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Naunyn-Schmiedeberg's Archives of... Jun 2024Lithium is the gold standard drug in the treatment of bipolar disorder. Despite increasing scientific interest, relatively few patients with bipolar disorder receive...
Lithium is the gold standard drug in the treatment of bipolar disorder. Despite increasing scientific interest, relatively few patients with bipolar disorder receive lithium therapy. Lithium is the only drug that is effective in the prophylaxis of manic, depressive, and suicidal symptoms. Lithium therapy is also associated with a variety of adverse drug reactions and the need for therapeutic drug monitoring. Numerous studies have focussed on the efficacy and safety of both lithium-monotherapy and lithium-add-on therapy. The aim of this study is to provide a systematic overview of clinical studies on lithium therapy for bipolar disorder from the last 7 years and to present a critical analysis of these studies. The results provide an up-to-date overview of the efficacy, tolerability, and safety of lithium therapy for bipolar disorder and thus improve the pharmacotherapy of bipolar disorder. A total of 59 studies were analysed using various analysis parameters. The studies were also categorised into different subgroups. These are lithium-monotherapy, lithium vs. placebo/drug, and lithium + adjunctive therapy. The majority of the studies (N = 20) had a duration of only 3-8 weeks. Only 13 studies lasted for > 40 weeks. Lithium was superior to aripiprazole, valproic acid, and quetiapine in terms of improving manic symptoms. Lithium therapy resulted in a lower relapse rate compared to valproic acid therapy. Lithium was more neuroprotectively effective than quetiapine. Fourteen of the 22 add-on therapies to lithium showed a predominantly positive effect on the treatment outcome compared to lithium-monotherapy. Only the add-on therapy with sertraline led to a higher rate of study discontinuations than lithium-monotherapy. Lithium is a safe and effective treatment option for children. However, risperidone and quetiapine were superior to lithium in some aspects, which is why these drugs should be considered as an alternative treatment option for children. Collectively, current clinical studies highlight the relevance of lithium in the treatment of bipolar disorder.
PubMed: 38916833
DOI: 10.1007/s00210-024-03210-8 -
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 -
Clinical Toxicology (Philadelphia, Pa.) Jun 2024Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying...
INTRODUCTION
Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive.
METHODS
To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
RESULTS
The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients ( ˂ 0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, = 0.010; 17.6 percent versus 5.2 percent, = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of exhibited significant differences in the concentrations of glutamine and glutamate concentrations ( ˂ 0.001 and = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, ˂ 0.001, respectively). Furthermore, logistic regression analysis indicated that ( = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate ( = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity ( = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
DISCUSSION
Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
CONCLUSION
Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, , glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.
PubMed: 38913595
DOI: 10.1080/15563650.2024.2366920 -
The Medico-legal Journal Jun 2024
Topics: Humans; Valproic Acid; Surgical Mesh
PubMed: 38912698
DOI: 10.1177/00258172231185488 -
Cureus May 2024Immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-known side effect of chimeric antigen receptor (CAR) T-cell therapy but has occasionally been...
Glofitamab-Associated Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Presenting as Serial Seizures and Responding Positively to Antiseizure Drugs and Anakinra: A Case Report.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-known side effect of chimeric antigen receptor (CAR) T-cell therapy but has occasionally been described with immune checkpoint inhibitors as well. Glofitamab-associated ICANS with a bispecific monoclonal antibody has rarely been reported. The patient is a 63-year-old male with a history of mantle cell lymphoma, diagnosed at age 37, and aggressive large-cell B-cell lymphoma, diagnosed at age 50. Despite adequate chemotherapy, immunotherapy, autologous stem cell transplantation, and CAR T-cell therapy, there were several relapses, including meningeal carcinomatosis at age 61 and intracerebral lymphoma at age 62. For this reason, glofitamab was started. One week after the ninth cycle, the patient developed drowsiness, behavioral changes, word-finding difficulties, aphasia, focal to bilateral tonic-clonic seizures, and focal onset seizures, which resolved after 16 days with levetiracetam, valproic acid, lorazepam, and midazolam. Since there was no infectious disease, electrolyte disturbance, metabolic disorder, cardiovascular disease, or relapse of lymphoma, glofitamab-associated ICANS was suspected, and anakinra was administered. The case shows that ICANS with drowsiness, behavioral changes, aphasia, and seizures can develop with glofitamab and that patients with structural brain abnormalities may be prone to this.
PubMed: 38910651
DOI: 10.7759/cureus.60833 -
Frontiers in Pharmacology 2024Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions....
Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last two decades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Therefore, the anticonvulsant effect of the H3R antagonist DL76, with proven high affinity, selectivity profile, and high antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76-provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist -(α)-methylhistamine (RAM, 10 mg/kg, i.p.). Furthermore, the administration of single (7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg, i.p.) or multiple doses (3 × 15 mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths , signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy.
PubMed: 38903994
DOI: 10.3389/fphar.2024.1364353 -
The New Zealand Medical Journal Jun 2024To compare sodium valproate dispensing in women of childbearing age diagnosed with borderline personality disorder in 2014 and 2019 to discover if prescribing practices...
AIMS
To compare sodium valproate dispensing in women of childbearing age diagnosed with borderline personality disorder in 2014 and 2019 to discover if prescribing practices in Aotearoa New Zealand have changed in response to international recommendations.
METHODS
National dispensing data from the Pharmaceutical Collection were linked with diagnostic data from PRIMHD (the national mental health and addiction database) to identify people diagnosed with borderline personality disorder in Aotearoa New Zealand who were dispensed psychotropic medication. Dispensing of sodium valproate for women of childbearing age was compared between 2014 and 2019. Rates of dispensing were compared between ethnicities.
RESULTS
In 2014, 10% of women of childbearing age diagnosed with borderline personality disorder were dispensed sodium valproate. This reduced to 6% of women in 2019 (p<0.001). In 2014, there was substantial ethnic disparity with 18.1% of Māori women and 15.8% of Pacific women dispensed sodium valproate compared with 7.4% of New Zealand Europeans. This disparity reduced in 2019, with 6.4% of Māori women and 12.5% of Pacific women dispensed sodium valproate compared with 5.6% of New Zealand Europeans.
CONCLUSIONS
These findings suggest that international recommendations and guidelines have been effective in changing clinical practice and reducing ethnic inequities. Given the significant risk to offspring exposed to sodium valproate, we echo warnings against off-label prescribing of sodium valproate in borderline personality disorder.
Topics: Humans; Borderline Personality Disorder; New Zealand; Female; Valproic Acid; Adult; Young Adult; Adolescent; Native Hawaiian or Other Pacific Islander; Practice Patterns, Physicians'; Middle Aged
PubMed: 38901047
DOI: 10.26635/6965.6544 -
International Immunopharmacology Jun 2024Delayed cerebral ischemia (DCI) is a common and serious complication of subarachnoid hemorrhage (SAH). Its pathogenesis is not fully understood. Here, we developed a...
BACKGROUND
Delayed cerebral ischemia (DCI) is a common and serious complication of subarachnoid hemorrhage (SAH). Its pathogenesis is not fully understood. Here, we developed a predictive model based on peripheral blood biomarkers and validated the model using several bioinformatic multi-analysis methods.
METHODS
Six datasets were obtained from the GEO database. Characteristic genes were screened using weighted correlation network analysis (WGCNA) and differentially expressed genes. Three machine learning algorithms, elastic networks-LASSO, support vector machines (SVM-RFE) and random forests (RF), were also used to construct diagnostic prediction models for key genes. To further evaluate the performance and predictive value of the diagnostic models, nomogram model were constructed, and the clinical value of the models was assessed using Decision Curve Analysis (DCA), Area Under the Check Curve (AUC), Clinical Impact Curve (CIC), and validated in the mouse single-cell RNA-seq dataset. Mendelian randomization(MR) analysis explored the causal relationship between SAH and stroke, and the intermediate influencing factors. We validated this by retrospectively analyzing the qPCR levels of the most relevant genes in SAH and SAH-DCI patients. This experiment demonstrated a statistically significant difference between SAH and SAH-DCI and normal group controls. Finally, potential small molecule compounds interacting with the selected features were screened from the Comparative Toxicogenomics Database (CTD).
RESULTS
The fGSEA results showed that activation of Toll-like receptor signaling and leukocyte transendothelial cell migration pathways were positively correlated with the DCI phenotype, whereas cytokine signaling pathways and natural killer cell-mediated cytotoxicity were negatively correlated. Consensus feature selection of DEG genes using WGCNA and three machine learning algorithms resulted in the identification of six genes (SPOCK2, TRRAP, CIB1, BCL11B, PDZD8 and LAT), which were used to predict DCI diagnosis with high accuracy. Three external datasets and the mouse single-cell dataset showed high accuracy of the diagnostic model, in addition to high performance and predictive value of the diagnostic model in DCA and CIC. MR analysis looked at stroke after SAH independent of SAH, but associated with multiple intermediate factors including Hypertensive diseases, Total triglycerides levels in medium HDL and Platelet count. qPCR confirmed that significant differences in DCI signature genes were observed between the SAH and SAH-DCI groups. Finally, valproic acid became a potential therapeutic agent for DCI based on the results of target prediction and molecular docking of the characterized genes.
CONCLUSION
This diagnostic model can identify SAH patients at high risk for DCI and may provide potential mechanisms and therapeutic targets for DCI. Valproic acid may be an important future drug for the treatment of DCI.
PubMed: 38897129
DOI: 10.1016/j.intimp.2024.112408 -
Revista Do Colegio Brasileiro de... 2024valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of...
INTRODUCTION
valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of the abdominal wall are studied.
METHOD
sixty Wistar rats were allocated into two groups: experimental (VPA) and control (0.9% sodium chloride), treated daily, starting three days before the intervention and until euthanasia. Under anesthesia, a median laparotomy was performed and repaired with two synthetic layers. Assessments took place 3, 7 and 14 days after surgery. The integrity of the wounds, the quality of the inflammatory reaction, the intensity of the leukocyte infiltrate, collagen synthesis, the intensity of angiogenesis and the presence of myofibroblasts were studied.
RESULTS
there was dehiscence of the PMA plane in 11 of the 30 animals (p=0.001) in the experimental group. There was no difference in the quality and intensity of the inflammatory reaction. Immunohistochemistry revealed, in the experimental group, less collagen I (p3=0.003, p7=0.013 and p14=0.001) and more collagen III (p3=0.003, p7=0.013 and p14= 0.001). Collagen evaluated by Sirus Supra Red F3BA showed, in the experimental group, less collagen at all three times (p<0.001) with less collagen I and collagen III (p<0.001). A lower number of vessels was found on the 3rd day (p<0.001) and on the 7th day (p=0.001) and did not affect the number of myofibroblasts.
CONCLUSION
VPA showed dehiscence of the PMA plane, with less deposition of total collagen and collagen I, less angiogenic activity, without interfering with the number of myofibroblasts.
Topics: Animals; Rats, Wistar; Wound Healing; Rats; Abdominal Wall; Valproic Acid; Male; Abdominal Muscles
PubMed: 38896636
DOI: 10.1590/0100-6991e-20243676-en -
Molecules (Basel, Switzerland) May 2024Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.
Topics: Animals; Zebrafish; Anticonvulsants; Disease Models, Animal; Pentylenetetrazole; Epilepsy; Seizures; Electroencephalography; Valproic Acid; Larva; Brain; Inositol
PubMed: 38893448
DOI: 10.3390/molecules29112572