian

1994-01-01

Parathion(phosphorothioic acid O, O-diethyl O-[4-nitrophenyl] ester) is a broad spectrum organophosphorus insecticide, used on a variety of crops and occasionally for mosquito control, and is highly toxic to birds (Smith 1987). Intentional poisoning with parathion is reported to have killed more than 8000 red-winged blackbirds (Agelaius phoeniceus), common grackles (Quiscalus quiscula), brown-headed cowbirds (Molothrus ater) and European starlings (Sturnus vulgaris) in two separate instances (Stone et al. 1984). Use of parathion on wheat fields has resulted in the mortality of about 1600 Canada geese (Branta canadensis) and other waterfowl in one instance (White et al. 1982) and about 200 Canada geese in another (Flickinger et al. 1991). More than 200 laughing gulls (Larus atricilla) died near cotton fields treated with parathion (White et al. 1979). Secondary poisoning of raptors resulting from the consumption of prey exposed to parathion, has been reported experimentally and in the field. Stone et al. (1984) found two dead red-tailed hawks (Buteo jamaicensis), a Cooper's hawk (Accipiter cooperii) and an American kestrel (Falco sparverius) that had fed on blackbirds killed by parathion. One of four American kestrels died after being fed cricket frogs (Acris crepitans) that had been exposed to 10ppm parathion for 96 hr (Fleming et al. 1982). The Mississippi kite (Ictinia mississippensis) is highly insectivorous (Brown and Amadon 1968) and is thus subject to secondary poisoning resulting from consumption of insects exposed to pesticides. I report here an instance of secondary parathion poisoning in wild Mississippi kites.

Poisoning first aid

MedlinePlus

... page: //medlineplus.gov/ency/article/007579.htm Poisoning first aid To use the sharing features on this page, ... burns Stupor Unconsciousness (coma) Unusual breath odor Weakness First Aid Seek immediate medical help. For poisoning by swallowing ...

Oxidative Metabolites of Curcumin Poison Human Type II Topoisomerases†

PubMed Central

Ketron, Adam C.; Gordon, Odaine N.; Schneider, Claus; Osheroff, Neil

2013-01-01

The polyphenol curcumin is the principal flavor and color component of the spice turmeric. Beyond its culinary uses, curcumin is believed to positively impact human health and displays antioxidant, anti-inflammatory, antibacterial, and chemopreventive properties. It also is in clinical trials as an anticancer agent. In aqueous solution at physiological pH, curcumin undergoes spontaneous autoxidation that is enhanced by oxidizing agents. The reaction proceeds through a series of quinone methide and other reactive intermediates to form a final dioxygenated bicyclopentadione product. Several naturally occurring polyphenols that can form quinones have been shown to act as topoisomerase II poisons (i.e., increase levels of topoisomerase II-mediated DNA cleavage). Because several of these compounds have chemopreventive properties, we determined the effects of curcumin, its oxidative metabolites, and structurally related degradation products (vanillin, ferulic acid, and feruloylmethane), on the DNA cleavage activities of human topoisomerase IIα and IIβ. Intermediates in the curcumin oxidation pathway increased DNA scission mediated by both enzymes ~4-5–fold. In contrast, curcumin and the bicyclopentadione, as well as vanillin, ferulic acid, and feruloylmethane, had no effect on DNA cleavage. As found for other quinone-based compounds, curcumin oxidation intermediates acted as redox-dependent (as opposed to interfacial) topoisomerase II poisons. Finally, under conditions that promote oxidation, the dietary spice turmeric enhanced topoisomerase II-mediated DNA cleavage. Thus, even within the more complex spice formulation, oxidized curcumin intermediates appear to function as topoisomerase II poisons. PMID:23253398

Treatment of toxicodendron dermatitis (poison ivy and poison oak).

PubMed

Guin, J D

2001-04-01

Toxicodendron dermatitis results from a reaction to an oil soluble oleoresin that is present in many parts of the poison ivy and poison oak plants. Prophylactic measures include avoidance, protective clothing, barrier creams and hyposensitization. Treatments include washing the area immediately with a solvent suitable for lipids and the use of anti-inflammatory agents, especially corticosteroids.

Jack-in-the-pulpit poisoning

MedlinePlus

... if known Time it was swallowed Amount swallowed Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

Development of water-phase derivatization followed by solid-phase microextraction and gas chromatography/mass spectrometry for fast determination of valproic acid in human plasma.

PubMed

Deng, Chunhui; Li, Ning; Ji, Jie; Yang, Bei; Duan, Gengli; Zhang, Xiangmin

2006-01-01

In this study, a simple, rapid, and sensitive method was developed and validated for the quantification of valproic acid (VPA), an antiepileptic drug, in human plasma, which was based on water-phase derivatization followed by headspace solid-phase microextraction (HS-SPME) and gas chromatography/mass spectrometry (GC/MS). In the proposed method, VPA in plasma was rapidly derivatized with a mixture of isobutyl chloroformate, ethanol and pyridine under mild conditions (room temperature, aqueous medium), and the VPA ethyl ester formed was headspace-extracted and simultaneously concentrated using the SPME technique. Finally, the analyte extracted on SPME fiber was analyzed by GC/MS. The experimental parameters and method validations were studied. The optimal conditions were obtained: PDMS fiber, stirring rate of 1100 rpm, sample temperature of 80 degrees C, extraction time of 20 min, NaCl concentration of 30%. The proposed method had a limit of quantification (0.3 microg/mL), good recovery (89-97%) and precision (RSD value less than 10%). Because the proposed method combined a rapid water-phase derivatization with a fast, simple and solvent-free sample extraction and concentration technique of SPME, the sample preparation time was less than 25 min. This much shortens the whole analysis time of VPA in plasma. The validated method has been successfully used to analyze VPA in human plasma samples for application in pharmacokinetic studies. All these results show that water-phase derivatization followed by HS-SPME and GC/MS is an alternative and powerful method for fast determination of VPA in biological fluids. Copyright 2006 John Wiley & Sons, Ltd.

Valproic acid exhibits different cell growth arrest effect in three HPV-positive/negative cervical cancer cells and possibly via inducing Notch1 cleavage and E6 downregulation.

PubMed

Feng, Shuyu; Yang, Yue; Lv, Jingyi; Sun, Lichun; Liu, Mingqiu

2016-07-01

We investigated the effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of VPA-induced growth inhibition on three cervical cancer cell lines with different molecular and genetic background. We found that VPA induced proliferation suppression, cell apoptosis and cell cycle arrest in all tested cell lines, with an increase of Notch1 active form ICN1 as a tumor suppressor and its target gene HES1. Noteworthy, blocking of Notch signaling with DAPT resulted in growth inhibition in ICN1-overexpressing CaSki and HT-3 cells. Thus, endogenous Notch signaling may be necessary for survival of ICN1-overexpressing cervical cancer cell lines. Furthermore, G1 phase arrest was induced in HeLa and CaSki cells by VPA while G2 phase arrest was induced in HT-3 cells, suggesting different mechanism in this cycle arrest. We also found VPA suppressed oncogene E6 in a Notch-independent manner, and induced significant apoptosis in E6-overexpressing HPV positive CaSki cells. Cell morphological change was also observed in HeLa and HT-3 cell lines after VPA treatment with an upregulation of EMT transcription factor Snail1. Notch signaling inhibitor DAPT partly reversed VPA-induced Snail1 upregulation in HeLa cells. This discovery supports that VPA may induce EMT at least partly via Notch activation.

Look what I found! Poison hunting on eBay.

PubMed

Cantrell, F Lee

2005-01-01

Many substances deemed too dangerous for commercial use are still available to the general public. The purchase of these substances may potentially place members of the general public at risk for serious poisonings. This study was designed to document the large variety of dangerous poisons readily available on a popular online auction Web site. Methods. Over a 10-month period, the online auction Web site eBays was searched daily using the terms "poison" and "contents." Product name, active ingredients, what form the product is in, amount in container, and relative toxicity rating (Clinical Toxicology of Commercial Products, Gosselin, et al.) were recorded. If available, pictures of the products were saved. One hundred twenty-one individual products were identified. Fifty-five were in solid/tablet form, 37 were powders, and 29 were liquids. Product containers were full for 56 items and partially full for 65. Twenty-four products contained ingredients rated as "supertoxic" and included strychnine (10), arsenic trioxide (8), cyanide (2) and nicotine, pilocarpine, phosphorus, powdered conium maculatum (1 each). Sixty-three products contained "extremely toxic" ingredients including thallium, picrotoxin, soluble barium, antimony, mercury, arsenates, podophyllin, fluoride, zinc phosphide, atropine, scopolamine, and plant extracts of gelsemium, aconite, larkspur, and croton. Twenty-one products contained "very toxic" ingredients including lead, copper, camphor, caffeine, theobromine, creosote, pyrogallic acid, sparteine, quinine, lindane, warfarin, phenol, and digitalis. The remaining 13 were "moderately-slightly toxic." While the viability of the labeled ingredients could not be verified, the transportation, handling, and potential utilization of these dangerous poisons by the general public could result in serious poisonings.

Bracken fern poisoning

USDA-ARS?s Scientific Manuscript database

Bracken fern (Pteridium aquilinum) is found throughout the world and enzootic hematuria, bright blindness, and bracken staggers. This chapter reviews the plant, the various poisoning syndrome that it produces, the current strategies to prevent poisoning, and recommended treatments....

American Association of Poison Control Centers

MedlinePlus

... all alerts right left NEW! Check out PoisonHelp.org Now there are two ways to get help ... AAPCC's new interactive online poison information tool, PoisonHelp.org. PoisonHelp.org Make your smartphone even smarter. Text " ...

[Electronic poison information management system].

PubMed

Kabata, Piotr; Waldman, Wojciech; Kaletha, Krystian; Sein Anand, Jacek

2013-01-01

We describe deployment of electronic toxicological information database in poison control center of Pomeranian Center of Toxicology. System was based on Google Apps technology, by Google Inc., using electronic, web-based forms and data tables. During first 6 months from system deployment, we used it to archive 1471 poisoning cases, prepare monthly poisoning reports and facilitate statistical analysis of data. Electronic database usage made Poison Center work much easier.

Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties.

PubMed

Gezginci-Oktayoglu, Selda; Turkyilmaz, Ismet Burcu; Ercin, Merve; Yanardag, Refiye; Bolkent, Sehnaz

2016-01-01

The aim of present study was to investigate the effect of vitamin U (vit U, S-methylmethionine) on oxidative stress, inflammation, and fibrosis within the context of valproic acid (VPA)-induced renal damage. In this study, female Sprague Dawley rats were randomly divided into four groups: Group I consisted of intact animals, group II was given vit U (50 mg/kg/day, by gavage), group III was given VPA (500 mg/kg/day, intraperitonally), and group IV was given VPA + vit U. The animals were treated by vit U 1 h prior to treatment with VPA every day for 15 days. The following results were obtained in vit U + VPA-treated rats: (i) the protective effect of vit U on renal damage was shown by a significant decrease in histopathological changes and an increase in Na(+)/K(+)-ATPase activity; (ii) anti-oxidant property of vit U was demonstrated by a decrease in malondialdehyde levels and xanthine oxidase activity and an increase in glutathione levels, catalase and superoxide dismutase activities; (iii) anti-inflammatory property of vit U was demonstrated by a decrease in tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1 levels, and adenosine deaminase activity; (iv) anti-fibrotic effect of vit U was shown by a decrease in transforming growth factor-β, collagen-1 levels, and arginase activity. Collectively, these data show that VPA is a promoter of inflammation, oxidative stress, and fibrosis which resulted in renal damage. Vit U can be proposed as a potential candidate for preventing renal damage which arose during the therapeutic usage of VPA.

Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism.

PubMed

Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen; Nyengaard, Jens R; Møller, Arne

2014-09-19

The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.

Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/daymore » over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.« less

Examination by EPR spectroscopy of free radicals in melanins isolated from A-375 cells exposed on valproic acid and cisplatin.

PubMed

Chodurek, Ewa; Zdybel, Magdalena; Pilawa, Barbara; Dzierzewicz, Zofia

2012-01-01

Drug binding by melanin biopolymers influence the effectiveness of the chemotherapy, radiotherapy and photodynamic therapy. Free radicals of melanins take part in formation of their complex with drugs. The aim of this work was to determine the effect of the two compounds: valproic acid (VPA) and cisplatin (CPT) on free radicals properties of melanin isolated from A-375 melanoma cells. Free radicals were examined by an X-band (9.3 GHz) electron paramagnetic resonance (EPR) spectroscopy. EPR spectra were measured for the model synthetic eumelanin - DOPA-melanin, the melanin isolated from the control A-375 cells and these cells treated by VPA, CPT and both VPA and CPT. For all the examined samples broad EPR lines (deltaBpp: 0.48-0.68 mT) with g-factors of 2.0045-2.0060 characteristic for o-semiquinone free radicals were observed. Free radicals concentrations (N) in the tested samples, g-factors, amplitudes (A), integral intensities (I) and linewidths (deltaBpp) of the EPR spectra, were analyzed. The EPR lines were homogeneously broadened. Continuous microwave saturation of the EPR spectra indicated that slow spin-lattice relaxation processes existed in all the tested melanin samples. The relatively slowest spin-lattice relaxation processes characterized melanin isolated from A-375 cells treated with both VPA and CPT. The changes of the EPR spectra with increasing microwave power in the range of 2.2-70 mW were evaluated. Free radicals concentrations in the melanin from A-375 cells were higher than in the synthetic DOPA-melanin. The strong increase of free radicals concentration in the melanin from A-375 cells was observed after their treating by VPA. CPT also caused the increase of free radicals concentrations in the examined natural melanin. The free radicals concentration in melanin isolated from A-375 cells treated with both VPA and CPT was slightly higher than those in melanin from the control cells.

A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

PubMed

Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

2015-03-01

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

Iatrogenic salt poisoning in captive sandhill cranes

USGS Publications Warehouse

Franson, J.C.; Sileo, L.; Fleming, W.J.

1981-01-01

Salt poisoning developed in captive sandhill cranes (Grus canadensis) when sea salt was added to normal drinking water to produce a sodium chloride concentration of 1%. Two of 18 cranes died and 2 were euthanatized when moribund. Muscle weakness, paresis, dyspnea, and depression were observed. Brain and serum sodium, serum uric acid,:and plasma osmolality values were abnormally high. Lesions were those of visceral gout, renal tubular necrosis, nephrosis, and skeletal muscle.necrosis.

Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons

PubMed Central

Jeitner, Thomas M.; Kalogiannis, Mike; Krasnikov, Boris F.; Gomlin, Irving; Peltier, Morgan R.; Moran, Graham R.

2016-01-01

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro. Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo. The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. PMID:27026709

Sweet clover poisoning

USDA-ARS?s Scientific Manuscript database

Sweet clover poisoning occurs when spoiled sweet clover (Melilotus officinalis and M. alva) hay or silage that contain dicumarol are consumed by livestock. This updated chapter is a succinct review of the clinical disease and pathologic lesions of poisoning. It also reviews current strategies and ...

Lead poisoning from an unexpected source in a 4-month-old infant.

PubMed

Shannon, M

1998-06-01

Childhood lead poisoning is characteristically a disease that occurs between the second and third years of life, generally resulting from the child's ingestion of lead-based paint or dust. However, lead poisoning may also appear in the first year of life. The case of a 4-month-old infant is reported in which the preparation of infant formula in a lead-soldered samovar (urn) resulted in venous blood lead levels as high as 46 microg/dl. The samovar had been brought into the United States by the parents while on a visit to Iran. The infant was placed on chelation therapy with parenteral CaNa2EDTA followed by oral meso-2,3-dimercaptosuccinic acid (DMSA) and d-penicillamine. This resulted in a rapid and substantial reduction in the blood lead level. Lead poisoning in infancy may have unusual etiologies such as in utero transmission of lead by lead-poisoned women. Because sources of lead poisoning in infancy may be unusual, a detailed environmental investigation may be necessary to identify the exact source. Children exposed to lead in the first 2 years of life have a special vulnerability to the neurotoxicity of lead, with the risk of enduring developmental handicaps. Continued public health initiatives to remove lead from the environment, in conjunction with routine lead screening of young children, will be key in meeting the goal of the Centers for Disease Control and Prevention to eliminate childhood lead poisoning by the year 2011.

Phosphorus poisoning in waterfowl

USGS Publications Warehouse

Coburn, D.R.; DeWitt, J.B.; Derby, J.V.; Ediger, E.

1950-01-01

Black ducks and mallards were found to be highly susceptible to phosphorus poisoning. 3 mg. of white phosphorus per kg. of body weight given in a single dose resulted in death of a black duck in 6 hours. Pathologic changes in both acute and chronic poisoning were studied. Data are presented showing that diagnosis can be made accurately by chemical analysis of stored tissues in cases of phosphorus poisoning.

Occupational poison ivy and oak dermatitis.

PubMed

Epstein, W L

1994-07-01

Among the growing and diverse groups of outdoor and environmental workers, poison ivy and poison oak continue to be the major cause of occupational contact dermatitis. This article reviews the practical and theoretic means to prevent poison ivy and poison oak dermatitis in workers occupationally exposed to these weeds.

Mortality due to poisoning in a developing agricultural country: trends over 20 years.

PubMed

Senanayake, N; Peiris, H

1995-10-01

The cause of death as recorded in 37,125 death certificates (DCs) issued in the Kandy District over 20 years at 5-year intervals beginning in 1967 were analysed to determine the trends in mortality caused by poisoning in the community. Poisoning accounted for 718 (19.3 per 1000) deaths, the highest number being in the third decade of life (41.9%). Male:female ratio was 3:1. The agent responsible for 77% of the deaths was pesticides. Acids and chemicals accounted for 6.9% of the deaths. Other poisons each contributing to less than 1% of the deaths were: plant poisons, food items, drugs, kerosine oil and alcohol. Nearly half the deaths had occurred outside the town area, at home or in small hospitals in the periphery. Mortality due to poisoning showed an increasing trend during the 20 years, from 11.8 to 43/1000 deaths, and this increase was most marked in the periphery, from 8/1000 to 70/1000. This increase paralleled the increase in suicide figures in the country. Our findings call for a shift in emphasis in public education towards first-aid management of intoxication. Health services of developing countries should provide appropriate resuscitative equipment, and ensure a regular supply of antidotes and other medication to all rural hospitals. Management of pesticide poisoning should be emphasised in the curricula for medical graduates, nurses, and paramedics.

Poisoning in Israel: annual report of the Israel Poison Information Center, 2012.

PubMed

Bentur, Yedidia; Lurie, Yael; Cahana, Alfred; Kovler, Nona; Bloom-Krasik, Anna; Gurevych, Bella; Klein-Schwartz, Wendy

2014-11-01

The Israel National Poison Information Center (IPIC), Rambam Health Care Campus, provides 24 hour telephone consultations in clinical toxicology as well as drug and teratogen information. It participates in research, teaching and regulatory activities, and also provides laboratory services. To report data on the epidemiology of poisonings and poison exposures in Israel. We made computerized queries and descriptive analyses of the medical records database of the IPIC during 2012. A total of 31,519 poison exposure cases were recorded, a 157.6% increase compared with 1995. Children < 6 years of age were involved in 43.1% of cases; 74.0% of calls were made by the public and 23.7% by physicians; 74.8% of exposures were unintentional and 9.1% intentional. Chemicals were involved in 35.8% of all cases (single and multiple substances), pharmaceuticals in 48.8%, bites and stings in 3.8%, and plants and mushrooms in 1.6%. Substances most frequently involved were analgesics, cleaning products and antimicrobials. Clinical severity was moderate/major in 3.4%. Substances most frequently involved in moderate/major exposures were corrosives, insecticides and snake venom. Four fatalities were recorded; all were intentional exposures in adults (corrosive, medications, energy drink). Poison exposures and poisonings have increased significantly and have contributed substantially to morbidity and mortality in Israel. The IPIC database is a valuable national resource for the collection and monitoring of poisoning exposure cases. It can be used as a real-time surveillance system for the benefit of public health. It is recommended that reporting to the IPIC become mandatory and its activities be adequately supported by national resources.

What is the definition of a poisoning?

PubMed

Uges, D R

2001-03-01

New insights in medicine and acceptable treatments necessitates an adjustment of the existing definition of clinical or forensic poisoning to: 'An individual's medical or social unacceptable condition as a consequence of being under influence of an exogenous substance in a dose too high for the person concerned'. For medical and legal purposes it is important to know how the victim became poisoned. In general, there are three ways of causing medical poisoning: accidental poisoning, including iatrogenic poisoning, experimental and intentional poisoning. Nowadays iatrogenic intoxication, poisoning caused by the Münchhausen's syndrome (by proxy) and experimental poisoning (designer drugs) have a major place in contemporary toxicology. Although some toxicologists use the word 'intoxication' only overdoses with central effects, in this article 'intoxication' and 'poisoning' are considered to be synonymous.

Histamine fish poisoning revisited.

PubMed

Lehane, L; Olley, J

2000-06-30

Histamine (or scombroid) fish poisoning (HFP) is reviewed in a risk-assessment framework in an attempt to arrive at an informed characterisation of risk. Histamine is the main toxin involved in HFP, but the disease is not uncomplicated histamine poisoning. Although it is generally associated with high levels of histamine (> or =50 mg/100 g) in bacterially contaminated fish of particular species, the pathogenesis of HFP has not been clearly elucidated. Various hypotheses have been put forward to explain why histamine consumed in spoiled fish is more toxic than pure histamine taken orally, but none has proved totally satisfactory. Urocanic acid, like histamine, an imidazole compound derived from histidine in spoiling fish, may be the "missing factor" in HFP. cis-Urocanic acid has recently been recognised as a mast cell degranulator, and endogenous histamine from mast cell degranulation may augment the exogenous histamine consumed in spoiled fish. HFP is a mild disease, but is important in relation to food safety and international trade. Consumers are becoming more demanding, and litigation following food poisoning incidents is becoming more common. Producers, distributors and restaurants are increasingly held liable for the quality of the products they handle and sell. Many countries have set guidelines for maximum permitted levels of histamine in fish. However, histamine concentrations within a spoiled fish are extremely variable, as is the threshold toxic dose. Until the identity, levels and potency of possible potentiators and/or mast-cell-degranulating factors are elucidated, it is difficult to establish regulatory limits for histamine in foods on the basis of potential health hazard. Histidine decarboxylating bacteria produce histamine from free histidine in spoiling fish. Although some are present in the normal microbial flora of live fish, most seem to be derived from post-catching contamination on board fishing vessels, at the processing plant or in the

Poison prevention practices and medically attended poisoning in young children: multicentre case-control study.

PubMed

Kendrick, Denise; Majsak-Newman, Gosia; Benford, Penny; Coupland, Carol; Timblin, Clare; Hayes, Mike; Goodenough, Trudy; Hawkins, Adrian; Reading, Richard

2017-04-01

Childhood poisonings are common, placing a substantial burden on health services. Case-control studies have found inconsistent evidence about modifiable risk factors for poisonings among children aged 0-4 years. This study quantifies associations between poison prevention practices and medically attended poisonings in children aged 0-4 years. Multicentre case-control study conducted at hospitals, minor injury units and family practices from four study centres in England between 2010 and 2013. Participants comprised 567 children presenting with unintentional poisoning occurring at home and 2320 community control participants matched on age, sex, date of event and study centre. Parents/caregivers provided data on safety practices, safety equipment use, home hazards and potential confounders by means of self-completion questionnaires. Data were analysed using conditional logistic regression. Compared with community controls, parents of poisoned children were significantly more likely not to store medicines out of reach (adjusted OR (AOR) 1.59; 95% CI 1.21 to 2.09; population attributable fraction (PAF) 15%), not to store medicines safely (locked or out of reach (AOR 1.83; 95% CI 1.38 to 2.42; PAF 16%) and not to have put all medicines (AOR 2.11; 95% CI 1.54 to 2.90; PAF 20%) or household products (AOR 1.79, 95% CI 1.29 to 2.48; PAF 11%) away immediately after use. Not storing medicines out of reach or locked away and not putting medicines and household products away immediately after use increased the odds of secondary care attended poisonings in children aged 0-4 years. If associations are causal, implementing these poison prevention practices could each prevent between 11% and 20% of poisonings. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Poison Ivy Rash

MedlinePlus

... Poison ivy rash is a type of allergic contact dermatitis caused by an oily resin called urushiol. It's ... so can help reduce the severity of the rash. If you think your pet may be ... think you've come into contact with poison ivy, wash your clothing promptly with ...

Effect of Na poisoning catalyst (V2O5-WO3/TiO2) on denitration process and SO3 formation

NASA Astrophysics Data System (ADS)

Xiao, Haiping; Chen, Yu; Qi, Cong; Ru, Yu

2018-03-01

This paper aims to study the effect of alkali metal sodium (Na) poisoning on the performance of the Selective Catalytic Reduction (SCR) catalyst. The result showed that Na2SO4 poisoning leads to a reduced denitration rate of the SCR catalyst and an increase in the SO3 generation rate. Na2O poisoning leads to a significant reduction in the denitration rate of the SCR catalyst and marginally improves the formation of SO3. The maximum of the SO3 generation rate for a Na2SO4-poisoned catalyst reached 1.35%, whereas it was only 0.85% for the SCR catalyst. When the SO2 was contained in flue gas, the denitration rate for the Na2O-poisoned catalyst clearly increased by more than 28%. However, the effect of SO2 on the Na2SO4-poisoned catalyst was very slight. The denitration rate of the SCR catalyst decreased with an increase in the Na content. The BET and XRD results showed that Na poisoning of the catalyst decreased the number of acid sites, the reducibility of the catalyst, the surface area, and pore volume. The H2-TPR and NH3-TPD results show that Na decreases the number of acid sites and the reducibility of the catalyst. The FT-IR and XPS results showed that Na2O poisoning led to the decrease of V5+dbnd O bonds and the consumptions of oxygen atoms. Na2SO4 poisoning can improve surface adsorbed oxygen, which was beneficial for the SO2-SO3 conversion reaction.

EPR studies of free radicals in A-2058 human melanoma cells treated by valproic acid and 5,7-dimethoxycoumarin.

PubMed

Zdybel, Magdalena; Chodurek, Ewa; Pilawa, Barbara

2014-01-01

Free radicals in A-2058 human melanoma cells were studied by the use of electron paramagnetic resonance (EPR) spectroscopy. The aim of this work was to determine the changes in relative free radical concentrations in tumor A-2058 cells after treatment by valproic acid (VPA) and 5,7-dimethoxycoumarin (DMC). The influences of VPA and DMC on free radicals in A-2058 cells were compared with those for human melanoma malignum A-375 and G-361 cells, which were tested by us earlier. Human malignant melanoma A-2058 cells were exposed to interactions with VPA, DMC, and both VPA and DMC. The tumor cells A-2058 were purchased from LGC Standards (Lomianki, Poland), and they were grown in the standard conditions: at 37°C and in an atmosphere containing 95% air and 5% CO2, in the Minimum Essential Medium Eagle (MEM, Sigma-Aldrich). The A-2058 cells were incubated with VPA (1 mM) and DMC (10 μM) for 4 days. The first-derivative EPR spectra of the control A-2058 cells, and the cells treated with VPA, DMC, and both VPA and DMC, were measured by the electron paramagnetic resonance spectrometer of Radiopan (Poznań, Poland) with microwaves from an X-band (9.3 GHz). The parameters of the EPR lines: amplitudes (A), integral intensities (I), line widths (ΔBpp), and g-factors, were analyzed. The changes of amplitudes and line widths with microwave power increasing from 2.2 to 70 mW were drawn evaluated, o-Semiquinone free radicals of melanin biopolymer are mainly responsible for the EPR lines of A-2058 melanoma malignum cells. The amounts of free radicals in A-2058 cells treated with VPA, and both VPA and DMC, were lower than in the untreated control cells. Application of the tested substances (VPA, and both VPA and DMC) as the antitumor compounds was discussed. DMC without VPA did not decrease free radicals concentration in A-2058 cells. The studies con-firmed that EPR spectroscopy may be used to examine interactions of free radicals with antitumor compounds.

GLC analysis of poison ivy and poison oak urushiol components in vegetable oil preparations.

PubMed

Elsohly, M A; Turner, C E

1980-05-01

A procedure is described for the analysis of urushiol content of pharmaceutical preparations containing extracts of poison ivy (Toxicodendron radicans) and poison oak (T. diversilobum) in vegetable oils. The procedure involves extraction of the urushiols from the oily solutions using 90% methanol in water followed by GLC analysis of the extracts. Recoveries of both poison ivy and poison oak urushiols from solutions in corn oil, olive oil, sesame seed oil, and cottonseed oil were calculated. Correlation coefficients (r2) ranged from 0.97 to 1.00, and the coefficients of variations ranged from 3.08 to 7.90%.

49 CFR 172.554 - POISON placard.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false POISON placard. 172.554 Section 172.554... SECURITY PLANS Placarding § 172.554 POISON placard. (a) Except for size and color, the POISON placard must be as follows: EC02MR91.057 (b) In addition to complying with § 172.519, the background on the POISON...

49 CFR 172.430 - POISON label.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false POISON label. 172.430 Section 172.430... SECURITY PLANS Labeling § 172.430 POISON label. (a) Except for size and color, the POISON label must be as follows: EC02MR91.029 (b) In addition to complying with § 172.407, the background on the POISON label must...

49 CFR 172.430 - POISON label.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false POISON label. 172.430 Section 172.430... SECURITY PLANS Labeling § 172.430 POISON label. (a) Except for size and color, the POISON label must be as follows: EC02MR91.029 (b) In addition to complying with § 172.407, the background on the POISON label must...

49 CFR 172.554 - POISON placard.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false POISON placard. 172.554 Section 172.554... SECURITY PLANS Placarding § 172.554 POISON placard. (a) Except for size and color, the POISON placard must be as follows: EC02MR91.057 (b) In addition to complying with § 172.519, the background on the POISON...

49 CFR 172.554 - POISON placard.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false POISON placard. 172.554 Section 172.554... SECURITY PLANS Placarding § 172.554 POISON placard. (a) Except for size and color, the POISON placard must be as follows: EC02MR91.057 (b) In addition to complying with § 172.519, the background on the POISON...

49 CFR 172.554 - POISON placard.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false POISON placard. 172.554 Section 172.554... SECURITY PLANS Placarding § 172.554 POISON placard. (a) Except for size and color, the POISON placard must be as follows: EC02MR91.057 (b) In addition to complying with § 172.519, the background on the POISON...

49 CFR 172.430 - POISON label.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false POISON label. 172.430 Section 172.430... SECURITY PLANS Labeling § 172.430 POISON label. (a) Except for size and color, the POISON label must be as follows: EC02MR91.029 (b) In addition to complying with § 172.407, the background on the POISON label must...

49 CFR 172.554 - POISON placard.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false POISON placard. 172.554 Section 172.554... SECURITY PLANS Placarding § 172.554 POISON placard. (a) Except for size and color, the POISON placard must be as follows: EC02MR91.057 (b) In addition to complying with § 172.519, the background on the POISON...

49 CFR 172.430 - POISON label.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false POISON label. 172.430 Section 172.430... SECURITY PLANS Labeling § 172.430 POISON label. (a) Except for size and color, the POISON label must be as follows: EC02MR91.029 (b) In addition to complying with § 172.407, the background on the POISON label must...

49 CFR 172.430 - POISON label.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false POISON label. 172.430 Section 172.430... SECURITY PLANS Labeling § 172.430 POISON label. (a) Except for size and color, the POISON label must be as follows: EC02MR91.029 (b) In addition to complying with § 172.407, the background on the POISON label must...

Lead Poisoning at an Indoor Firing Range.

PubMed

Kang, Kyung Wook; Park, Won Ju

2017-10-01

In March 2014, a 39-year-old Korean male presented with a 6-month history of various nonspecific symptoms including dizziness, fatigue, asthenia, irritability, elevated blood pressure, palpitation, eyestrain, and tinnitus. His occupational history revealed that he had been working as an indoor firing range manager for 13 months; therefore, he was subjected to a blood lead level (BLL) test. The test results showed a BLL of 64 μg/dL; hence, he was diagnosed with lead poisoning and immediately withdrawn from work. As evident from the workplace environmental monitoring, the level of lead exposure in the air exceeded its limit (0.015-0.387 mg/m³). He received chelation treatment with calcium-disodium ethylenediaminetetraacetic acid (1 g/day) for 5 days without any adverse effects. In the follow-up results after 2 months, the BLL had decreased to 9.7 μg/dL and the symptoms resolved. This report represents the first occupational case of lead poisoning in firing ranges in Korea, and this necessitates institutional management to prevent the recurrence of poisoning through this route. Workplace environmental monitoring should be implemented for indoor firing ranges, and the workers should undergo regularly scheduled special health examinations. In clinical practice, it is essential to question the patient about his occupational history. © 2017 The Korean Academy of Medical Sciences.

Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats.

PubMed

Kumar, Hariom; Sharma, Bhupesh

2016-06-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, commonly characterized by altered social behavior, communication, biochemistry and pathological conditions. One percent of the worldwide population suffers from autism and males suffer more than females. NMDA receptors have the important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. This study has been designed to investigate the role of memantine, a NMDA receptor modulator, in prenatal valproic acid-induced autism in rats. Animals with prenatal valproic acid have shown the reduction in social interaction (three-chamber social behavior apparatus), spontaneous alternation (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, prenatal valproic acid-treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood-brain barrier permeability. Treatment with memantine has significantly attenuated prenatal valproic acid-induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, memantine has also attenuated the prenatal valproic acid-induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood-brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behavior, biochemistry and blood-brain barrier impairment in animals, which were significantly attenuated by memantine. NMDA receptor modulators like memantine should be explored further for the therapeutic

A bedside test for methaemoglobinemia improved antidote use in propanil poisoning.

PubMed

Shihana, Fathima; Dawson, Andrew H; Dobbins, Timothy; Dissanayake, Dhammika; Buckley, Nicholas A

2016-08-01

In 2008, self-poisoning with the herbicide propanil had a case-fatality of around 11% in Sri Lanka. A simple quantitative methaemoglobinemia bedside test was developed so that treatment could be titrated according to the methaemoglobin level. To determine whether the new method influenced patient management and changed the case fatality of propanil self-poisoning. The bedside test (using an inexpensive validated colour chart) was introduced in three hospitals (Anuradhapura, Polonnaruwa and Galle) in Sri Lanka from 2008. Junior ward staff were given a brief training on how to use the chart for quantitative estimation of methaemoglobin in patients with propanil poisoning and utilize the results in the context of the national treatment guidelines for propanil poisoning. It was taught that the bedside test should be done repeatedly from admission until it showed consistently low values of methaemoglobin. Treatment with the antidote methylene blue was suggested for patients whose methaemoglobin was greater than 20%. Limited clinical data on poisoning have been prospectively collected from these hospitals from 2003. The case-fatality and management before and after the change were compared with data up to December 2014. The case-fatality decreased from (38/401) 9.5% to (8/262) 3.1% [difference: -6.4%, 95% CI: -10 to -3]. Methylene blue use increased from under 10% of patients before to 55% of patients after the intervention. More patients received repeat doses and infusions, and few received ascorbic acid and exchange transfusion. The simple bedside test for methaemoglobinemia was readily adopted into routine practice and led to large changes in management. A substantial reduction in mortality from propanil poisoning occurred after this intervention.

Dermoscopy of black-spot poison ivy.

PubMed

Rader, Ryan K; Mu, Ruipu; Shi, Honglan; Stoecker, William V; Hinton, Kristen A

2012-10-15

Black-spot poison ivy is an uncommon presentation of poison ivy (Toxicodendron) allergic contact dermatitis. A 78-year-old sought evaluation of a black spot present on her right hand amid pruritic vesicles. The presentation of a black spot on the skin in a clinical context suggesting poison ivy is indicative of black-spot poison ivy. Dermoscopy revealed a jagged, centrally homogeneous, dark brown lesion with a red rim. A skin sample was obtained and compared against a poison ivy standard using ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS). This finding confirmed the presence of multiple urushiol congeners in the skin sample. Black-spot poison ivy may be added to the list of diagnoses that show a specific dermoscopic pattern.

Scombroid Poisoning: A Practical Approach.

PubMed

Guergué-Díaz de Cerio, O; Barrutia-Borque, A; Gardeazabal-García, J

2016-09-01

Scombroid poisoning is a common cause of food poisoning worldwide. It is caused by ingestion of oily fish contaminated with bacteria that trigger the formation of high concentrations of histamine. Scombroid poisoning manifests mainly as a skin complaint (flushing that spreads downward and/or an erythematous urticarial rash affecting the face and upper trunk). Although the clinical course is usually self-limiting and benign, vascular compromise, bronchospasm, and arrhythmias have been described. It is important to establish a differential diagnosis that includes conditions such as fish allergy. Oral antihistamines are the mainstay of treatment. Scombroid poisoning is best prevented by refrigerating fish properly. The practical review of scombroid poisoning provided here is intended for dermatologists. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Bubble bath soap poisoning

MedlinePlus

... medlineplus.gov/ency/article/002762.htm Bubble bath soap poisoning To use the sharing features on this page, please enable JavaScript. Bubble bath soap poisoning occurs when someone swallows bubble bath soap. ...

[Acute poisonings in Poland during the period 1997-1999. An analysis of files from the Krakow Poison Information Center].

PubMed

Kotwica, Małgorzata; Rogaczewska, Anna

2002-01-01

This work analyses the 1997-1999 data received from Polish poison units at Gdańsk, Kraków, Lublin, Łódź, Poznań, Rzeszów, Tarnów, Sosnowiec, Warszawa, Wrocław on patients hospitalised there and patients treated at other hospitals but consulted by specialists of those centres. The analysis shows that drugs constituted the most frequent cause of the poisonings (over 45% all poisonings). Poisonings with: alcohols accounted for 17.6%, gases (primarily by carbon monoxide) for 5.3%, pesticides for 4.5%, substances of abuse for 4.1%, and with organic solvents for 4.0% total poisonings. Suicidal poisonings constituted about 36% total poisonings, accidental over 25%, poisonings resulting for street-drugs and alcohol abuse over 23%, chemical emergency or fire 1%, while occupational poisonings constituted only 0.9% total poisonings. In 1997-1999, the highest numbers of deaths were recorded after intake of: drugs (102), ethylene glycol (39), alcohols (49, including 16 after intake of methanol and 33 after intake of ethanol), pesticides (15 deaths).

Lead poisoning from an unexpected source in a 4-month-old infant.

PubMed Central

Shannon, M

1998-01-01

Childhood lead poisoning is characteristically a disease that occurs between the second and third years of life, generally resulting from the child's ingestion of lead-based paint or dust. However, lead poisoning may also appear in the first year of life. The case of a 4-month-old infant is reported in which the preparation of infant formula in a lead-soldered samovar (urn) resulted in venous blood lead levels as high as 46 microg/dl. The samovar had been brought into the United States by the parents while on a visit to Iran. The infant was placed on chelation therapy with parenteral CaNa2EDTA followed by oral meso-2,3-dimercaptosuccinic acid (DMSA) and d-penicillamine. This resulted in a rapid and substantial reduction in the blood lead level. Lead poisoning in infancy may have unusual etiologies such as in utero transmission of lead by lead-poisoned women. Because sources of lead poisoning in infancy may be unusual, a detailed environmental investigation may be necessary to identify the exact source. Children exposed to lead in the first 2 years of life have a special vulnerability to the neurotoxicity of lead, with the risk of enduring developmental handicaps. Continued public health initiatives to remove lead from the environment, in conjunction with routine lead screening of young children, will be key in meeting the goal of the Centers for Disease Control and Prevention to eliminate childhood lead poisoning by the year 2011. Images Figure 1 PMID:9618346

Thermal stability and structural changes in bacterial toxins responsible for food poisoning

PubMed Central

Regenthal, Paulina; Hansen, Jesper S.; André, Ingemar

2017-01-01

The staphylococcal enterotoxins (SEs) are secreted by the bacteria Staphylococcus aureus and are the most common causative agent in staphylococcal food poisoning. The staphylococcal enterotoxin A (SEA) has been associated with large staphylococcal food poisoning outbreaks, but newer identified SEs, like staphylococcal enterotoxin H (SEH) has recently been shown to be present at similar levels as SEA in food poisoning outbreaks. Thus, we set out to investigate the thermo-stability of the three-dimensional structures of SEA, SEH and staphylococcal enterotoxin E (SEE), since heat inactivation is a common method to inactivate toxins during food processing. Interestingly, the investigated toxins behaved distinctly different upon heating. SEA and SEE were more stable at slightly acidic pH values, while SEH adopted an extremely stable structure at neutral pH, with almost no effects on secondary structural elements upon heating to 95°C, and with reversible formation of tertiary structure upon subsequent cooling to room temperature. Taken together, the data suggests that the family of staphylococcal enterotoxins have different ability to withstand heat, and thus the exact profile of heat inactivation for all SEs causing food poisoning needs to be considered to improve food safety. PMID:28207867

Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.

PubMed

Jeitner, Thomas M; Kalogiannis, Mike; Krasnikov, Boris F; Gomolin, Irving; Peltier, Morgan R; Moran, Graham R

2016-06-01

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Tips to Prevent Poisonings

MedlinePlus

... CDC: Prescription Drug Overdose Poison Help (Department of Health & Human Services) American Association of Poison Control Centers, Inc. ... 232-6348 Email CDC-INFO U.S. Department of Health & Human Services HHS/Open USA.gov Top

Poison exposures in young Israeli military personnel: a National Poison Center Data analysis.

PubMed

Lavon, Ophir; Bentur, Yedidia

2017-06-01

To characterize poison exposures in young Israeli military personnel as reported to the national poison center. Retrospective poison center chart review over a 14-year period. Cases included were Israeli soldiers aged 18-21 years, the compulsory military service age required by the Israeli law. 1770 records of poison exposures in young military personnel were identified. Most exposed individuals involved males (n = 1268, 71.6%). Main routes of exposure were ingestion (n = 854, 48.3%), inhalation (n = 328, 18.6%) and ocular (n = 211, 11.9%). Accidents or misuse (n = 712, 40.2%) were the most frequently reported circumstances, followed by suicide attempts (370, 20.9%), and bites and stings (161, 9.1%). More than half of the cases involved chemicals (n = 939, 53.1%); hydrocarbons, gases and corrosives were the main causative agents. Pharmaceuticals (mainly analgesics) were involved in 519 (29.3%) cases, venomous animals (mainly scorpions, centipedes, and snakes) in 79 (4.5%). Clinical manifestations were reported in 666 (37.6%) cases, mostly gastrointestinal, neurologic, and respiratory. The vast majority of cases (1634, 92.3%) were asymptomatic or mildly affected; no fatalities were recorded. In 831 (46.9%) cases the clinical toxicologist recommended referral to an emergency department; ambulatory observation was recommended in 563 (31.8%) cases, and hospitalization in 86 (4.9%). Our data show that poison exposures among young soldiers involve mainly males, accidents, misuse and suicides, oral route and chemicals; most exposures were asymptomatic or with mild severity. Repeated evaluations of poison center data pertaining to military personnel is advised for identifying trends in poison exposure and characteristics in this particular population.

Glycemic Status in Organophosphorus Poisoning.

PubMed

Panda, S; Nanda, R; Mangaraj, M; Rathod, P K; Mishra, P K

2015-01-01

Organophosphorus(OP) poisoning, in addition to its cholinergic manifestations shows metabolic derangements leading to hyperglycemia. Apart from inhibiting acetylcholinesterase it also induces oxidative stress to exhibit this manifestation. The present study aims to assess the glycemic status of OP poisoned patients and its association with various factors in OP poisoning like oxidative stress and dose of atropine. This is a prospective study which recruited 102 patients above 18 years of age with history of OP poisoning. They were categorized into 3 grades-mild, moderate and severe based on the Peradeniya Organophosphorus Poisining Scale. The routine biochemical parameters along with serum malondialdehyde (MDA) and cholinesterase were estimated in the study group. Hyperglycemia and glycosuria were observed, with majority cases of hyperglycemia (57%) noticed in the severe group. There was a rise in the random plasma glucose (RPG), serum malondialdehyde (MDA), total dose of atropine across the groups along with a fall in the serum cholinesterase with increase in severity of poisoning. The fall in plasma glucose at the time of discharge was significant in all three groups when compared to the admission random plasma glucose(RPG) level. This transient hyperglycemia exhibited a significant positive association with serum MDA and dose of atropine administered during treatment (p<0.05). Glycemic status in OP poisoning may play a role in identifying the severity of poisoning at the time of admission.

In-Situ Atomic Force Microscope Imaging of Calcite Etch Pit Morphology Changes in Undersaturated and 1-Hydroxyethylidene-1,1-diphosphonic Acid Poisoned Solutions

PubMed Central

Britt, David W.

2012-01-01

Morphology changes in etch pits formed on the (1014) cleavage plane of calcite were induced by varying the ratio of [Ca2+] to [CO32−] in the bulk solution as well as through the addition of the crystal poison 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP). Three distinct morphologies were noted: symmetric rhombic, asymmetric rhombic, and triangular with a rough curved hypotenuse. The latter represents a transient morphology which is only observed during the actual dissolution process, while the former morphologies persist after dissolution is halted. PMID:25125794

[The prevention and therapeutics effect of sodium bicarbonate with gastric lavage, atomization inhalation and intravenous injection on the patients with paraquat poisoning and pulmonary fibrosis induced by paraquat poisoning].

PubMed

Ren, Ainong; Ren, Siqing; Jian, Xiangdong; Zhang, Qing

2015-09-01

To observe the prevention effects of patients with lung exudation and pulmonary fibrosis induced by paraquat poisoning in sodium bicarbonate (SB) with gastric lavage, atomization inhalation and intravenous injection. To collect 38 patients with paraquat poisoning in hospital, after poison immediately with gastric lavage of 1.5% SB, and atomization inhalation of 5% SB 10~15 ml twice daily and intravenous injection of 5% SB twice a day, continuous application of 5~7 days. and the HRCT score and liver and kidney function was performed on patients with lung after treatment. And the extraction of 38 SB patients with previously untreated with SB for comparison. Lung HRCT average score in 72 h, 7 d, 30 d on patients with paraquat poisoning untreated with SB reached 2.87, 3.12, 2.13, HRCT display shows that the appearance of the wear glass shadow, grid shadow, honeycomb shadow, and other signs of fibrosis. Average HRCT reached 1.95, 2.20, 1.67 on patients treated with SB,signs of lung exudation and fibrosis was significantly reduced,compare two groups,there was statistically significance (P<0.01). And compared to the control group, activity of serum alanine aminotransferase (ALT) and aspartic acid transaminase (AST) decreased significantly in group of paraquat poisoning with triple application of SB, the level of serum urea nitrogen (BUN) and creatinine (Cr) significantly decreased, the difference is statistically significant (P<0.01). The triple application of SB can reduced the pulmonary fibrosis and effusion induced by paraquat poisoning,and protective effect on the function of liver and kidney is obvious, suggesting that the method for treatment of paraquat poisoning, prevention of paraquat lung and improve survival rate has the exact effect.

Cardiological aspects of carbon monoxide poisoning.

PubMed

Marchewka, Jakub; Gawlik, Iwona; Dębski, Grzegorz; Popiołek, Lech; Marchewka, Wojciech; Hydzik, Piotr

2017-01-01

The aim of this study was to assess cardiological manifestations of carbon monoxide (CO) poisoning. Background/introduction: Carbon monoxide intoxication is one of the most important toxicological causes of morbidity and mortality worldwide. Early clinical manifestation of CO poisoning is cardiotoxicity. We enrolled 75 patients (34 males and 41 females, mean age 37.6 ± 17.7 y/o) hospitalized due to CO poisoning. Laboratory tests including troponin I, blood pressure measurements, HR and electrocardiograms (ECG) were collected. Pach's scale scoring and grading system was used to establish severity of poisoning. Grade of poisoning is positively correlated with troponin I levels and systolic blood pressure. Moreover, troponin levels are significantly correlated with exposition time, lactates and are higher in tachycardiac, hypertensive and positive ECG subpopulations. COHb levels are indicative of exposure but do not correlate with grade of poisoning. The main cause of CO poisoning were bathroom heaters - 83%, only 11% of examined intoxicated population were equipped with CO detectors. Complex cardiological screening covering troponin levels, ECG, blood pressure and heart rate measurements as well as complete blood count with particular attention to platelet parameters should be performed in each case where CO intoxication is suspected. More emphasis on education on CO poisoning is needed.

Identification and treatment of poison ivy dermatitis.

PubMed

Briant, D; Brouder, G

1983-01-01

Poison ivy dermatitis is an acute self-limiting problem of two or three weeks' duration that can cause significant discomfort. Poison ivy, poison oak and poison sumac cause more cases of allergic contact dermatitis than all the other contact allergens combined. Treatment of poison ivy dermatitis depends on the severity of the reaction. The nurse practitioner can manage the majority of poison ivy cases. However, if there is systemic involvement, a physician consultation is necessary. The patient can best be assisted by assessing the severity of the dermatitis, prescribing an appropriate supportive therapy and teaching preventive measures.

Circumstances of Accidental Poisoning in Childhood

PubMed Central

Jackson, R. H.; Walker, J. H.; Wynne, N. A.

1968-01-01

Of 377 children with accidental poisoning, the commonest ages were 1, 2, and 3. The most important contributory factor was that the poison was kept in an inappropriate place. Most containers were closed, but the children found them easy to open. In some cases the container itself was unsuitable for the contents. The frequency of poisoning in childhood might be reduced in six main ways: (1) a reduction in the quantity of drugs kept in the home; (2) the provision of drug cupboards; (3) the provision of containers that are difficult for children to open, or individually foil-wrapping tablets; (4) making tablets less attractive to children; (5) clear identification of potential poisons; and (6) increasing parental awareness of the circumstances under which poisoning occurs. A plea is made for further sociomedical research into the prevention of poisoning. PMID:5682329

Childhood self-poisoning: a one-year review.

PubMed

Neilson, Z E; Morrison, W

2012-11-01

Self-poisoning in children is a serious health concern accounting for 2% and 5% of childhood deaths in the developed and developing world, respectively. Type of poison and intent varies between age groups, with alcohol poisoning becoming increasingly common in teenagers. The aim of the study was to identify the characteristics of paediatric self-poisoning at Ninewells Hospital, Dundee, as a function of age, sex, intent and type of poison. Data from patients under the age of 17 presenting to Ninewells Hospital's Emergency Department with self-poisoning from 1 December 2008 to 30 November 2009 inclusive were identified, classified and analysed using chi-square testing. Overall there was no significant difference in gender. However, females significantly dominated in the ≥12<17 years age group, with older females also significantly more likely to deliberately self-poison. Alcohol was the sole cause of accidental self-poisoning in this age group while paracetamol was used in the majority of cases of deliberate self-poisoning. In the <6 years age group, household chemical ingestion and over-the-counter medications were the most common poisons. The findings reflect previous published data and national trends. The prevalence of alcohol abuse in the ≥12<17 years age group is a major public health issue that must be addressed.

[Household gas poisonings].

PubMed

Maloca, Ivana; Macan, Jelena; Varnai, Veda Marija; Turk, Rajka

2006-12-01

Exposure to toxic gases which can induce serious health effects, can occur in the working as well as in general environment, including home. The severity of gas poisoning is determined by its physical and chemical characteristics, intensity and duration of exposure, and concomitant diseases and injuries in the poisoned person. Manifestations of gas toxic action involve simple asphyxia, local irritation of respiratory mucosa, systemic toxicity, and a combination of these mechanisms. This article describes the characteristics, modes of exposure and health effects of most common gases causing poisoning at home. These include gas fuels, carbon monoxide, ammonia, chlorine, and fire gases such as nitrogen and sulphur oxides, hydrogen cyanide and phosgene. First aid as well as preventive measures to avoid exposure to toxic gases and prevent fire at home are also given. The Croatian Poison Control Centre gathered data on toxic gas exposures in households between November 2005 and July 2006. During this period 30 persons (3 % of the total number of cases) were exposed to toxic gases at home, including carbon monoxide, irritating vapours from cleaning agents and disinfectants, gas fuels, septic tank gases, tear-gas, and chlorofluorocarbons from refrigerators.

[Three cases of scombroid poisoning].

PubMed

Harmelin, Y; Hubiche, T; Pharaon, M; Del Giudice, P

2018-01-01

Scombroid poisoning is a poorly known type of food poisoning due to the presence of histamine in spoiled fish of the Scombridae family. We report 3 cases of scombroid poisoning seen at the Fréjus-Saint-Raphaël hospital in the Var region. Within around thirty minutes of eating a meal containing tuna, three patients presented varied symptoms: malaise, itchy rash, headache, and for two of them, nausea. The diagnosis of scombroid poisoning was based on the circumstances in which the clinical signs appeared and on the signs themselves. The patients were given antihistamines and one injection of intravenous corticosteroids, and symptoms regressed rapidly within a few hours. The symptoms of scombroid poisoning appear within a few minutes after eating fish of the Scombridae family and related species. The first symptoms are cutaneous, with flush, pruritus, and erythema of the face and trunk having an urticarial appearance, together with faintness. Gastrointestinal symptoms include nausea, vomiting, abdominal cramps and occasionally diarrhea. Symptoms subside within a few hours. Histamine is present in the flesh of these fish due to decarboxylation of histidine through the action of Gram-negative bacteria whose development is enhanced by heat and sun. Scombroid poisoning is one of the most common types of poisoning caused by eating fish but it is underdiagnosed by dermatologists. The diagnosis is made by measuring histamine levels in the incriminated fish or in the patient's plasma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Scombroid Poisoning

PubMed Central

Lerke, Peter A.; Werner, S. Benson; Taylor, Stephen L.; Guthertz, Linda S.

1978-01-01

An outbreak of scombroid poisoning occurred in San Francisco in the fall of 1977. The vehicle was sashimi prepared from spoiled tuna fish. Prompt public health measures prevented further consumption of the implicated food. Laboratory studies showed the presence in the tuna of bacterial species capable of producing large amounts of histamine, a substance strongly implicated in scombroid poisoning. Chemical analysis showed that histamine is very unevenly distributed in the flesh of spoiling tuna, therefore accounting for the sometimes random occurrence of disease among people eating the same food at the same table. PMID:569397

Poisoning - fish and shellfish

MedlinePlus

... waters. Scombroid poisoning most often occurs from large, dark meat fish such as tuna, mackerel, mahi mahi, and albacore. Because this poison develops after a fish is caught and dies, it does not matter where the fish is caught. The main factor ...

Chronic boric acid poisoning in infants.

PubMed Central

O'Sullivan, K; Taylor, M

1983-01-01

We report 7 infants suffering from seizures induced by chronic boric acid ingestion. The boric acid was given by dipping a soother in a proprietary borax and honey mixture. The babies have remained well since the mixture was withheld. PMID:6625636

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

PubMed Central

Happold, Caroline; Gorlia, Thierry; Chinot, Olivier; Gilbert, Mark R.; Nabors, L. Burt; Wick, Wolfgang; Pugh, Stephanie L.; Hegi, Monika; Cloughesy, Timothy; Roth, Patrick; Reardon, David A.; Perry, James R.; Mehta, Minesh P.; Stupp, Roger

2016-01-01

Purpose Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma. Patients and Methods To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV). Results VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no

Heavy metal poisoning and concurrent septicemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singer, R.H.

1976-01-01

Poisoning occurring in animals caused by agents such as arsenic, lead, tin, and other necrotizing substances is often accompanied by a Clostridial septicemia. The toxins of the Clostridia involved bring about clinical signs and pathologic changes that differ considerably from those caused by the poisonous agent; thereby overshadowing those produced by the poison. The Clostridia involved most frequently are Clostridium septicum, sordelli, and novyi. Therapy in cases of poisoning by necrotizing substances should include measures to prevent possible Clostridial involvement.

Handbook of Common Poisonings in Children.

ERIC Educational Resources Information Center

Food and Drug Administration (DHEW), Washington, DC.

This handbook for physicians, emergency room personnel and pharmacists lists the manufacturer, description, toxicity, symptoms and findings, treatment, and references for 73 poison substances considered by the Subcommittee on Accidental Poisoning of the American Academy of Pediatrics to be most significant in terms of accidental poisoning of…

49 CFR 172.540 - POISON GAS placard.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false POISON GAS placard. 172.540 Section 172.540... SECURITY PLANS Placarding § 172.540 POISON GAS placard. (a) Except for size and color, the POISON GAS... the POISON GAS placard and the symbol must be white. The background of the upper diamond must be black...

49 CFR 172.540 - POISON GAS placard.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false POISON GAS placard. 172.540 Section 172.540... SECURITY PLANS Placarding § 172.540 POISON GAS placard. (a) Except for size and color, the POISON GAS... the POISON GAS placard and the symbol must be white. The background of the upper diamond must be black...

49 CFR 172.540 - POISON GAS placard.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false POISON GAS placard. 172.540 Section 172.540... SECURITY PLANS Placarding § 172.540 POISON GAS placard. (a) Except for size and color, the POISON GAS... the POISON GAS placard and the symbol must be white. The background of the upper diamond must be black...

49 CFR 172.540 - POISON GAS placard.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false POISON GAS placard. 172.540 Section 172.540... SECURITY PLANS Placarding § 172.540 POISON GAS placard. (a) Except for size and color, the POISON GAS... the POISON GAS placard and the symbol must be white. The background of the upper diamond must be black...

49 CFR 172.540 - POISON GAS placard.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false POISON GAS placard. 172.540 Section 172.540... SECURITY PLANS Placarding § 172.540 POISON GAS placard. (a) Except for size and color, the POISON GAS... the POISON GAS placard and the symbol must be white. The background of the upper diamond must be black...

Paracetamol (acetaminophen) pack size restrictions and poisoning severity: time trends in enquiries to a UK poisons centre.

PubMed

Morgan, O; Hawkins, L; Edwards, N; Dargan, P

2007-10-01

In September 1998, legislation was introduced in the United Kingdom to limit paracetamol pack sizes to 16 tablets of 500 mg at general sales outlets and 32 tablets of 500 mg at pharmacies. The effect of the regulations on severity of paracetamol poisoning is unclear. The aim of this study was to describe trends in the severity of paracetamol poisoning and to assess the impact of the 1998 Regulations on the enquiries to a UK poisons centre. We extracted data about the age, sex and number of tablets or capsules of paracetamol ingested by patients notified to Guy's and St Thomas' Poisons Unit (London, UK) between 1996 and 2004. During the study period, there were approximately 140 000 patients with suspected paracetamol poisoning, accounting for around 11% of all patients reported to the poisons unit. The median number of tablets fell from 25 to 20 for males and 20 to 16 for females after 1998. There was also a reduction in the proportion of patients who ingested 17-32 tablets (from 36% to 30%) and 33-100 tablets (from 25% to 19%). Following the 1998 Regulations there was a decline in the severity, but not frequency, of paracetamol poisoning cases reported to Guy's and St Thomas' Poisons Unit. It is unclear whether the decline in severity was a direct consequence of the regulations.

Common causes of poisoning: etiology, diagnosis and treatment.

PubMed

Müller, Dieter; Desel, Herbert

2013-10-01

In 2011, German hospitals treated approximately 205 000 patients suffering from acute poisoning. Change is seen over time both in the types of poisoning that occur and in the indications for specific treatment. This article is based on a selective review of the literature, with special attention to the health reports of the German federal government, the annual reports of the GIZ-Nord Poisons Center (the poison information center for the four northwestern states of Germany, i.e. Bremen, Hamburg, Lower Saxony and Schleswig-Holstein), and the recommendations of international medical associations. From 1996 to 2011, the GIZ-Nord Poisons Center answered more than 450 000 inquiries, most of which involved exposures to medical drugs, chemicals, plants, foods, or cosmetics. Poisoning was clinically manifest in only a fraction of these cases. Ethanol intoxication is the commonest type of acute poisoning and suicide by medical drug overdose is the commonest type of suicide by poisoning. Death from acute poisoning is most commonly the result of either smoke inhalation or illegal drug use. Severe poisoning is only rarely due to the ingestion of chemicals (particularly detergents and cleaning products), cosmetics, or plant matter. Medical procedures that are intended to reduce the absorption of a poison or enhance its elimination are now only rarely indicated. Antidotes (e.g., atropine, 4-dimethylaminophenol, naloxone, toluidine blue) are available for only a few kinds of poisoning. Randomized clinical trials of treatment have been carried out for only a few substances. Most exposures to poisons can be treated with general emergency care and, if necessary, with symptomatic intensive-care measures. Poison information centers help ensure that cases of poisoning are dealt with efficiently. The data they collect are a useful aid to toxicological assessment and can serve as a point of departure for research projects.

49 CFR 172.416 - POISON GAS label.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false POISON GAS label. 172.416 Section 172.416... SECURITY PLANS Labeling § 172.416 POISON GAS label. (a) Except for size and color, the POISON GAS label... POISON GAS label and the symbol must be white. The background of the upper diamond must be black and the...

49 CFR 172.416 - POISON GAS label.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false POISON GAS label. 172.416 Section 172.416... SECURITY PLANS Labeling § 172.416 POISON GAS label. (a) Except for size and color, the POISON GAS label... POISON GAS label and the symbol must be white. The background of the upper diamond must be black and the...

49 CFR 172.416 - POISON GAS label.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false POISON GAS label. 172.416 Section 172.416... SECURITY PLANS Labeling § 172.416 POISON GAS label. (a) Except for size and color, the POISON GAS label... POISON GAS label and the symbol must be white. The background of the upper diamond must be black and the...

49 CFR 172.416 - POISON GAS label.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false POISON GAS label. 172.416 Section 172.416... SECURITY PLANS Labeling § 172.416 POISON GAS label. (a) Except for size and color, the POISON GAS label... POISON GAS label and the symbol must be white. The background of the upper diamond must be black and the...

49 CFR 172.416 - POISON GAS label.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false POISON GAS label. 172.416 Section 172.416... SECURITY PLANS Labeling § 172.416 POISON GAS label. (a) Except for size and color, the POISON GAS label... POISON GAS label and the symbol must be white. The background of the upper diamond must be black and the...

Predictors of pesticide poisoning.

PubMed

Ferguson, J A; Sellar, C; McGuigan, M A

1991-01-01

The analysis of 1,026 reports of suspected pesticide poisonings to the regional Poison Control Centre at the Hospital for Sick Children, Toronto consisted of 597 (58.2%) cases less than six years of age. Age was the strongest predictor: there was a risk of 3.1 that young children would encounter rodenticide poisoning compared to that of insecticides; a ten-fold risk of having symptoms from pesticide poisoning if the victim was over five years of age; an increased risk of 5.9 of exposure to moderate or large amounts of pesticide, compared to small quantities, for those over five years of age; and there was less treatment referral for young children, and a 5.7 risk of being referred if the victim was over the age of five years. Other significant predictor variables include the type of person making the inquiry (lay or physician/nurse), the calendar season of the event, and the location (metropolitan or nonmetropolitan) of the event.

SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

PubMed

Swoboda, Kathryn J; Scott, Charles B; Crawford, Thomas O; Simard, Louise R; Reyna, Sandra P; Krosschell, Kristin J; Acsadi, Gyula; Elsheik, Bakri; Schroth, Mary K; D'Anjou, Guy; LaSalle, Bernard; Prior, Thomas W; Sorenson, Susan L; Maczulski, Jo Anne; Bromberg, Mark B; Chan, Gary M; Kissel, John T

2010-08-19

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should

Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.

PubMed

Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa; Leng, Yan; Liao, Hsiao-Mei; Maric, Dragan; Chuang, De-Maw

2016-07-01

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells

Childhood Lead Poisoning: Blueprint for Prevention.

ERIC Educational Resources Information Center

Rochow, K. W. James; Rapuano, Maria

Current programs to deal with childhood lead poisoning, the primary environmental disease of U.S. children, screen individual children, treat those with serious cases of lead poisoning, and subsequently return children to hazardous environments. This approach has led to repeated diagnoses of lead poisoning. This handbook is designed to convince…

Poison ivy dermatitis. Nuances in treatment.

PubMed

Williford, P M; Sheretz, E F

1994-02-01

Acute allergic contact dermatitis due to poison ivy or poison oak is a common presenting complaint in the practices of many primary care physicians. While the clinical features are well described, reported treatment regimens vary in both topical and systemic therapies. We review herein the variability of presenting morphologic features of the disease and common treatment regimens, with attention given to complications of therapy. We also comment on the correct botanical designation, incidence, and immune mechanisms of the disease state and review measures to avoid allergic contact dermatitis due to poison ivy and poison oak.

Lead Poisoning: A Need for Education.

ERIC Educational Resources Information Center

Lipnickey, Susan Cross

1981-01-01

Each year approximately 200 children die of lead poisoning. Especially vulnerable to the toxic effects of lead poisoning are the nervous system, kidneys, and the bones. Physiological effects of lead on the school-age child, screening processes, and roles of school personnel in dealing with suspected victims of lead poisoning are discussed. (JN)

National Poison Prevention Week Promotional Materials.

ERIC Educational Resources Information Center

Poison Prevention Week Council, Washington, DC.

This collection of materials for parents, early childhood workers, the elderly, and anyone in situations requiring safeguards against poisoning, spans the years 1993 and 1994 and is intended to promote National Poison Prevention Week. The materials included are: (1) the 31-page, illustrated report on National Poison Prevention Week for 1993,…

Chemical and Biological Summer Poisons

PubMed Central

Lees, Ronald E. M.

1972-01-01

Summer has its own special poisoning hazards for the vacationer, gardener or outdoorsman. Because of the comparative variety of accidental human poisonings from contact with these seasonal toxic substances, either artificial or natural, many family physicians are unfamiliar with their effects. Some of us, unfortunately, will be called upon to deal with them over the next few months. This article highlights some of the hazards, outlines their toxicology and summarizes the treatment of the poisoned patient. PMID:20468771

The epidemiology of childhood poisonings in Cyprus.

PubMed

Koliou, Maria; Ioannou, Chrystalla; Andreou, Kyriaki; Petridou, Alexandra; Soteriades, Elpidoforos Soterakis

2010-07-01

Information on childhood poisonings in Cyprus is limited. Our objective was to examine the epidemiology of poisonings among children in Cyprus. All children up to 15 years of age admitted for poisoning to the Archbishop Makarios Hospital in Nicosia, Cyprus between 2005 and 2008 were included in our study. All hospital poisoning records were reviewed. A total of 257 children were admitted for poisoning. The mean age of children was 3.1 years, of which 83.7% were below the age of 5 years old, while 53% were boys. The poisoning hospitalizations accounted for about 3% of all admissions to the pediatric department during the study period (4 years). The annual cumulative incidence of childhood poisoning hospitalizations was 116 per 100,000 children. Medications accounted for 46.1% of all poisonings, the most frequent cause being paracetamol (9.8%), cardiovascular medications (5.3%), antitussive medications (4.5%), and other painkillers (4.1%). Another 37.6% of hospitalizations involved household products such as household cleaning products (11.8%), petroleum products (11.0%), and rodenticides (5.7%). Among children who ingested petroleum distillates, 55.6% developed clinical symptomatology. The vast majority of cases were accidental (93.8%). Suicidal cases involved children 8-14 years old, mainly girls, and the most frequent poisoning ingested was paracetamol (46.7%). Poisoning hospitalizations represent an important cause of morbidity among children in Cyprus. Preventive strategies should include the education of caregivers on the handling of medications and household products as well as legislation requiring child-resistant packaging for all medications and household products including petroleum distillates.

Chronic arsenic poisoning following ayurvedic medication.

PubMed

Pinto, Benzeeta; Goyal, Palvi; Flora, S J S; Gill, K D; Singh, Surjit

2014-12-01

Ayurveda, Indian traditional system of medicine, is practiced commonly in South East Asia and in many parts of the world. Many ayurvedic drugs contain heavy metals and may lead to metal toxicity. Of these, chronic lead poisoning is the most common. Chronic arsenic poisoning following the use of ayurvedic medication, though reported, is rare. We describe three patients who presented with features of chronic arsenic poisoning following prolonged ayurvedic medication use. The diagnosis of chronic arsenic poisoning was confirmed by high arsenic levels in the blood, urine, hair, and nails in all the three patients and in ayurvedic drug in two patients. The ayurvedic medication was discontinued and treatment with D-penicillamine started. At 6 months after treatment, blood arsenic levels returned to normal with clinical recovery in all of them. Arsenic poisoning following ayurvedic medication is much less common than lead poisoning, though mineral ayurvedic medicines may lead to it. We used D-penicillamine as chelator and all of them recovered. Whether withdrawal of medication alone or D-penicillamine also played a role in recovery is unclear and needs to be assessed.

[A relational database to store Poison Centers calls].

PubMed

Barelli, Alessandro; Biondi, Immacolata; Tafani, Chiara; Pellegrini, Aristide; Soave, Maurizio; Gaspari, Rita; Annetta, Maria Giuseppina

2006-01-01

Italian Poison Centers answer to approximately 100,000 calls per year. Potentially, this activity is a huge source of data for toxicovigilance and for syndromic surveillance. During the last decade, surveillance systems for early detection of outbreaks have drawn the attention of public health institutions due to the threat of terrorism and high-profile disease outbreaks. Poisoning surveillance needs the ongoing, systematic collection, analysis, interpretation, and dissemination of harmonised data about poisonings from all Poison Centers for use in public health action to reduce morbidity and mortality and to improve health. The entity-relationship model for a Poison Center relational database is extremely complex and not studied in detail. For this reason, not harmonised data collection happens among Italian Poison Centers. Entities are recognizable concepts, either concrete or abstract, such as patients and poisons, or events which have relevance to the database, such as calls. Connectivity and cardinality of relationships are complex as well. A one-to-many relationship exist between calls and patients: for one instance of entity calls, there are zero, one, or many instances of entity patients. At the same time, a one-to-many relationship exist between patients and poisons: for one instance of entity patients, there are zero, one, or many instances of entity poisons. This paper shows a relational model for a poison center database which allows the harmonised data collection of poison centers calls.

Poisoning

MedlinePlus

... The Harriet Lane Handbook . 21st ed. Philadelphia, PA: Elsevier; 2018:chap 2. Kostic MA. Poisoning. In: Kliegman ... Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap 63. Meehan TJ. Approach to the ...

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning.

PubMed

Schier, J G; Hunt, D R; Perala, A; McMartin, K E; Bartels, M J; Lewis, L S; McGeehin, M A; Flanders, W D

2013-12-01

Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6-75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14-118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ-43.3 mcg/mL). Significant differences and associations were identified

16 CFR 1700.15 - Poison prevention packaging standards.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Poison prevention packaging standards. 1700.15 Section 1700.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS POISON PREVENTION PACKAGING § 1700.15 Poison prevention packaging...

16 CFR 1700.15 - Poison prevention packaging standards.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Poison prevention packaging standards. 1700.15 Section 1700.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS POISON PREVENTION PACKAGING § 1700.15 Poison prevention packaging...

16 CFR 1700.15 - Poison prevention packaging standards.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Poison prevention packaging standards. 1700.15 Section 1700.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS POISON PREVENTION PACKAGING § 1700.15 Poison prevention packaging...

16 CFR 1700.15 - Poison prevention packaging standards.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Poison prevention packaging standards. 1700.15 Section 1700.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS POISON PREVENTION PACKAGING § 1700.15 Poison prevention packaging...

Ciguatera fish poisoning.

PubMed

Armstrong, Patrick; Murray, Peter; Nesdale, Annette; Peckler, Brad

2016-10-28

Ciguatera fish poisoning (CFP) is the most common cause of seafood-toxin poisoning in the world and is most prevalent in tropical and subtropical areas. It causes gastroenteritis but also myriad neurological and cardiovascular symptoms. We present a cluster of CFP that occurred in Wellington Hospital, New Zealand. It resulted in three patients with life threatening cardiotoxicity and a fourth case with severe gastro-intestinal symptoms. The epidemiology, clinical manifestations, diagnosis, treatment and public health issues are discussed.

Lead Poisoning in Children.

ERIC Educational Resources Information Center

Lin-Fu, Jane S.

This publication is a guide to help social and health workers plan a preventive campaign against lead poisoning, a cause of mental retardation other neurological handicaps, and death among children. The main victims are 1- to 6-year-olds living in areas where deteriorating housing prevails. Among the causes of lead poisoning are: ingestion of…

Carbon monoxide poisoning at motels, hotels, and resorts.

PubMed

Weaver, Lindell K; Deru, Kayla

2007-07-01

Each year, more than 200 people in the United States die from carbon monoxide (CO) poisoning. Poisoning has occurred at motels, hotels, and resorts. Congressional mandate requires smoke alarms in all guest rooms; however, smoke alarms do not detect CO. Data on patients poisoned at hotels, motels, and resorts were evaluated at a hyperbaric medicine service. In 2005, legal databases and online news databanks were searched to discover additional incidents. Only victims evaluated in hospitals or declared dead at the scene were included. Cases of intentional poisoning and poisoning from fires were excluded. Between 1989 and 2004, 68 incidents of CO poisoning occurring at hotels, motels, and resorts were identified, resulting in 772 accidentally poisoned: 711 guests, 41 employees or owners, and 20 rescue personnel. Of those poisoned, 27 died, 66 had confirmed sequelae, and 6 had sequelae resulting in a jury verdict. Lodging-operated, faulty room heating caused 45 incidents, pool/spa boilers 16, CO entrained from outdoors 5, and unreported sources caused 2 incidents. Public verdicts have averaged $4.8 million per incident (range, $1 million to $17.5 million). Poisoning occurred at hotels of all classes. Despite these incidents, most properties did not install CO alarms, and requirements for CO alarms at hotels, motels, and resorts are rare. Guests of motels, hotels, and resorts remain at risk for injury or death from CO poisoning. Measures to prevent CO poisoning of guests and employees of the lodging industry should be evaluated.

[Pidemiological analysis of pesticide poisoning in hangzhou during 2006-2013].

PubMed

Zhang, Lei; Hao, Li; Zhang, Xuhui; Chen, Jianchun; Wang, Qiang; Yu, Long

2015-01-01

The purpose of this current investigation was to describe the distribution characteristics of pesticides poisoning in Hangzhou during 2006-2013. The registration data of pesticide poisoning in Hangzhou during 2006-2013 were collected from health disserve surveillance information system which was part of China information system for disease control and prevention. The statistical analysis method included Pearson Chi-square test and Cochran-Armitage trend test. There were totally 6232 cases with pesticide poisoning during 2006-2013, of which 414 cases died. The fatality rate of poisoning patients was 6.64%. The pesticides, especially organophosphorus pesticides, were the main poison that caused poisoning, and patients with pesticide poisoning accounted for 80.60% of all the poisoning patient. There was more female patients than male patients among non-productive pesticide poisoning, but on the contrary among productive pesticide poisoning. The incidence of pesticides poisoning had significant increase in the third season. Occupational pesticide poisoning and non-occupational pesticide poisoning had the different distribution character. Non-occupational pesticide poisoning was the chief reason of pesticide poisoning. The pesticides, especially organophosphorus pesticides, were the main poisons threatening the health of people in Hangzhou, and the effective prevention and control measures should be taken immediately.

Pesticide poisoning and its related factors among Korean farmers.

PubMed

Shin, D C; Kim, H J; Jung, S H; Park, C Y; Lee, S Y; Kim, C B

1998-01-01

This study has been carried out to assess the health damages due to pesticide use and its related risk factors among Korean farmers. Data regarding pesticide handling and poisoning symptoms were collected by means of a questionnaire filled in by 1,032 farmers from two provinces. The results showed that during summer farming 21.9% of the subjects experienced suspected pesticide poisoning. 18.8% mild poisoning, and 2% more serious poisoning. Univariate and logistic regression analyses between "no poisoning", including the "suspected poisoning" and "poisoning" groups, were performed to select significant variables related to pesticide poisoning. Four variables were significantly associated: sex, days of consecutive pesticide use, hours of pesticide use per day, having received safety education (weakly associated), and compliance with safety guidelines for application. Safety education was weakly associated with poisoning, while age, education, wearing protective gear, and compliance with safety guidelines for personal hygiene after pesticide use were not significant risk factors to determine pesticide poisoning.

Poison control center - emergency number

MedlinePlus

For a POISON EMERGENCY call: 1-800-222-1222 ANYWHERE IN THE UNITED STATES This national hotline number will let you ... is a free and confidential service. All local poison control centers in the United States use this ...

Methanol poisoning among travellers to Indonesia.

PubMed

Giovanetti, Franco

2013-01-01

Common Travel Medicine sources generally do not provide information on the risk of methanol poisoning among travellers who visit Indonesia. The aim of this analysis was to increase knowledge on this topic through reports from bibliographic databases and Internet sources. Case reports and studies on methanol poisoning in Indonesia were retrieved through PubMed, Embase and Google Scholar database searching. The Google search was used to retrieve the Web Media articles reporting fatal and non-fatal methanol poisoning in Indonesia, in a timeframe from 01.01.2009 to 03.03.2013. Three case reports of methanol poisoning involving four travellers to Indonesia were found in bibliographic databases. The media sources searching identified 14 articles published online, reporting 22 cases of methanol poisoning among travellers after consumption of local alcohol beverages. The total number of death cases was 18. Some sources report also a large number of cases among the local population. Methanol poisoning is likely to be an emerging public health problem in Indonesia, with an associated morbidity and mortality among travellers and local people. Some strategies can be implemented to prevent or reduce harm among travellers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Benzodiazepine poisoning in elderly.

PubMed

Vukcević, Natasa Perković; Ercegović, Gordana Vuković; Segrt, Zoran; Djordjević, Snezana; Stosić, Jasmina Jović

2016-03-01

Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patient's characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

[Charcoal, cocaine and rattlesnakes: evidence-based treatment of poisoning].

PubMed

Schaper, A

2013-10-01

Since ancient times poisoning has been treated medicinally. Clinical toxicology, in the narrow sense of the term, developed from the foundation of specialized medical treatment units for poisoning and the formation of the first poison information centers in the second half of the twentieth century. Historically, the first poison information centers were often localized at pediatric clinics or departments of internal medicine. It became increasingly more obvious that this pooling of competences made sense. This article gives a general introduction in clinical toxicology and presents the functions and key activities of emergency poison centers. The organisation and work of a poisons centre is demonstrated on the basis of the Poisons Information Center (GIZ) North annual report for 2011. In a short summary the basic principles of clinical toxicology are elucidated: the primary removal of poisons by gastric lavage and administration of activated charcoal, secondary removal of poisons by enhanced elimination using hemodialysis, hemoperfusion, multi-dose activated charcoal and molecular adsorbent recirculating systems (MARS) and the indications for administration of specific antidotes or antivenins (antisera against poisoning by poisonous animals). Gastric lavage is indicated within 1 h after ingestion of a potentially life-threatening dose of a poison. In cases of poisoning with substances which penetrate the central nervous system (CNS) gastric lavage should be performed only after endotracheal intubation due to the risk of aspiration. The basic management of poisoned patients by emergency medicine personnel out of hospital and on the way to hospital is presented. The Bremen list, a compilation of the five antidotes, atropine, 4-dimethylaminophenol (4-DMAP), tolonium chloride, naloxone and activated charcoal for out of hospital treatment by emergency doctors is presented. In all, even questionable cases of poisoning consultation at emergency poison centers is

Fatal methanol poisoning: features of liver histopathology.

PubMed

Akhgari, Maryam; Panahianpour, Mohammad Hadi; Bazmi, Elham; Etemadi-Aleagha, Afshar; Mahdavi, Amirhosein; Nazari, Saeed Hashemi

2013-03-01

Methanol poisoning has become a considerable problem in Iran. Liver can show some features of poisoning after methanol ingestion. Therefore, our concern was to examine liver tissue histopathology in fatal methanol poisoning cases in Iranian population. In this study, 44 cases of fatal methanol poisoning were identified in a year. The histological changes of the liver were reviewed. The most striking features of liver damage by light microscopy were micro-vesicular steatosis, macro-vesicular steatosis, focal hepatocyte necrosis, mild intra-hepatocyte bile stasis, feathery degeneration and hydropic degeneration. Blood and vitreous humor methanol concentrations were examined to confirm the proposed history of methanol poisoning. The majority of cases were men (86.36%). In conclusion, methanol poisoning can cause histological changes in liver tissues. Most importantly in cases with mean blood and vitreous humor methanol levels greater than 127 ± 38.9 mg/dL more than one pathologic features were detected.

Comparison of fatal poisonings by prescription opioids.

PubMed

Häkkinen, Margareeta; Launiainen, Terhi; Vuori, Erkki; Ojanperä, Ilkka

2012-10-10

There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Non-accidental salt poisoning.

PubMed Central

Meadow, R

1993-01-01

The clinical features of 12 children who incurred non-accidental salt poisoning are reported. The children usually presented to hospital in the first six months of life with unexplained hypernatraemia and associated illness. Most of the children suffered repetitive poisoning before detection. The perpetrator was believed to the mother for 10 children, the father for one, and either parent for one. Four children had serum sodium concentrations above 200 mmol/l. Seven children had incurred other fabricated illness, drug ingestion, physical abuse, or failure to thrive/neglect. Two children died; the other 10 remained healthy in alternative care. Features are described that should lead to earlier detection of salt poisoning; the importance of checking urine sodium excretion, whenever hypernatraemia occurs, is stressed. PMID:8503665

Differences in immunolocalization of Kim-1, RPA-1, and RPA-2 in kidneys of gentamicin-, cisplatin-, and valproic acid-treated rats: potential role of iNOS and nitrotyrosine.

PubMed

Zhang, Jun; Goering, Peter L; Espandiari, Parvaneh; Shaw, Martin; Bonventre, Joseph V; Vaidya, Vishal S; Brown, Ronald P; Keenan, Joe; Kilty, Cormac G; Sadrieh, Nakissa; Hanig, Joseph P

2009-08-01

The present study compared the immunolocalization of Kim-1, renal papillary antigen (RPA)-1, and RPA-2 with that of inducible nitric oxide synthase (iNOS) and nitrotyrosine in kidneys of gentamicin sulfate (Gen)- and cisplatin (Cis)-treated rats. The specificity of acute kidney injury (AKI) biomarkers, iNOS, and nitrotyrosine was evaluated by dosing rats with valproic acid (VPA). Sprague-Dawley (SD) rats were injected subcutaneously (sc) with 100 mg/kg/day of Gen for six or fourteen days; a single intraperitoneal (ip) dose of 1, 3, or 6 mg/kg of Cis; or 650 mg/kg/day of VPA (ip) for four days. In Gen-treated rats, Kim-1 was expressed in the epithelial cells, mainly in the S1/S2 segments but less so in the S3 segment, and RPA-1 was increased in the epithelial cells of collecting ducts (CD) in the cortex. Spatial expression of iNOS or nitrotyrosine with Kim-1 or RPA-1 was detected. In Cis-treated rats, Kim-1 was expressed only in the S3 segment cells, and RPA-1 and RPA-2 were increased in the epithelial cells of medullary CD or medullary loop of Henle (LH), respectively. Spatial expression of iNOS or nitrotyrosine with RPA-1 or RPA-2 was also identified. These findings suggest that peroxynitrite formation may be involved in the pathogenesis of Gen and Cis nephrotoxicity and that Kim-1, RPA-1, and RPA-2 have the potential to serve as site-specific biomarkers for Gen or Cis AKI.

Poisoning

MedlinePlus

... of illegal drugs Carbon monoxide from gas appliances Household products, such as laundry powder or furniture polish Pesticides ... products exactly as their labels say. Keep dangerous products where children ... call your local poison control center at 1-800-222-1222 right away.

Study on the treatment of acute thallium poisoning.

PubMed

Zhang, Hong-Tao; Qiao, Bao-Ping; Liu, Bao-Ping; Zhao, Xian-Guo

2014-05-01

Acute thallium poisoning rarely occurs but is a serious and even fatal medical condition. Currently, patients with acute thallium poisoning are usually treated with Prussian blue and blood purification therapy. However, there are few studies about these treatments for acute thallium poisoning. Nine patients with acute thallium poisoning from 1 family were treated successfully with Prussian blue and different types of blood purification therapies and analyzed. Prussian blue combined with sequential hemodialysis, hemoperfusion and/or continuous veno-venous hemofiltration were effective for the treatment of patients with acute thallium poisoning, even after delayed diagnosis. Blood purification therapies help in the clearance of thallium in those with acute thallium poisoning. Prussian blue treatment may do the benefit during this process.

Prospects of poisoning - a multi facet study.

PubMed

Mishra, Pradeep K; Kulkarni, Rashmi; Sane, Mandar R; Deshpande, Ajit; Kushwah, Manish

2016-01-01

Aim of the study is to find out demographic profile, clinical characteristics and analysis of poison in clinical set up. The study carried out in Sri Aurobindo Medical College and PG Institute Indore, Madhya Pradesh. Total 75 cases of poisoning were studied for demographic profile, vitals (BP, pulse, heart rate, pupils, etc.), clinical features (such as vomiting, salivation, consciousness, etc.), type of poison and its analysis. Results: Poisoning was more common in cases between 15 and 25 years of age, in males than in females and in Hindu religion. Poisoning cases were predominantly from rural areas and in married people. Majority of cases were discharged after proper treatment and counseling. Altered vitals and clinical features were found in most of the cases. Organophosphate and aluminum phosphide compound were evaluated in most of the cases. Conclusions: Preventive measures should be applied through educating people, proper counseling, promoting poison information centers, and introducing separate toxicological units in hospitals.

A nationwide evidence-based study of factors associated with hospitalisations due to unintentional poisoning and poisoning mortality in Taiwan.

PubMed

Chien, Wu-Chien; Chung, Chi-Hsiang; Lin, Chia-Hsin; Lai, Ching-Huang

2013-01-01

The aim of this study was to explore the epidemiologic characteristics of unintentional poisoning cases and the factors associated with inpatient mortality. Data were retrieved from the National Health Insurance database from 2005 to 2007. Patients with diagnosis classifications of ICD-9-CM E850-E869 (unintentional poisoning) were selected. SPSS 18.0 software was used for the analysis. In Taiwan between 2005 and 2007, a total of 11,523 patients were hospitalised due to unintentional poisoning, with a hospitalisation rate of 16.83 per 100,000, of which 60.1% and 39.9% were attributable to drug poisoning and solid, liquid and gas substance poisoning, respectively. The hospitalisation rate in men was higher than that of women. The age group of 45-64 had the highest hospitalisation rate of 52.85 per 100,000. The inpatient mortality rate increased with the presence of the following factors: age of 65 or older, surgery or procedure, a higher Charlson Comorbidity Index (CCI), short length of hospital stays, acute respiratory failure, alcohol poisoning, pesticide poisoning and a higher-level hospital visited. Methanol, herbicides and organophosphorus pesticide intoxications are associated with higher mortality rates. Therefore, when caring for patients poisoned by the above agents, healthcare professionals should look out for their clinical development to ensure quality of care and to reduce mortality.

Evidence that histamine is the causative toxin of scombroid-fish poisoning.

PubMed

Morrow, J D; Margolies, G R; Rowland, J; Roberts, L J

1991-03-14

The highest morbidity worldwide from fish poisoning results from the ingestion of spoiled scombroid fish, such as tuna and mackerel, and its cause is not clear. Histamine could be responsible, because spoiled scombroid fish contain large quantities of histamine. Whether histamine is the causative toxin, however, has remained in question. To address this issue, we investigated whether histamine homeostasis is altered in poisoned people. The urinary excretion of histamine and its metabolite, N-methylhistamine, was measured in three persons who had scombroid-fish poisoning (scombrotoxism) after the ingestion of marlin. We measured 9 alpha, 11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid (PGD-M), the principal metabolite of prostaglandin D2, a mast-cell secretory product, to assess whether mast cells had been activated to release histamine. The fish contained high levels of histamine (842 to 2503 mumol per 100 g of tissue). Symptoms of scombrotoxism--flushing and headache--began 10 to 30 minutes after the ingestion of fish. In urine samples collected one to four hours after fish ingestion, the levels of histamine and N-methylhistamine were 9 to 20 times and 15 to 20 times the normal mean, respectively. During the subsequent 24 hours, the levels fell to 4 to 15 times and 4 to 11 times the normal values. Levels of both were normal 14 days later. PGD-M excretion was not increased at any time. Two persons treated with diphenhydramine had prompt amelioration of symptoms. Scombroid-fish poisoning is associated with urinary excretion of histamine in quantities far exceeding those required to produce toxicity. The histamine is most likely derived from the spoiled fish. These results identify histamine as the toxin responsible for scombroid-fish poisoning.

[Lithium poisoning: neurological signs, nephrological therapy].

PubMed

Pastori, Giordano; Gentile, Manrico

2016-01-01

Lithium is an effective drug in the treatment of bipolar disorder and other psychiatric and neurological diseases. Unfortunately, its therapeutic index is narrow. There are three types of lithium poisoning: acute poisoning (in untreated patients), acute on chronic poisoning, when an overdose is taken accidentally or with suicidal intent, in patients under treatment and chronic poisoning (patient treated with lithium) when drug intake is correct but excessive in relation to its elimination (increased dose or more often reduced clearance) resulting in lithium overload. In this last condition, the clinical presentation is primary neurological while therapy involves the nephrologist provided that lithium clearance is mainly renal and hemodialysis is the most effective method for removal.

14 CFR 137.39 - Economic poison dispensing.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Economic poison dispensing. 137.39 Section... AIRCRAFT OPERATIONS Operating Rules § 137.39 Economic poison dispensing. (a) Except as provided in... economic poison that is registered with the U.S. Department of Agriculture under the Federal Insecticide...

14 CFR 137.39 - Economic poison dispensing.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Economic poison dispensing. 137.39 Section... AIRCRAFT OPERATIONS Operating Rules § 137.39 Economic poison dispensing. (a) Except as provided in... economic poison that is registered with the U.S. Department of Agriculture under the Federal Insecticide...

14 CFR 137.39 - Economic poison dispensing.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Economic poison dispensing. 137.39 Section... AIRCRAFT OPERATIONS Operating Rules § 137.39 Economic poison dispensing. (a) Except as provided in... economic poison that is registered with the U.S. Department of Agriculture under the Federal Insecticide...

14 CFR 137.39 - Economic poison dispensing.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Economic poison dispensing. 137.39 Section... AIRCRAFT OPERATIONS Operating Rules § 137.39 Economic poison dispensing. (a) Except as provided in... economic poison that is registered with the U.S. Department of Agriculture under the Federal Insecticide...

14 CFR 137.39 - Economic poison dispensing.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Economic poison dispensing. 137.39 Section... AIRCRAFT OPERATIONS Operating Rules § 137.39 Economic poison dispensing. (a) Except as provided in... economic poison that is registered with the U.S. Department of Agriculture under the Federal Insecticide...

Carbon monoxide poisoning from portable electric generators.

PubMed

Hampson, Neil B; Zmaeff, Jennette L

2005-01-01

While the overall death rate from unintentional carbon monoxide (CO) poisoning has decreased in the United States due to improved automobile emissions controls and a decline in CO poisonings from motor vehicles, exposures have not changed from some sources of CO. One of these is the operation of portable electrical generators in poorly ventilated spaces. This study sought to describe the population poisoned from CO produced by portable electric generators, and to determine the reasons that generators are operated in a hazardous fashion. Cases of CO poisoning referred for treatment with hyperbaric oxygen at Virginia Mason Medical Center in Seattle from November 1978 to March 2004 were reviewed. Those cases that resulted from portable generator use were selected for analysis. Sixty-three patients aged 2 to 85 years were treated for CO poisoning from portable electric generators. They included 34 males and 29 females who were poisoned in 37 separate incidents. Thirty-four lost consciousness with the exposure. Of the 63 total patients, 60 spoke English. Generators were typically used when normal electrical service was disrupted by a storm or in remote locations. In 29 of 37 incidents, the generator was operated in the home environment, most commonly in the garage. Lack of awareness of the dangers of CO poisoning or lack of knowledge of ventilation requirements were the most commonly identified reasons. CO poisoning from portable electric generators occurs in a characteristic population, in a few typical locations and for a limited number of reasons. This information may help target prevention efforts for this form of poisoning, such as warning labels or educational programs.

Thirty-three-year experience on childhood poisoning.

PubMed

Ozdemir, Ramazan; Bayrakci, Benan; Tekşam, Ozlem; Yalçin, Bilgehan; Kale, Gülsev

2012-01-01

By comparing our data for the period 1985-2008 with findings from a previous report covering the period 1975-1984, we aimed to share our experience with poisoning cases in order to contribute toward its prevention, diagnosis and treatment. The records of patients admitted to the Pediatric Intensive Care Unit with acute poisoning between November 1985 and October 2008 were evaluated retrospectively. The records of 2251 patients with acute poisoning could be retrieved. Poisoning mostly occurred in the home (92%), via the oral route (92.5%) and by a single intoxicant (81.3%). Two distinct peaks were observed: in boys between 1-5 years of age and in girls between 13-16 years of age. It was noted that 67.4% of poisoning cases were accidental, whereas 25.9% were suicidal and 6.7% were a result of a therapeutic error. Nearly two-thirds (64%) of cases were drug-related, while 36% were non-drug-related. Analgesics-antipyretics ranked first among the drug-related cases, whereas ingestion of a corrosive substance was most common among cases with non-drug poisoning. Colchicine was associated with the highest fatality, while among the causes of non-drug poisoning, carbon monoxide was the deadliest. The overall mortality rate in this study was 1.9%. Mortality from non-drug poisoning was higher than from drug-related causes (3.9% vs. 1.3%). Almost all cases of poisoning below the age of 6 years are potentially preventable. The results of this study highlight the need for reforms in industrial and health policies, with the aim of increasing awareness regarding potential toxins, appropriate storage of potential toxins, and general precautions to promote safety in the home.

Identifying Plant Poisoning in Livestock

USDA-ARS?s Scientific Manuscript database

Poisonous plant intoxication is a common and often deadly problem that annually costs the livestock industry more than $340 million in the western United States alone. Despite the cost or frequency, definitively identifying or diagnosing poisoning by plants in livestock is challenging. The purpos...

Epidemiology and characteristics of acute poisoning treated at an emergency center.

PubMed

Chen, Feng; Wen, Jun-Ping; Wang, Xiao-Ping; Lin, Qing-Ming; Lin, Cai-Jing

2010-01-01

Acute poisoning is frequently encountered at emergency department. This study was to investigate the epidemiology and characteristics of patients with acute poisoning who were treated at the Emergency Center, Fujian Provincial Hospital, China. We retrospectively analyzed the gender, age, causes of poisoning, types of poisons, poisoning route, emergency diagnoses, outcomes, and prognoses of these patients. Altogether 2867 patients with acute poisoning were treated from January 2004 to December 2009. The ratio of male to female was 1:1.04, and their average age was 33.8 years. Of the 2867 patients, 76.39% were between 18 and 40 years old. The incidence of acute poisoning was as high as 11.33% in January each year. The incidence of poisoning was in a descending order: alcohol poisoning (54.55%), medication poisoning (25.95%), pesticide poisoning (5.65%), and drug poisoning (4.88%). Most (56.44%) of the patients with drug poisoning were under 25 years and their mean age was significantly lower than that of patients with medication poisoning or alcohol poisoning (P < 0.01). Approximately 69.54% of the patients were followed up after emergency treatment, 30.39% were hospitalized, and four patients died. Acute poisoning is largely alcohol poisoning and medication poisoning in a city. The emergency green channel "pre-hospital emergency care-emergency department-hospital treatment" can significantly improve the survival rate of patients with acute poisoning.

Interpersonal problem-solving deficits in self-poisoning patients.

PubMed

McLeavey, B C; Daly, R J; Murray, C M; O'Riordan, J; Taylor, M

1987-01-01

Self-poisoning patients (n = 40) were compared with psychiatric patients (n = 40) and nonpatient controls (n = 20) on measures of interpersonal problem-solving skills and locus of control in an effort to determine the importance of these cognitive and personality variables in self-poisoning behavior. The psychiatric and self-poisoning groups showed deficits on measures assessing interpersonal problem solving when compared with nonpatient controls. The self-poisoning group performed below the level of the psychiatric patients on all except one test, on which they performed at the level of the psychiatric group. Locus of control did not differentiate self-poisoning patients from nonpatient controls, and it was concluded that this variable is not an important factor in self-poisoning behavior.

Ciguatera and scombroid fish poisoning in the United States.

PubMed

Pennotti, Radha; Scallan, Elaine; Backer, Lorraine; Thomas, Jerry; Angulo, Frederick J

2013-12-01

Ciguatera and scombroid fish poisonings are common causes of fish-related foodborne illness in the United States; however, existing surveillance systems underestimate the overall human health impact. This study aimed to describe existing data on ciguatera and scombroid fish poisonings from outbreak and poison control center reports and to estimate the overall number of ciguatera and scombroid fish-poisoning illnesses, hospitalizations, and deaths in the United States. We analyzed outbreak data from the Foodborne Disease Outbreak Surveillance Systems (FDOSS) from 2000 to 2007 and poison control center call data from the National Poison Data System (NPDS) from 2005 to 2009 for reports of ciguatera and scombroid fish poisonings. Using a statistical model with many inputs, we adjusted the outbreak data for undercounting due to underreporting and underdiagnosis to generate estimates. Underreporting and underdiagnosis multipliers were derived from the poison control call data and the published literature. Annually, an average of 15 ciguatera and 28 scombroid fish-poisoning outbreaks, involving a total of 60 and 108 ill persons, respectively, were reported to FDOSS (2000-2007). NPDS reported an average of 173 exposure calls for ciguatoxin and 200 exposure calls for scombroid fish poisoning annually (2005-2009). After adjusting for undercounting, we estimated 15,910 (90% credible interval [CrI] 4140-37,408) ciguatera fish-poisoning illnesses annually, resulting in 343 (90% CrI 69-851) hospitalizations and three deaths (90% CrI 1-7). We estimated 35,142 (90% CrI: 10,496-78,128) scombroid fish-poisoning illnesses, resulting in 162 (90% CrI 0-558) hospitalizations and 0 deaths. Ciguatera and scombroid fish poisonings affect more Americans than reported in surveillance systems. Although additional data can improve these assessments, the estimated number of illnesses caused by seafood intoxication illuminates this public health problem. Efforts, including education, can reduce

Depletion optimization of lumped burnable poisons in pressurized water reactors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kodah, Z.H.

1982-01-01

Techniques were developed to construct a set of basic poison depletion curves which deplete in a monotonical manner. These curves were combined to match a required optimized depletion profile by utilizing either linear or non-linear programming methods. Three computer codes, LEOPARD, XSDRN, and EXTERMINATOR-2 were used in the analyses. A depletion routine was developed and incorporated into the XSDRN code to allow the depletion of fuel, fission products, and burnable poisons. The Three Mile Island Unit-1 reactor core was used in this work as a typical PWR core. Two fundamental burnable poison rod designs were studied. They are a solidmore » cylindrical poison rod and an annular cylindrical poison rod with water filling the central region.These two designs have either a uniform mixture of burnable poisons or lumped spheroids of burnable poisons in the poison region. Boron and gadolinium are the two burnable poisons which were investigated in this project. Thermal self-shielding factor calculations for solid and annular poison rods were conducted. Also expressions for overall thermal self-shielding factors for one or more than one size group of poison spheroids inside solid and annular poison rods were derived and studied. Poison spheroids deplete at a slower rate than the poison mixture because each spheroid exhibits some self-shielding effects of its own. The larger the spheroid, the higher the self-shielding effects due to the increase in poison concentration.« less

Affective disorders and completed suicide by self-poisoning, trend of using antidepressants as a method of self-poisoning.

PubMed

Löfman, Sanna; Hakko, Helinä; Mainio, Arja; Riipinen, Pirkko

2017-09-01

The aim of this research was to study the role and trend of antidepressant use as a method of suicide in completed self-poisoning suicides in patients with affective disorders during a 23-year follow up period. The data consisted of 483 completed self-poisoning suicides from 1988 to 2011 in the province of Oulu in Northern Finland (286 men and 197 women). Of the self-poisoning victims, 26.9% (n=130) had hospital-treated unipolar depression and 3.1% (n=15) hospital-treated bipolar disorder. Further, 53.8% (n=70) of those with unipolar depression and 53.3% (n=8) of those with bipolar depression died by suicide using antidepressants. During the 23-year follow-up period, the proportion of those using antidepressants doubled among all self-poisoning victims of suicide. A significant decline was observed in the use of tricyclic antidepressants in self- poisoning suicides while a linear increase was found in the use of SSRIs (selective serotonin reuptake inhibitors) and other antidepressants. During recent years one in five self-poisoning suicides involved the use of antiepileptics. A limitation of our study was that the psychiatric diagnoses only include hospital inpatient episodes. In conclusion, the use of new antidepressants has increased rapidly, but the risk of their use in self-poisoning suicide has perhaps been underestimated. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

[Epidemiological analysis for Quzhou pesticide poisoning of year 2008 to 2010].

PubMed

Zhao, Shi-guang; Liu, Si-feng

2012-09-01

To provide scientific evidence of making measures for prevention of pesticide poisoning, the investigation on the condition of pesticide poisoning was carried out in Quzhou. Registration data of pesticide poisoning from 2008 to 2010 in Quzhou were collected and statistically analyzed by SPSS 12.0. During the three years, there were 1222 cases reported for pesticide poisoning. Among them, the number of occupational poisoning was 225 (1 case died), with fatality rate of 0.44%. The number of non-occupational poisoning was 997 (77 cases died), and its fatality rate was 7.72% . The incidence of occupational poisoning and non-occupational poisoning accounted for 18.4% and 81.6% respectively. Male patients were in the majority in occupational pesticides poisoning (accounting for 76.4%), female patients in non-occupational poisoning (accounting for 52.1%). The pesticide poisoning mainly occurred from July to September. Occupational poisoning and non-occupational poisoning cases mainly concentrated in over 65 age group, accounting for 36.0% (81 cases) and 26.3% (262 cases) respectively. Insecticide ranks the first in the terms of total poisoning cases caused by pesticide, and organophosphate poisoning ranks the first in all insecticides. Pesticides poisoning has badly threatened the public health in Quzhou, attention should be paid to non-occupational poisoning. The pesticides poisoning was mainly caused by organophosphate insecticides.

Paraquat poisoning calls to the Malaysia National Poison Centre following its ban and subsequent restriction of the herbicide from 2004 to 2015.

PubMed

Leong, Yin-Hui; Ariff, Adilah Mohamed; Khan, Halilol Rahman Mohamed; Rani, Noor Afiza Abdul; Majid, Mohamed Isa Abdul

2018-05-01

This study analyses the incidences and patterns of paraquat poisoning from calls received at the Malaysia National Poison Centre (NPC) since 2004 following the ban of the herbicide (2004-2006) and subsequent restriction up to year 2015. Related reported cases to the centre over twelve years (2004-2015) were retrieved and studied in respect to socio-demographic characteristics, mode and type of poisonings, exposure routes and location of incident. Ages of poisoned victims range from 10 months old to 98 years with males being intoxicated more frequently than females (ratio male to female = 2.7). The age group mainly involved in the poisoning was 20-39 years. The most common mode was intentional (62.8%) followed by unintentional (36.9%). Among the 1232 reported cases, suicidal poisoning was the highest (57.2%); accidental poisoning (30.8%) and occupational poisoning (3.3%). The findings showed an upward trend of suicidal poisoning over the years, clearly emphasizing the need for more stringent and effective enforcement to ensure the safe use of paraquat. Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Poisonous plants in New Zealand: a review of those that are most commonly enquired about to the National Poisons Centre.

PubMed

Slaughter, Robin J; Beasley, D Michael G; Lambie, Bruce S; Wilkins, Gerard T; Schep, Leo J

2012-12-14

New Zealand has a number of plants, both native and introduced, contact with which can lead to poisoning. The New Zealand National Poisons Centre (NZNPC) frequently receives enquiries regarding exposures to poisonous plants. Poisonous plants can cause harm following inadvertent ingestion, via skin contact, eye exposures or inhalation of sawdust or smoked plant matter. The purpose of this article is to determine the 15 most common poisonous plant enquiries to the NZNPC and provide a review of current literature, discussing the symptoms that might arise upon exposure to these poisonous plants and the recommended medical management of such poisonings. Call data from the NZNPC telephone collection databases regarding human plant exposures between 2003 and 2010 were analysed retrospectively. The most common plants causing human poisoning were selected as the basis for this review. An extensive literature review was also performed by systematically searching OVID MEDLINE, ISI Web of Science, Scopus and Google Scholar. Further information was obtained from book chapters, relevant news reports and web material. For the years 2003-2010 inclusive, a total of 256,969 enquiries were received by the NZNPC. Of these enquiries, 11,049 involved exposures to plants and fungi. The most common poisonous plant enquiries, in decreasing order of frequency, were: black nightshade (Solanum nigrum), arum lily (Zantedeschia aethiopica), kowhai (Sophora spp.), euphorbia (Euphorbia spp.), peace lily (Spathiphyllum spp.), agapanthus (Agapanthus spp.), stinking iris (Iris foetidissima), rhubarb (Rheum rhabarbarum), taro (Colocasia esculentum), oleander (Nerium oleander), daffodil (Narcissus spp.), hemlock (Conium maculatum), karaka (Corynocarpus laevigatus), foxglove (Digitalis purpurea) and ongaonga/New Zealand tree nettle (Urtica ferox). The combined total of enquiries for these 15 species was 2754 calls (representing approximately 25% of all enquiries regarding plant exposures). The signs

Antifreeze poisoning

MedlinePlus

The poisonous ingredients in antifreeze are: Ethylene glycol Methanol Propylene glycol ... For ethylene glycol: Death may occur within the first 24 hours. If the patient survives, there may be little ...

[Mortality due to pesticide poisoning in Colombia, 1998-2011].

PubMed

Chaparro-Narváez, Pablo; Castañeda-Orjuela, Carlos

2015-08-01

Poisoning due to pesticides is an important public health problem worldwide due its morbidity and mortality. In Colombia, there are no exact data on mortality due to pesticide poisoning. To estimate the trend of mortality rate due to pesticide poisoning in Colombia between 1998 and 2011. We carried out a descriptive analysis with the database reports of death as unintentional poisoning, self-inflicted intentional poisoning, aggression with pesticides, and poisoning with non-identified intentionality, population projections between 1998 and 2011, and rurality indexes. Crude and age-adjusted mortality rates were estimated and trends and Spearman coefficients were evaluated. A total of 4,835 deaths were registered (age-adjusted mortality rate of 2.38 deaths per 100,000 people). Mortality rates were higher in rural areas, for self-inflicted intentional poisoning, in men and in age groups between 15 and 39 years old. The trend has been decreasing since 2002. Municipality mortality rates due to unintentional poisoning and aggression correlated significantly with the rurality index in less rural municipalities. Mortality rates due to pesticide poisoning presented a mild decrease between 1998 and 2011. It is necessary to adjust and reinforce the measures conducive to reducing pesticide exposure in order to avoid poisoning and reduce mortality.

Helping Parents Prevent Lead Poisoning. ERIC Digest.

ERIC Educational Resources Information Center

Binns, Helen J.; Ricks, Omar Benton

Children are at greater risk than adults for lead poisoning because children absorb lead more readily than adults, and a small amount of lead in children's bodies can do a great deal of harm. Some of the causes and effects of childhood lead poisoning and suggests some lead poisoning prevention strategies that parent educators can share with…

[Poisonous animals at bathing beaches].

PubMed

Junghanss, T; Bodio, M

2000-05-18

Tourists and native inhabitants of tropical and subtropical regions differ significantly with regard to the risk and nature of incidents involving venomous and poisonous animals. While the indigenous population encounters such risks daily during work and other activities, tourists are usually endangered while swimming or diving, or by ingesting toxin-containing fish and/or other seafood. Whether abroad or at home, allergic reactions to the stings of bees, wasps and hornets are probably the most common manifestations of an encounter with a "poisonous animal". Travellers should be well acquainted with the dangers entailed in encountering or ingesting a venomous or poisonous animal--prevention is the most important measure.

Oleander poisoning

MedlinePlus

Oleander poisoning occurs when someone eats the flowers or chews the leaves or stems of the oleander plant ( Nerium oleander ), or its relative, the yellow oleander ( Cascabela thevetia ). This article is ...

Mistletoe poisoning

MedlinePlus

... this page: //medlineplus.gov/ency/article/002883.htm Mistletoe poisoning To use the sharing features on this page, please enable JavaScript. Mistletoe is an evergreen plant with white berries. Mistletoe ...

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa: A Randomized Phase 2 Multicenter Placebo-Controlled Clinical Trial.

PubMed

Birch, David G; Bernstein, Paul S; Iannacone, Alessandro; Pennesi, Mark E; Lam, Byron L; Heckenlively, John; Csaky, Karl; Hartnett, Mary Elizabeth; Winthrop, Kevin L; Jayasundera, Thiran; Hughbanks-Wheaton, Dianna K; Warner, Judith; Yang, Paul; Fish, Gary Edd; Teske, Michael P; Sklaver, Neal L; Erker, Laura; Chegarnov, Elvira; Smith, Travis; Wahle, Aimee; VanVeldhuisen, Paul C; McCormack, Jennifer; Lindblad, Robert; Bramer, Steven; Rose, Stephen; Zilliox, Patricia; Francis, Peter J; Weleber, Richard G

2018-06-07

There are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness. To evaluate the potential efficacy and assess the safety of orally administered valproic acid (VPA) in the treatment of autosomal dominant retinitis pigmentosa. Multicenter, phase 2, prospective, interventional, placebo-controlled, double-masked randomized clinical trial. The study took place in 6 US academic retinal degeneration centers. Individuals with genetically characterized autosomal dominant retinitis pigmentosa were randomly assigned to receive treatment or placebo for 12 months. Analyses were intention-to-treat. Oral VPA 500 mg to 1000 mg daily for 12 months or placebo. The primary outcome measure was determined prior to study initiation as the change in visual field area (assessed by the III4e isopter, semiautomated kinetic perimetry) between baseline and month 12. The mean (SD) age of the 90 participants was 50.4 (11.6) years. Forty-four (48.9%) were women, 87 (96.7%) were white, and 79 (87.8%) were non-Hispanic. Seventy-nine participants (87.8%) completed the study (42 [95.5%] received placebo and 37 [80.4%] received VPA). Forty-two (46.7%) had a rhodopsin mutation. Most adverse events were mild, although 7 serious adverse events unrelated to VPA were reported. The difference between the VPA and placebo arms for mean change in the primary outcome was -150.43 degree2 (95% CI, -290.5 to -10.03; P = .035). This negative value indicates that the VPA arm had worse outcomes than the placebo group. This study brings to light the key methodological considerations that should be applied to the rigorous evaluation of treatments for these conditions. This study does not provide support for the use of VPA in the treatment of autosomal dominant retinitis pigmentosa. ClinicalTrials.gov Identifier: NCT01233609.

16 CFR § 1700.15 - Poison prevention packaging standards.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Poison prevention packaging standards. § 1700.15 Section § 1700.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS POISON PREVENTION PACKAGING § 1700.15 Poison prevention packaging...

24 CFR 965.701 - Lead-based paint poisoning prevention.

Code of Federal Regulations, 2010 CFR

2010-04-01

... URBAN DEVELOPMENT PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Lead-Based Paint Poisoning Prevention § 965.701 Lead-based paint poisoning prevention. The requirements of the Lead-Based Paint Poisoning... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Lead-based paint poisoning...

24 CFR 965.701 - Lead-based paint poisoning prevention.

Code of Federal Regulations, 2014 CFR

2014-04-01

... URBAN DEVELOPMENT PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Lead-Based Paint Poisoning Prevention § 965.701 Lead-based paint poisoning prevention. The requirements of the Lead-Based Paint Poisoning... 24 Housing and Urban Development 4 2014-04-01 2014-04-01 false Lead-based paint poisoning...

24 CFR 965.701 - Lead-based paint poisoning prevention.

Code of Federal Regulations, 2012 CFR

2012-04-01

... URBAN DEVELOPMENT PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Lead-Based Paint Poisoning Prevention § 965.701 Lead-based paint poisoning prevention. The requirements of the Lead-Based Paint Poisoning... 24 Housing and Urban Development 4 2012-04-01 2012-04-01 false Lead-based paint poisoning...

24 CFR 965.701 - Lead-based paint poisoning prevention.

Code of Federal Regulations, 2011 CFR

2011-04-01

... URBAN DEVELOPMENT PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Lead-Based Paint Poisoning Prevention § 965.701 Lead-based paint poisoning prevention. The requirements of the Lead-Based Paint Poisoning... 24 Housing and Urban Development 4 2011-04-01 2011-04-01 false Lead-based paint poisoning...

24 CFR 965.701 - Lead-based paint poisoning prevention.

Code of Federal Regulations, 2013 CFR

2013-04-01

... URBAN DEVELOPMENT PHA-OWNED OR LEASED PROJECTS-GENERAL PROVISIONS Lead-Based Paint Poisoning Prevention § 965.701 Lead-based paint poisoning prevention. The requirements of the Lead-Based Paint Poisoning... 24 Housing and Urban Development 4 2013-04-01 2013-04-01 false Lead-based paint poisoning...

Topoisomerase poisoning activity of novel disaccharide anthracyclines.

PubMed

Guano, F; Pourquier, P; Tinelli, S; Binaschi, M; Bigioni, M; Animati, F; Manzini, S; Zunino, F; Kohlhagen, G; Pommier, Y; Capranico, G

1999-07-01

Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I.

Hyperbaric oxygen therapy for carbon monoxide poisoning.

PubMed

Weaver, Lindell K

2014-01-01

Despite established exposure limits and safety standards, and the availability of carbon monoxide (CO) alarms, each year 50,000 people in the United States visit emergency departments for CO poisoning. Carbon monoxide poisoning can occur from brief exposures to high levels of CO, or from longer exposures to lower levels. Common symptoms include headaches, nausea and vomiting, dizziness, general malaise, and altered mental status. Some patients may have chest pain, shortness of breath and myocardial ischemia, and may require mechanical ventilation and treatment of shock. Individuals poisoned by CO often go on to develop neurological problems, including cognitive sequelae, anxiety and depression, persistent headaches, dizziness, sleep problems, motor weakness, vestibular and balance problems, gaze abnormalities, peripheral neuropathies, hearing loss, tinnitus and Parkinsonian-like syndrome. While breathing oxygen hastens the removal of carboxyhemoglobin (COHb), hyperbaric oxygen (HBO2) hastens COHb elimination and favorably modulates inflammatory processes instigated by CO poisoning, an effect not observed with breathing normobaric oxygen. Hyperbaric oxygen improves mitochondrial function, inhibits lipid peroxidation transiently, impairs leukocyte adhesion to injured microvasculature, and reduces brain inflammation caused by the CO-induced adduct formation of myelin basic protein. Based upon three supportive randomized clinical trials in humans and considerable evidence from animal studies, HBO2 should be considered for all cases of acute symptomatic CO poisoning. Hyperbaric oxygen is indicated for CO poisoning complicated by cyanide poisoning, often concomitantly with smoke inhalation.

Snakebite poisoning in Spain.

PubMed

Martín-Sierra, Cristina; Nogué-Xarau, Santiago; Pinillos Echeverría, Miguel Ángel; Rey Pecharromán, José Miguel

2018-01-01

Emergencies due to snakebites, although unusual in Spain, are potentially serious. Of the 13 species native to the Iberian peninsula, only 5 are poisonous: 2 belong to the Colubridae family and 3 to the Viperidae family. Bites from these venemous snakes can be life-threatening, but the venomous species can be easily identified by attending to certain physical traits. Signs denoting poisoning from vipers, and the appropriate treatment to follow, have changed in recent years.

An Unusual Cause of Carbon Monoxide Poisoning: Narghile Smoking

PubMed Central

Ateş, Alpay; Arikan, Müge; Özgök, Ayşegül

2016-01-01

Patient: Male, 27 Final Diagnosis: Carbon monoxide poisoning Symptoms: Dizziness • nausea • Syncope Medication: — Clinical Procedure: O2 treatment Specialty: Anesthesiology Objective: Challenging differential diagnosis Background: Carbon monoxide (CO) poisoning is commonly seen during the winter season in Turkey due to use of charcoal stoves and water heaters, but narghile smoking is a rare cause of CO poisoning. Case Report: In this paper, we report a CO poisoning case caused by narghile smoking. The patient was admitted to the ED with nausea, dizziness, vertigo, and syncope. Conclusions: The diagnosis of CO poisoning depends on suspicious anamnesis. The major treatment of CO poisoning is oxygen supply. PMID:27618983

NCHS Data on Drug-poisoning Deaths

MedlinePlus

... NCHS Materials NCHS NCHS Data on Drug-poisoning Deaths Format: Select One PDF [303K] Recommend on Facebook ... NCHS, National Vital Statistics System, Mortality. Drug-poisoning death rates, by state Deaths per 100,000 population ...

Epidemiology of acute poisoning in children presenting to the poisoning treatment center at Ain Shams University in Cairo, Egypt, 2009-2013.

PubMed

Azab, Sonya M S; Hirshon, Jon Mark; Hirshon, John Mark; Hayes, Bryan D; El-Setouhy, Maged; Smith, Gordon S; Sakr, Mahmoud Lotfy; Tawfik, Hany; Klein-Schwartz, Wendy

2016-01-01

Pediatric poisonings represent a major and preventable cause of morbidity and mortality throughout the world. Epidemiologic information about poisoning among children in many lower- and middle-income countries is scarce. This study describes the epidemiology of acute poisonings in children presenting to Ain Shams University's Poisoning Treatment Center (ASU-PTC) in Cairo and determines the causative agents and characteristics of acute poisoning in several pediatric age groups. This retrospective study involved acutely poisoned patients, 0-18 years of age, who presented to the ASU-PTC between 1 January 2009 and 31 December 2013. Data were extracted from electronic records maintained by the ASU-PTC. Collected data included demographics, substance of exposure, circumstances of the poisoning, patient disposition, and outcome. During the 5-year study period, 38 470 patients meeting our criteria were treated by the ASU-PTC; 19 987 (52%) were younger than 6 years of age; 4196 (11%) were 6-12 years; and 14 287 (37%) were >12 years. Unintentional poisoning accounted for 68.5% of the ingestions, though among adolescents 84.1% of ingestions were with self-harm intent. In all age groups, the most frequent causative drugs were non-opioid analgesics, antipyretics, and antirheumatics. The most common nonpharmaceutical agents were corrosives in preschool children and pesticides in adolescents. Most patients had no/minor effects (29 174 [75.8%]); hospitalization rates were highest among adolescents. There were 119 deaths (case fatality rate of 0.3), primarily from pesticide ingestion. Poisoning in preschool children is mainly unintentional and commonly due to nonpharmaceutical agents whereas poisoning in adolescents is mainly intentional (self-harm). Pesticides, mainly organophosphorous compounds and carbamates, were the most frequent agents leading to morbidity and mortality.

The good and the bad of poisonous plants: an introduction to the USDA-ARS Poisonous Plant Research Laboratory.

PubMed

Welch, Kevin D; Panter, Kip E; Gardner, Dale R; Stegelmeier, Bryan L

2012-06-01

This article provides an overview of the Poisonous Plant Research Laboratory (PPRL), about the unique services and activities of the PPRL and the potential assistance that they can provide to plant poisoning incidences. The PPRL is a federal research laboratory. It is part of the Agricultural Research Service, the in-house research arm of the U.S. Department of Agriculture. The mission of the PPRL is to identify toxic plants and their toxic compounds, determine how the plants poison animals, and develop diagnostic and prognostic procedures for poisoned animals. Furthermore, the PPRL's mission is to identify the conditions under which poisoning occurs and develop management strategies and treatments to reduce losses. Information obtained through research efforts at the PPRL is mostly used by the livestock industry, natural resource managers, veterinarians, chemists, plant and animal scientists, extension personnel, and other state and federal agencies. PPRL currently has 9 scientists and 17 support staff, representing various disciplines consisting of toxicology, reproductive toxicology, veterinary medicine, chemistry, animal science, range science, and plant physiology. This team of scientists provides an interdisciplinary approach to applied and basic research to develop solutions to plant intoxications. While the mission of the PPRL primarily impacts the livestock industry, spinoff benefits such as development of animal models, isolation and characterization of novel compounds, elucidation of biological and molecular mechanisms of action, national and international collaborations, and outreach efforts are significant to biomedical researchers. The staff at the PPRL has extensive knowledge regarding a number of poisonous plants. Although the focus of their knowledge is on plants that affect livestock, oftentimes, these plants are also poisonous to humans, and thus, similar principles could apply for cases of human poisonings. Consequently, the information provided