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Valproic Acid Toxicity

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2. Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase (Full text)

Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues (...) homolog sec -butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec -butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD

2017 International journal of molecular sciences PubMed

3. Thrombotic microangiopathy associated with Valproic acid toxicity. (Full text)

Thrombotic microangiopathy associated with Valproic acid toxicity. Thrombotic microangiopathy (TMA) is a serious, sometimes life-threatening disorder marked by the presence of endothelial injury and microvascular thrombi. Drug-induced thrombotic microangiopathy (DI-TMA) is one specific TMA syndrome that occurs following drug exposure via drug-dependent antibodies or direct tissue toxicity. Common examples include calcineurin inhibitors Tacrolimus and Cyclosporine and antineoplastics Gemcitabine (...) valproic acid toxicity.

2017 BMC Nephrology PubMed

4. Should Pharmacies Be Included in Medication Reconciliation? A Report of Recurrent Valproic Acid Toxicity (Full text)

Should Pharmacies Be Included in Medication Reconciliation? A Report of Recurrent Valproic Acid Toxicity Including outpatient pharmacies in the medication reconciliation process upon hospital discharge is not commonly performed. This case highlights the consequences of a patient refilling a discontinued prescription for valproic acid (VPA). We present a 32-year old male found unresponsive after ingesting delayed release divalproex sodium. Cerebral edema was visualized on magnetic resonance (...) imaging. Hemodialysis and levo-carnitine treatment led to improved mental status, and VPA was discontinued. The same patient presented with VPA overdose eight months later after he continued to fill an outdated prescription. This case highlights consequences of VPA toxicity; it also demonstrates an opportunity to improve patient safety and high-value care by collaborating with outpatient pharmacies in the medication reconciliation process upon hospital discharge.

2017 Clinical Practice and Cases in Emergency Medicine PubMed

5. Valproic Acid Toxicity

Valproic Acid Toxicity Valproic Acid Toxicity Toggle navigation Brain Head & Neck Chest Endocrine Abdomen Musculoskeletal Skin Infectious Disease Hematology & Oncology Cohorts Diagnostics Emergency Findings Procedures Prevention & Management Pharmacy Resuscitation Trauma Emergency Procedures Ultrasound Cardiovascular Emergencies Lung Emergencies Infectious Disease Pediatrics Neurologic Emergencies Skin Exposure Miscellaneous Abuse Cancer Administration 4 Valproic Acid Toxicity Valproic Acid (...) Toxicity Aka: Valproic Acid Toxicity , Valproate Toxicity , Depakote Toxicity , VPA Toxicity II. Mechanism is a simple 2-n-propylpentanoic acid Eight carbon branched-chain carboxylic acid Metabolism: Three primary mechanisms Hepatic Glucuronidation (50%) Glucuronic acid conjugation occurs in the liver Primary metabolism pathway Non-hepatic metabolism Mitochondrial Beta-oxidation (40%) Primary and preferred non-hepatic pathway undergoes beta-oxidation in the mitochondria Requires acetyl-coA to enter

2018 FP Notebook

6. Valproic acid and Stevens-Johnson syndrome: a systematic review of descriptive studies. (PubMed)

Valproic acid and Stevens-Johnson syndrome: a systematic review of descriptive studies. Valproic acid (VPA) is a commonly used antiepileptic drug (AED). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis are the rare but fatal cutaneous adverse drug reactions for VPA. We aimed to identify and critically evaluate all the literature of SJS in association with VPA and to describe the clinical features of the condition. A literature search was conducted in MEDLINE/PubMed from inception (...) of controlling the condition. It is essential for healthcare professionals to be aware of the importance of monitoring SJS or any other cutaneous reactions followed by the use of valproic acid even though the incidence is low, but it is injurious to the patient.© 2019 The International Society of Dermatology.

2019 International Journal of Dermatology

7. Use of meropenem to treat valproic acid overdose. (PubMed)

Use of meropenem to treat valproic acid overdose. Overdose of valproic acid (VPA) or its derivatives can cause significant toxicities such as hyperammonemia or altered mental status. While levocarnitine has been used historically to manage VPA-associated hyperammonemia, no standard of therapy exists to manage VPA toxicity. We present a case of VPA overdose managed with meropenem in addition to levocarnitine. A 38-year old female presented to the emergency department after intentionally

2019 American Journal of Emergency Medicine

8. Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia - identification of responders by gene expression profiling of pretreatment leukemic cells. (Full text)

, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes (...) Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia - identification of responders by gene expression profiling of pretreatment leukemic cells. Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy

2017 BMC Cancer PubMed

9. Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos (Full text)

Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos Failure of neural tube closure in the early embryo causes neural tube defects including spina bifida. Spina bifida lesions predominate in the distal spine, particularly after exposure to the anticonvulsant valproic acid (VPA). How VPA specifically disturbs late stages of neural tube closure is unclear, as neurulation is usually viewed as a uniform 'zippering' process along the spine. We recently (...) identified a novel closure site ("Closure 5") which forms at the caudal extremity of the mouse posterior neuropore (PNP) when completion of closure is imminent. Here we investigated whether distal spina bifida in VPA-exposed embryos involves disruption of Closure 5. Exposure of E8.5 mouse embryos to VPA in whole embryo culture had marked embryotoxic effects, whereas toxic effects were less pronounced in more developmentally advanced (E9) embryos. Only 33% of embryos exposed to VPA from E9 to E10.5

2018 Mechanisms of development PubMed

10. Pharmacokinetics and Safety of High-Dose Intravenous Valproic Acid in Healthy Subjects: A Dose Escalation Trial To Support Clinical Translational Studies (Full text)

valproic acid in healthy humans.A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid.Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg (...) . The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R 2

2018 Clinical pharmacokinetics PubMed

11. Leptin and camel milk abate oxidative stress status, genotoxicity induced in valproic acid rat model of autism (Full text)

Leptin and camel milk abate oxidative stress status, genotoxicity induced in valproic acid rat model of autism The aspect of treatment of autistic behaviour was investigated using valproic acid rat model of pregnant female rats. Two main groups (10 male rats/group) were treated for 6 days and then divided into six subgroups. The first group of normal rats was divided into three subgroups: (A) - control group, (B) - treated with camel milk (CAM; 2 mL/p.o) and (C) - treated with leptin (1000 µg (...) /kg i.p) twice daily. The second group of autistic rats was randomly distributed into four subgroups as follows: (D) - positive control (autistics rats), (E) - treated with CAM, (F) - treated with a moderate dose of leptin and (G) - treated with a higher dose of leptin. Autistic behaviours of male offspring were checked by grooming and elevated pulz maze tests. Valproic acid (VPA)-induced autistic rats showed severe changes in oxidative stress markers, neurotransmitters and inflammatory cytokines

2018 International journal of immunopathology and pharmacology PubMed

12. Lamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome (Full text)

Lamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens-Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered (...) with valproic acid (VPA). Hereby, we present the case of an 8-year-old boy who suffered from SJS and other complications two weeks after LTG was added to his VPA treatment in order to control his seizures. VPA is known to decrease LTG clearance via reduced glucuronidation. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of an arene oxide metabolite would be enhanced. As this reactive metabolite is detoxified mainly by enzymatic reactions, involving

2018 Case reports in medicine PubMed

13. Valproic acid is protective in cellular and worm models of oculopharyngeal muscular dystrophy. (PubMed)

Valproic acid is protective in cellular and worm models of oculopharyngeal muscular dystrophy. To explore valproic acid (VPA) as a potentially beneficial drug in cellular and worm models of oculopharyngeal muscular dystrophy (OPMD).Using a combination of live cell imaging and biochemical measures, we evaluated the potential protective effect of VPA in a stable C2C12 muscle cell model of OPMD, in lymphoblastoid cell lines derived from patients with OPMD and in a transgenic Caenorhabditis elegans (...) OPMD model expressing human mutant PABPN1.We demonstrated that VPA protects against the toxicity of mutant PABPN1. Of note, we found that VPA confers its long-term protective effects on C2C12 cell survival, proliferation, and differentiation by increasing the acetylated level of histones. Furthermore, VPA enhances the level of histone acetylation in lymphoblastoid cell lines derived from patients with OPMD. Moreover, treatment of nematodes with moderate concentrations of VPA significantly improved

2018 Neurology

14. Avelumab With Valproic Acid in Virus-associated Cancer

Avelumab With Valproic Acid in Virus-associated Cancer Avelumab With Valproic Acid in Virus-associated Cancer - Full Text View - ClinicalTrials.gov Hide glossary Glossary Study record managers: refer to the if submitting registration or results information. Search for terms x × Study Record Detail Saved Studies Save this study Warning You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Avelumab With Valproic Acid in Virus-associated (...) a person symptoms, and may be able to escape detection by a person's own immune system. One of the medications being studied in this clinical trial (Valproic acid) may be able to unmask a chronic viral infection from a person's own immune system, therefore making the virus susceptible to attack by the immune system. In this study Valproic acid is being combined with an immune therapy, Avelumab. Avelumab is an antibody that targets a person's own immune cells, or lymphocytes. Lymphocytes must

2017 Clinical Trials

15. L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report (Full text)

of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia (...) L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction

2017 The Journal of international medical research PubMed

16. Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes (Full text)

Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore (...) of the steatosis-related gene EP300 provided novel insight into the mechanisms of toxicity induced by VPA treatment. Furthermore, we suggest that VPA induces a crosstalk between nDNA hypermethylation and mtDNA hypomethylation that plays a role in oxidative stress and steatosis development. Although most VPA-induced methylation patterns appeared reversible upon terminating VPA treatment, 31 nDNA DMRs (including 5 zinc finger protein genes) remained persistent after the WO period. Overall, we have shown

2017 Chemical research in toxicology PubMed

17. pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans (Full text)

pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans Current antifungal drugs suffer from limitations including toxicity, the emergence of resistance and decreased efficacy at low pH that are typical of human vaginal surfaces. Here, we have shown that the antipsychotic drug valproic acid (VPA) exhibited a strong antifungal activity against both sensitive and resistant Candida albicans in pH condition similar to that encountered in vagina. VPA

2017 Frontiers in microbiology PubMed

18. Valproic acid promotes neural regeneration of olfactory epithelium in adult mice after methimazole-induced damage. (PubMed)

Valproic acid promotes neural regeneration of olfactory epithelium in adult mice after methimazole-induced damage. Recent experiments have revealed that valproic acid (VPA), a histone deacetylase inhibitor, has neuroregenerative effects in rodent models of spinal cord and optic nerve injury. VPA has a potential to provide a new therapeutic strategy for sensorineural olfactory dysfunction. To elucidate the effects of VPA on regeneration of olfactory sensory neurons, we examined the in vivo (...) effects of oral VPA administration on recovery from methimazole-induced degeneration of olfactory neuroepithelium in mice.Male ICR mice (10 weeks old) were intraperitoneally injected with methimazole (75 mg/kg), an olfactory toxic reagent, to induce degenerative changes in the olfactory neuroepithelium. The effects of daily VPA administration on recovery from methimazole-induced changes were examined histologically.Oral VPA administration dose dependently enhanced increases in epithelial thickness

2017 American journal of rhinology & allergy

19. A Study to Evaluate the Safety and Tolerability of Valproic Acid in Trauma Patients(Part 2)

A Study to Evaluate the Safety and Tolerability of Valproic Acid in Trauma Patients(Part 2) A Study to Evaluate the Safety and Tolerability of Valproic Acid in Trauma Patients(Part 2) - Full Text View - ClinicalTrials.gov Hide glossary Glossary Study record managers: refer to the if submitting registration or results information. Search for terms x × Study Record Detail Saved Studies Save this study Warning You have reached the maximum number of saved studies (100). Please remove one or more (...) studies before adding more. A Study to Evaluate the Safety and Tolerability of Valproic Acid in Trauma Patients(Part 2) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our for details. ClinicalTrials.gov Identifier: NCT02872428 Recruitment Status : Terminated (at request of funding group because of failure to enroll more than one patient) First Posted

2016 Clinical Trials

20. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia (Full text)

Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia Palliative care in acute myeloid leukaemia (AML) is inadequate. For elderly patients, unfit for intensive chemotherapy, median survival is 2-3 months. As such, there is urgent demand for low-toxic palliative alternatives. We have repositioned two commonly administered anti-leukaemia drugs, valproic acid (VPA) and hydroxyurea (HU), as a combination therapy in AML. The anti-leukemic effect of VPA and HU

2016 Oncotarget PubMed

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