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Behavioural Brain Research Jun 2022Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficit and repetitive behaviour. In the past few years, increasing...
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficit and repetitive behaviour. In the past few years, increasing clinical evidence has shown that the cerebellum may contribute to the neuropathology of ASD. However, studies in the mechanism for the involvement of the cerebellum in autism remained speculative. Although some have suggested the possibility of a change of glutamate decarboxylases in the cerebellum of autistic patients, this remains controversial and is limited to the alteration in transcriptional level. This study aimed to investigate the cerebellar structure and determine the expression of rate-limiting GABAergic enzymes in GABA signalling of the autism cerebellum. Pregnant C57BL/6 J mice were intraperitoneally injected with a dosage of 500 mg/kg valproic acid (VPA) on embryonic day 10.5 for autistic behavioural induction. This study found that early prenatal exposure to VPA led to tail deformation and decreased cerebellar weight and size. Early adult mouse models with autistic behaviour showed reduced expression of both isoforms of glutamate decarboxylases (GAD) 65 and 67 in the cerebellum. Also, protein expressions of cerebellar type 1 GABA transporter (GAT-1) and GABA transaminase (GABAT) were reduced in VPA mice. It indicated that abnormal GABA production, recycling, and metabolism could alter the excitatory-inhibitory balance in the autistic cerebellum. Thus, our findings provide supporting evidence that cerebellum impairment could be an etiology of environmentally induced autism. Changes in cerebellar structure and the altered GABAergic enzymes in the cerebellum provide targets for future therapeutic studies in idiopathic autism.
Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Cerebellum; Disease Models, Animal; Female; Glutamate Decarboxylase; Glutamates; Humans; Mice; Mice, Inbred C57BL; Pregnancy; Prenatal Exposure Delayed Effects; Valproic Acid; gamma-Aminobutyric Acid
PubMed: 35436531
DOI: 10.1016/j.bbr.2022.113896 -
Bioorganic Chemistry Jun 2020Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the...
Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Isoenzymes; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Valproic Acid
PubMed: 32247939
DOI: 10.1016/j.bioorg.2020.103797 -
Journal of Breath Research Sep 2023Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes....
Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes. Routine analyses rely on the quantification of systemic blood concentrations of drugs. Alternative matrices such as exhaled breath are appealing because of their inherent non-invasive nature. This is especially the case for pediatric patients. We have recently showcased the possibility of predicting systemic concentrations of valproic acid (VPA), an anti-seizure medication by real-time breath analysis in two real clinical settings. This approach, however, comes with the limitation of the patients having to physically exhale into the mass spectrometer. This restricts the possibility of sampling from patients not capable or available to exhale into the mass spectrometer located on the hospital premises. In this work, we developed an alternative method to overcome this limitation by collecting the breath samples in customized bags and subsequently analyzing them by secondary electrospray ionization coupled to high-resolution mass spectrometry (SESI-HRMS). A total of= 40 patients (mean ± SD, 11.5 ± 3.5 y.o.) diagnosed with epilepsy and taking VPA were included in this study. The patients underwent three measurements: (i) serum concentrations of total and free VPA, (ii) real-time breath analysis and (iii) off-line analysis of exhaled breath collected in bags. The agreement between the real-time and the off-line breath analysis methods was evaluated using Lin's concordance correlation coefficient (CCC). CCC was computed for ten mass spectral predictors of VPA concentrations. Lin's CCC was >0.6 for all VPA-associated features, except for two low-signal intensity isotopic peaks. Finally, free and total serum VPA concentrations were predicted by cross validating the off-line data set. Support vector machine algorithms provided the most accurate predictions with a root mean square error of cross validation of 29.0 ± 7.4 mg land 3.9 ± 1.4 mg lfor total and free VPA (mean ± SD), respectively. As a secondary analysis, we explored whether exhaled metabolites previously associated with side-effects and response to medication could be rendered by the off-line analysis method. We found that five features associated with side effects showed a CCC > 0.6, whereas none of the drug response-associated peaks reached this cut-off. We conclude that the clinically relevant free fraction of VPA can be predicted by this combination of off-line breath collection with rapid SESI-HRMS analysis. This opens new possibilities for breath based TDM in clinical settings.
Topics: Humans; Adolescent; Child; Female; Valproic Acid; Breath Tests; Algorithms; Body Fluids; Breast Neoplasms
PubMed: 37678210
DOI: 10.1088/1752-7163/acf782 -
The Journal of Pharmacy and Pharmacology Nov 2017This study was aimed to investigate the potential of formulated valproic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavailability of valproic acid... (Comparative Study)
Comparative Study
OBJECTIVE
This study was aimed to investigate the potential of formulated valproic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavailability of valproic acid (VPA).
METHODS
Valproic acid-encapsulated nanoemulsions were formulated and physically characterised (osmolarity, viscosity, drug content, drug encapsulation efficiency). Further investigations were also conducted to estimate the drug release, cytotoxic profile, in-vitro blood-brain barrier (BBB) permeability, pharmacokinetic parameter and the concentration of VPA and VANE in blood and brain.
KEY FINDINGS
Physical characterisation confirmed that VANE was suitable for parenteral administration. Formulating VPA into nanoemulsion significantly reduced the cytotoxicity of VPA. In-vitro drug permeation suggested that VANEs crossed the BBB as freely as VPA. Pharmacokinetic parameters of VANE-treated rats in plasma and brain showed F3 VANE had a remarkable improvement in AUC, prolongation of half-life and reduction in clearance compared to VPA. Given the same extent of in-vitro BBB permeation of VPA and VANE, the higher bioavailability of VANE in brain was believed to have due to higher concentration of VANE in blood. The brain bioavailability of VPA was improved by prolonging the half-life of VPA by encapsulating it within the nanoemulsion-T80.
CONCLUSIONS
Nanoemulsion containing VPA has alleviated the cytotoxic effect of VPA and improved the plasma and brain bioavailability for parenteral delivery of VPA.
Topics: Animals; Anticonvulsants; Area Under Curve; Biological Availability; Blood-Brain Barrier; Brain; Cell Line; Chemistry, Pharmaceutical; Drug Compounding; Drug Delivery Systems; Drug Liberation; Emulsions; Half-Life; Humans; Nanoparticles; Rats; Rats, Sprague-Dawley; Tissue Distribution; Valproic Acid
PubMed: 28809443
DOI: 10.1111/jphp.12800 -
Expert Review of Clinical Pharmacology May 2022This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to...
Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder.
BACKGROUND
This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance.
METHODS
Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting).
RESULTS
Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting.
CONCLUSION
In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.
Topics: Adult; Anticonvulsants; Bayes Theorem; Bipolar Disorder; Child; China; Epilepsy; Humans; Inpatients; Models, Biological; Valproic Acid
PubMed: 35536685
DOI: 10.1080/17512433.2022.2075849 -
Minerva Ginecologica Jun 2018Valproic acid (VPA) is an anti-epileptic drug (AED) which is currently being investigated for its potential application in the treatment of several types of cancers,... (Review)
Review
Valproic acid (VPA) is an anti-epileptic drug (AED) which is currently being investigated for its potential application in the treatment of several types of cancers, including solid and non-solid tumor. It is well-known that prenatal exposure to VPA largely increases the risk for malformations and other developmental disorders. This review concentrates on clinical and experimental data on congenital anomalies attributed to maternal VPA exposure. Particular emphasis is placed on the potential mechanisms underlying VPA-induced malformations. Although several mechanisms have been suggested, there appears to be no data in the literature in support of a single definitive mechanism for VPA-exposure-related fetal malformations.
Topics: Abnormalities, Drug-Induced; Animals; Anticonvulsants; Antineoplastic Agents; Female; Humans; Neoplasms; Pregnancy; Teratology; Valproic Acid
PubMed: 28398022
DOI: 10.23736/S0026-4784.17.04063-1 -
Expert Review of Neurotherapeutics May 2016Recent studies of reflex epileptic mechanisms in human epilepsy using advanced methods of neurophysiology and functional neuroimaging have contributed much to elucidate... (Review)
Review
Recent studies of reflex epileptic mechanisms in human epilepsy using advanced methods of neurophysiology and functional neuroimaging have contributed much to elucidate pathophysiological processes of seizure generation. Whereas in lesional focal epilepsies reflex mechanisms usually relate directly to the anatomical focus, in system epilepsies they have helped to define which functional anatomical systems serving physiological function are recruited by the ictogenic mechanisms. Reflex epileptic seizures can often be prevented by avoidance or modification of triggers or by prophylactic benzodiazepine administration. Surgical options apply to focal cases. According to restricted experiences with pharmacotherapy, without controlled studies and little information on new AEDs, reflex seizures in system epilepsies appear to respond best to valproic acid and in focal epilepsies, to carbamazepine.
Topics: Epilepsies, Partial; Epilepsy; Epilepsy, Reflex; Humans; Seizures; Valproic Acid
PubMed: 26999567
DOI: 10.1586/14737175.2016.1169174 -
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 -
Molecules (Basel, Switzerland) May 2021High performance liquid chromatography with ultra-violet detection (HPLC-UV) and gas chromatography-mass spectrometry (GC-MS) methods were developed and validated for...
High performance liquid chromatography with ultra-violet detection (HPLC-UV) and gas chromatography-mass spectrometry (GC-MS) methods were developed and validated for the determination of chlorambucil (CLB) and valproic acid (VPA) in plasma, as a part of experiments on their anticancer activity in chronic lymphocytic leukemia (CLL). CLB was extracted from 250 µL of plasma with methanol, using simple protein precipitation and filtration. Chromatography was carried out on a LiChrospher 100 RP-18 end-capped column using a mobile phase consisting of acetonitrile, water and formic acid, and detection at 258 nm. The lowest limit of detection LLOQ was found to be 0.075 μg/mL, showing sufficient sensitivity in relation to therapeutic concentrations of CLB in plasma. The accuracy was from 94.13% to 101.12%, while the intra- and inter-batch precision was ≤9.46%. For quantitation of VPA, a sensitive GC-MS method was developed involving simple pre-column esterification with methanol and extraction with hexane. Chromatography was achieved on an HP-5MSUI column and monitored by MS with an electron impact ionization and selective ion monitoring mode. Using 250 µL of plasma, the LLOQ was found to be 0.075 μg/mL. The accuracy was from 94.96% to 109.12%, while the intra- and inter-batch precision was ≤6.69%. Thus, both methods fulfilled the requirements of FDA guidelines for the determination of drugs in biological materials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calibration; Chlorambucil; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Valproic Acid
PubMed: 34068372
DOI: 10.3390/molecules26102903 -
The Lancet. Healthy Longevity Jun 2021Histone deacetylase inhibitors (HDACi) regulate gene expression via epigenetic mechanisms. Accumulating evidence suggests that HDACi exert antiproliferative,... (Review)
Review
Histone deacetylase inhibitors (HDACi) regulate gene expression via epigenetic mechanisms. Accumulating evidence suggests that HDACi exert antiproliferative, antioxidant, antineoplastic, and proapoptotic effects through epigenetic mechanisms. Furthermore, HDACi also exert antithrombotic and antifibrotic effects through regulation of thrombotic and fibrotic transduction mechanisms. One of the oldest HDACi is valproic acid, which was first synthesised in 1882. After the discovery of its anticonvulsant properties for the treatment of epilepsy, the use of valproic acid was extended to other conditions, such as bipolar disorder and migraine. Given the accumulating evidence supporting the role of HDACi in the treatment of multiple medical conditions beyond epilepsy, the interest in novel potential indications for HDACi has been renewed. Considering the pleotropic epigenetic effects of HDACi, future studies could assess their efficacy and safety for cardiovascular disease prevention and treatment; treatment of venous thrombosis, Alzheimer's disease, autoimmune and proinflammatory conditions, chronic thromboembolic pulmonary hypertension, and pulmonary arterial hypertension; and as a coadjuvant therapy for cancer. Adequately designed and powered clinical trials are required to assess the efficacy and safety of HDACi before their clinical repurposing.
Topics: Antineoplastic Agents; Cardiovascular Diseases; Histone Deacetylase Inhibitors; Humans; Longevity; Valproic Acid
PubMed: 36098145
DOI: 10.1016/S2666-7568(21)00061-1