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The Journal of Toxicological Sciences 2024Placental dysfunction can disrupt pregnancy. However, few studies have assessed the effects of chemical-induced toxicity on placental function. Here, we examined the...
Placental dysfunction can disrupt pregnancy. However, few studies have assessed the effects of chemical-induced toxicity on placental function. Here, we examined the effects of valproic acid (VPA) as a model chemical on production of hormones and on glucose uptake in human choriocarcinoma cell line BeWo. Cells were treated with forskolin to differentiate into syncytiotrophoblasts, which were then treated with VPA for 72 hr. Real-time RT-PCR analysis showed that VPA significantly increased the mRNA expression of chorionic gonadotropin β (CGB), a hormone that is produced by the placenta in the first trimester of pregnancy, relative to that in the forskolin-only group. It also suppressed the increase in intracellular glucose uptake and GLUT1 level observed in the forskolin-only group. RNA-seq analysis and pathway database analysis revealed that VPA consistently decreased the level of HIF-1α protein and expression of its downstream target genes HK2 and ADM in the hypoxia pathway. Cobalt chloride, a HIF-1α inducer, inhibited CGB upregulation in VPA-treated cells and rescued VPA-induced suppression of glucose uptake and GLUT1 level. Thus, HIF-1α-mediated elevation of CGB expression and suppression of glucose uptake by VPA is a novel mechanism of placental dysfunction.
Topics: Pregnancy; Female; Humans; Valproic Acid; Placenta; Colforsin; Glucose Transporter Type 1; Glucose; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line, Tumor
PubMed: 38296531
DOI: 10.2131/jts.49.69 -
MedRxiv : the Preprint Server For... Apr 2024Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with...
Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.
PubMed: 38712133
DOI: 10.1101/2024.04.23.24304634 -
Trauma Surgery & Acute Care Open 2023Valproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic...
BACKGROUND
Valproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic shock, and combined injuries. This study was designed to investigate the ability of VPA to mitigate ischemia-reperfusion injury produced by prolonged tourniquet application to an extremity.
METHODS
The ischemia-reperfusion model in anesthetized rats was established using hemorrhage and a 3-hour tourniquet application. VPA was administered intravenously prior to tourniquet wear and removal. Ischemia-reperfusion injury was evaluated by investigating pathway signaling, immune modulation of cytokine release, remote organ injury, and skeletal muscle function during convalescence.
RESULTS
We found that VPA sustained Protein kinase B (Akt) phosphorylation and Insulin-like growth factor signaling and modulated the systemic release of interleukin (IL)-1β, tumor necrosis factor alpha, and IL-6 after 2 hours of limb reperfusion. Additionally, VPA attenuated a loss in glomerular filtration rate at 3 days after injury. Histological and functional evaluation of extremity skeletal muscle at 3, 7, and 21 days after injury, however, demonstrated no significant differences in myocytic degeneration, necrotic formation, and maximal isometric tetanic torque.
CONCLUSIONS
Our results demonstrate that VPA sustains early prosurvival cell signaling, reduces the inflammatory response, and improves renal function in a hemorrhage with prolonged ischemia and reperfusion model. However, these do not translate into meaningful preservation in limb function when applied as a pharmaceutical augmentation to tourniquet wear.
LEVEL OF EVIDENCE
IV.
PubMed: 37484837
DOI: 10.1136/tsaco-2022-001074 -
Archives of Biochemistry and Biophysics Oct 2023Mucopolysaccharidoses (MPS) are a group of inherited disorders, caused by mutations in the genes coding for proteins involved (directly or indirectly) in...
Mucopolysaccharidoses (MPS) are a group of inherited disorders, caused by mutations in the genes coding for proteins involved (directly or indirectly) in glycosaminoglycan (GAG) degradation. A lack or drastically decreased residual activity of a GAG-degrading enzyme leads to the storage of these compounds, thus damaging proper functions of different cells, including neurons. The disease leads to serious psycho-motor dysfunctions and death before reaching the adulthood. Until now, induction of the autophagy process was considered as one of the therapeutic strategies for treatment of diseases caused by protein aggregation (Alzheimer's, Parkinson's, and Huntington's diseases). However, this strategy has only been recently suggested as a potential therapy for MPS. In this work, we show that the pharmacological stimulation of autophagy, by using valproic acid and lithium chloride, led to accelerated degradation of accumulated GAGs. Cytotoxicity tests indicated the safety of the use of the investigated compounds. We observed an increased number of lysosomes and enhanced degradation of heparan sulfate (one of GAGs). Induction of the autophagy process was confirmed by measuring abundance of the marker proteins, including LC3-II. Moreover, inhibition of this process resulted in abolition of the valproic acid- and LiCl-mediated reduction in GAG levels. This is the first report on the possibility of using valproic acid and lithium chloride for reducing levels of GAGs in neuronopathic forms of MPS.
PubMed: 37708928
DOI: 10.1016/j.abb.2023.109754 -
International Journal of Antimicrobial... Feb 2024Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced...
BACKGROUND
Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced hypofibrinogenaemia, it remains unknown whether valproic acid or voriconazole in combination with tigecycline is associated with the decrease in fibrinogen, as both drugs could lead to coagulation disorders. The aim of this study was to develop a nomogram for the prediction of tigecycline-induced hypofibrinogenaemia.
METHODS
This was a multi-centre retrospective case-control study. The primary outcome was the accurate prediction of tigecycline-induced hypofibrinogenaemia. Nomograms were developed from logistic regression models with least absolute shrinkage and selection operator regression for variable selection. Model performance was assessed via calibration plots, and models were validated internally using bootstrapping on a validation cohort.
RESULTS
In total, 2362 patients were screened, of which 611 were eligible for inclusion in this study. These 611 patients were divided into the training cohort (n=488) and the validation cohort (n=123). Predictors included in the nomogram for the total population were total dose, age, fibrinogen, prothrombin time (PT), comorbidity, and concomitant use of voriconazole. Total dose, fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concomitant use of voriconazole were selected to predict hypofibrinogenaemia in patients with malignant haematologic diseases. Both models were calibrated adequately, and their predictions were correlated with the observed outcome. The cut-offs for treatment duration in the total population and the subgroup were 10 and 6 days, respectively.
CONCLUSIONS
Tigecycline in combination with voriconazole could increase the risk of hypofibrinogenaemia, and tigecycline-induced hypofibrinogenaemia is more likely to occur in patients with malignant haematologic diseases.
Topics: Humans; Tigecycline; Nomograms; Afibrinogenemia; Retrospective Studies; Case-Control Studies; Voriconazole; Fibrinogen
PubMed: 38104947
DOI: 10.1016/j.ijantimicag.2023.107062 -
American Journal of Cancer Research 2023Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic...
Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic astrocytoma (AA) or glioblastoma (GBM) treated with concomitant and adjuvant 20-30 mg/m/dose of vinorelbine and 30 mg/kg/day valproic acid (VA) in combination to consolidated TMZ and focal RT after maximal surgery. We evaluated the feasibility of treating children diagnosed with HGG. The median follow-up time was 51.4 months (range, 6.2-106.6 months). The 5-year OS was 57.9% (CI 95%, 33.2-76.3) and the 5-year PFS was 57.9% (CI 95%, 33.2-76.3). Eight patients (42.1%) have progressed so far, with a median time to progression of 9 months from diagnosis (range, 4.6-34.7 months). All of them died for disease progression. At time of analysis, 11 patients were still alive with no evidence of disease. It is notable that all events occurred within 35 months from the start of therapy. All 19 treated patients reported low-grade drug-related adverse events (AEs). The treatment was well tolerated in our limited cohort of patients without significant toxicity. Further studies of the efficacy and safety of combination of vinorelbine/VA to consolidated RT/TMZ therapy in children with HGG are underway in a clinical trial setting.
PubMed: 37693163
DOI: No ID Found -
Gels (Basel, Switzerland) Jul 2023Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability...
GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.
Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on T for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% /). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.
PubMed: 37623058
DOI: 10.3390/gels9080603 -
Molecular Biology Research... 2024Among leading causes of the ischemic stroke pathogenesis, oxidative stress strongly declines rate of stem cell engraftment at the injury site, and disables stem...
Valproic acid and/or rapamycin preconditioning protects hair follicle stem cells from oxygen glucose serum deprivation-induced oxidative injury via activating Nrf2 pathway.
Among leading causes of the ischemic stroke pathogenesis, oxidative stress strongly declines rate of stem cell engraftment at the injury site, and disables stem cell-based therapy as a key treatment for ischemia stroke. To overcome this therapeutic limitation, preconditioning has been represented a possible approach to augment the adaptation and viability of stem cells to oxidative stress. Here, we illustrated protective impacts of valproic acid (VPA) and/or rapamycin (RAPA) preconditioning unto oxygen glucose and serum deprivation (OGSD)-stimulated cell damage in hair follicle-derived stem cells (HFSCs) and surveyed the plausible inducement mechanisms. OGSD, as an cell injury model, was established and HFSCs viability was observed using MTT assay after VPA, RAPA, and VPA-RAPA preconditioning under OGSD. ROS and MDA production was assessed to reflect oxidative stress. Real-time PCR and western blotting were employed to investigate Nrf2 expression. The activity of Nrf2-related antioxidant enzymes including NQO1, GPx and GSH level were examined. and mRNA expression levels were analyzed. Our results showed that VPA and/or RAPA preconditioning ameliorated OGSD-induced decline in HFSCs viability. In addition, they considerably prohibited ROS and MDA generation in the OGSD-treated HFSCs. Furthermore, VPA and/or RAPA preconditioning stimulated Nrf2 nuclear repositioning and NQO1 and GPx activity and GSH amount, as well as expression of paracrine factors and in OGSD-treated HFSCs. Thus, the protective effects afforded by VPA and/or RAPA preconditioning, which involved Nrf2-modulated oxidant stress and regulation of and expression, display a simple strategy to augment cell-transplantation efficiency for ischemic stroke.
PubMed: 38915453
DOI: 10.22099/mbrc.2024.49302.1922 -
Epilepsia Open Sep 2023Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions...
Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q -Q ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.
Topics: Humans; Anticonvulsants; Pharmacogenetics; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Pilot Projects; Cytochrome P-450 CYP2C9; Saliva; Epilepsy; Phenytoin; Clobazam; Phenobarbital
PubMed: 36840436
DOI: 10.1002/epi4.12717 -
CNS Drugs Nov 2023Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The...
Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.
BACKGROUND AND OBJECTIVES
Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials.
METHODS
The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly.
RESULTS
This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021.
CONCLUSION
Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.
Topics: Humans; Child; Adult; Female; Middle Aged; Aged; Aged, 80 and over; Male; Anticonvulsants; Phenytoin; Midazolam; Levetiracetam; Valproic Acid; Propofol; Lacosamide; Hospitals, University; Status Epilepticus; Phenobarbital; Benzodiazepines; Medical Records
PubMed: 37979095
DOI: 10.1007/s40263-023-01049-w