-
Pharmacogenetics and Genomics Apr 2013
Topics: Cytochrome P-450 Enzyme System; Humans; Metabolic Networks and Pathways; Pharmacogenetics; Valproic Acid
PubMed: 23407051
DOI: 10.1097/FPC.0b013e32835ea0b2 -
Issues in Mental Health Nursing Nov 2022
Topics: Humans; Valproic Acid; Delirium; Brain Injuries, Traumatic
PubMed: 36136610
DOI: 10.1080/01612840.2022.2122431 -
Neurotherapeutics : the Journal of the... Jan 2007The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become... (Review)
Review
The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.
Topics: Animals; Anticonvulsants; Brain; Clinical Trials as Topic; Epilepsy; Humans; Structure-Activity Relationship; Valproic Acid
PubMed: 17199028
DOI: 10.1016/j.nurt.2006.11.007 -
Indian Pediatrics Aug 1991
Review
Topics: Dosage Forms; Drug Administration Schedule; Drug Interactions; Female; Humans; Infant, Newborn; Milk, Human; Pregnancy; Pregnancy Complications; Seizures; Valproic Acid
PubMed: 1808081
DOI: No ID Found -
European Journal of Pharmacology Sep 2018Breast cancer is one of the leading causes of cancer-related death among women. A significant challenge in treating breast cancer is the limited array of therapeutic... (Review)
Review
Breast cancer is one of the leading causes of cancer-related death among women. A significant challenge in treating breast cancer is the limited array of therapeutic options and the rapid development of resistance to existing agents. Indeed, breast cancer patients, particularly those with hormone-receptor (HR)-positive breast cancer, initially respond to systemic treatment with cytotoxic, hormonal, and immunotherapeutic agents but frequently progress to a more advanced disease that is refractory to therapy. Thus, new agents are needed to improve the effectiveness of current agents, decrease the emergence of resistance, and increase disease-free survival. To this end, numerous agents have been investigated for use in combination with existing therapies. Histone deacetylase (HDAC) inhibitors are a class of potent epigenetic modulators that have been investigated recently for their potential use in the treatment of breast cancer. In this review, we will discuss the underlying molecular rationale for using HDAC inhibitors for the treatment of breast cancer. In particular, we will focus our discussion on the FDA approved HDAC inhibitor valproic acid (VPA) which has been shown to alter proliferation, survival, cell migration, and hormone receptor expression of breast cancer cells in both the pre-clinical and clinical settings. We also discuss the promising pre-clinical data suggesting that VPA can be repurposed as an adjunctive agent in combination with many cytotoxic, hormonal, and immunotherapeutic agents for the treatment of breast cancer. Finally, we will examine the current models used to study the actions of VPA on breast cancer alone and in tandem with other agents.
Topics: Animals; Breast Neoplasms; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Valproic Acid
PubMed: 30075223
DOI: 10.1016/j.ejphar.2018.07.057 -
Brazilian Journal of Biology = Revista... 2022Valproic acid in association with sodium valproate (VPA) is an important anticonvulsant drug used for decades to treat neurological disorders. VPA also acts as an... (Review)
Review
Valproic acid in association with sodium valproate (VPA) is an important anticonvulsant drug used for decades to treat neurological disorders. VPA also acts as an epigenetic modulator by inhibiting histone deacetylases, permitting histone acetylation, affecting the DNA and histone methylation status and gene expression, and inducing chromatin remodeling. Insects represent an important animal model for studies in several areas of science. Their high phenotypic plasticity makes them alternative models for epigenetic studies. This brief review emphasizes recent reports on insect epigenetics and the contribution of studies on the VPA action in insects, including effects on epigenetic markers, extending the pharmacological understanding of the potential of this drug, and demonstrating the usefulness of insects as an alternative animal model to drug studies.
Topics: Acetylation; Animals; Disease Models, Animal; Epigenesis, Genetic; Histones; Insecta; Valproic Acid
PubMed: 35416850
DOI: 10.1590/1519-6984.256045 -
Folia Biologica 2007Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and... (Review)
Review
Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the behaviour of cancer cells.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Teratogens; Valproic Acid
PubMed: 17448293
DOI: No ID Found -
Molecules (Basel, Switzerland) Dec 2021Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and... (Review)
Review
Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.
Topics: Amides; Animals; Anticonvulsants; Drug Monitoring; Epilepsy; Humans; Molecular Structure; Structure-Activity Relationship; Teratogens; Urea; Valproic Acid
PubMed: 35011339
DOI: 10.3390/molecules27010104 -
Drugs Feb 1994Valproic acid is a branched-chained fatty acid, structurally unrelated to any other antiepileptic drug. Since publication of the original review in the Journal in 1977,... (Review)
Review
Valproic acid is a branched-chained fatty acid, structurally unrelated to any other antiepileptic drug. Since publication of the original review in the Journal in 1977, several clinical trials have documented its efficacy and safety in adults and children for the treatment of generalised seizures (absence, tonic-clonic, myoclonic), partial seizures (simple, complex, secondarily generalised) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Valproic acid monotherapy has demonstrated efficacy equivalent to that of carbamazepine, phenytoin, and phenobarbital in the treatment of both generalised and partial seizures and ethosuximide in the treatment of absence seizures. Adverse effects associated with the drug are primarily gastrointestinal (nausea, vomiting, dyspepsia) in nature, although the use of enteric-coated formulations has reduced the incidence of abdominal discomfort. Weight gain, tremor and transient hair loss are commonly reported. Importantly, valproic acid has minimal neurological adverse effects (sedation, ataxia, impairment of cognitive function) compared with other antiepileptic drugs, a finding that may be of particular relevance in many patients with epilepsy. The incidence of rare, fatal liver failure has been greatly reduced by identifying and avoiding administration of valproic acid to high risk patient populations. An estimated risk of 1 to 2% for neural tube defects, predominantly spina bifida aperta, with maternal use of valproic acid therapy has been reported. Valproic acid inhibits hepatic drug metabolism and displaces other highly bound drugs from their plasma protein binding sites. Therefore, coadministered drugs which are highly protein bound or hepatically metabolised may require dosage adjustment. Enzyme-inducing antiepileptic drugs may increase valproic acid metabolism and necessitate increasing its dosage. Thus, comparative trials and extensive clinical experience have demonstrated the efficacy and tolerability of valproic acid and support its role as a valuable and well established first-line treatment for patients with a broad range of seizure types.
Topics: Adult; Aged; Aging; Animals; Anticonvulsants; Child; Clinical Trials as Topic; Drug Interactions; Electroencephalography; Epilepsy; Humans; Valproic Acid
PubMed: 7512905
DOI: No ID Found -
Cells Jun 2020The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technology, with the potential to generate transgenic...
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technology, with the potential to generate transgenic animals. Particularly, efficient and precise genetic editing with CRISPR/Cas9 offers immense prospects in various biotechnological applications. Here, we report that the histone deacetylase inhibitor valproic acid (VPA) significantly increases the efficiency of CRISPR/Cas9-mediated gene editing in mouse embryonic stem cells and embryos. This effect may be caused through globally enhanced chromatin accessibility, as indicate by histone hyperacetylation. Taken together, our results suggest that VPA can be used to increase the efficacy of CRISPR/Cas9 in generating transgenic systems.
Topics: Animals; CRISPR-Cas Systems; Gene Editing; Humans; Mice; Mice, Transgenic; Valproic Acid
PubMed: 32532133
DOI: 10.3390/cells9061447