鑒于丙戊酸(Valproate, VPA)宮內暴露的致畸風險及其對胎兒生長發育的影響, 2014年10月隸屬于歐洲藥品管理局(European Medicines Agency, EMA)的相互認證和分布處理協調小組(Coordination Group for Mutual Recognition and Decentralised Procedures-Human, CMDh)建議加強對女性使用VPA的限制, 隨后國際抗癲癇聯盟歐洲事務委員會(Commission on European Affairs of the International League Against Epilepsy, CEA-ILAE)及歐洲神經病學學會(European Academy of Neurology, EAN)組成的工作小組在《Epilepsia》上撰文, 旨在對育齡期女性使用VPA做出指導。撰文時, 工作小組充分考慮了使用VPA與其它替代藥物的致畸風險、控制癲癇發作的重要性、癲癇發作對患者及胎兒的危害、VPA及其它抗癲癇藥物對癲癇控制效力等因素。最終的建議包括以下7點:①育齡期女性應盡量避免使用VPA; ②應在醫生及患者(必要時患者代理人)共同商議后決定治療方案, 依據癲癇類型及發作形式選擇合理的治療方案時, 應仔細進行風險-獲益評估; ③對于最適合VPA治療的發作類型及綜合征, 應該充分向患者及家屬解釋VPA及其它替代藥物的獲益和潛在風險; ④VPA不應作為局灶性癲癇的一線治療藥物; ⑤VPA或許可以作為治療某些癲癇綜合征的一線用藥, 如特發性(遺傳性)全面性癲癇伴有強直陣攣發作; ⑥VPA或許可作為生育可能性極小的女性癲癇患者的一線用藥, 如合并嚴重的智力或身體殘疾; ⑦應持續隨訪服用VPA的育齡期女性患者, 以確定最佳治療方案
ObjectiveTo investigate the effect of valproic acid (VPA) coadministred with lamotrigine (LTG) on epileptic patients' ammonia and evaluate the influencing factors of elevated blood ammonia in epileptic patients.MethodsA retrospective analysis of clinical data from 146 patients with epilepsy (including newly diagnosed epilepsy patients) who were admitted to the Seventh Affiliated Hospital of Sun Yat-Sen University from May 2018 to April 2020 was performed. The patients were divided into no antiepileptic drug group (group A), VPA group only (group B) and VPA combined LTG group (group C), and the concentration of the blood ammonia of the patients were analyzed.ResultThe average ammonia levels in groups A, B and C were (18.14±1.19), (25.89±0.87) and (36.60±4.34) μmol/L, and the incidence of blood ammonia higher than normal were 2.77%, 8.89% and 20.0%, respectively.The difference between group B and group A and group C were statistically significant (P<0.05), the difference between group C and group A was statistically significant (P<0.05).ConclusionPatients with epilepsy who use VPA were at increased risk of blood ammonia and LTG can increase ammonia in epileptic patients who were treated with VPA. So when VPA was combined with LTG, more attention should be paid to ammonia of patient to avoid adverse reactions.
Objective To investigate the effects of sodium valproate (VPA) in inhibiting Erastin-induced ferroptosis in bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. Methods BMSCs were isolated from bone marrow of 8-week-old Spragur Dawley rats and identified [cell surface antigens CD90, CD44, and CD45 were analyzed by flow cytometry, and osteogenic and adipogenic differentiation abilities were assessed by alizarin red S (ARS) and oil red O staining, respectively]. Cells of passage 3 were used for the Erastin-induced ferroptosis model, with different concentrations of VPA for intervention. The optimal drug concentration was determined using the cell counting kit 8 assay. The experiment was divided into 4 groups: group A, cells were cultured in osteogenic induction medium for 24 hours; group B, cells were cultured in osteogenic induction medium containing optimal concentration Erastin for 24 hours; group C, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA for 24 hours; group D, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA, and 8 μmol/L EX527 for 24 hours. The mitochondrial state of the cells was evaluated, including the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS). Osteogenic capacity was assessed by alkaline phosphatase (ALP) activity and ARS staining. Western blot analysis was performed to detect the expressions of osteogenic-related proteins [Runt-related transcription factor 2 (RUNX2) and osteopontin (OPN)], ferroptosis-related proteins [glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11)], and pathway-related proteins [adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1)]. Results The cultured cells were identified as BMSCs. VPA inhibited Erastin-induced ferroptosis and the decline of osteogenic ability in BMSCs, acting through the activation of the AMPK/SIRT1 pathway. VPA significantly reduced the levels of ROS and MDA in Erastin-treated BMSCs and significantly increased GSH levels. Additionally, the expression levels of ferroptosis-related proteins (GPX4, FTH1, and SLC7A11) significantly decreased. VPA also upregulated the expressions of osteogenic-related proteins (RUNX2 and OPN), enhanced mineralization and osteogenic differentiation, and increased the expressions of pathway-related proteins (AMPK and SIRT1). These effects could be reversed by the SIRT1 inhibitor EX527. ConclusionVPA inhibits ferroptosis in BMSCs through the AMPK/SIRT1 axis and promotes osteogenesis.
Objective To study the correlation of changes in liver function during long-term treatment with sodium valproate (VPA) in children with epilepsy in Putian, and to explore individualized administration to improve the compliance of children with medication. Methods The blood concentration of VPA and related biochemical test data of 350 children with epilepsy from June 1, 2018 to March 1, 2021 were collected in our hospital. According to the results of VPA blood concentration, they were classified as low Blood concentration group (<50 μg/mL), therapeutic blood concentration group (50 ~ 100 μg/mL) and high blood concentration group (>100 μg/mL). Results There was no significant difference in liver function indexes between the VPA treatment group and the control group (P>0.05). There were significant differences in liver function ALT, AST, AST/ALT, TBIL and DBIL among the groups of VPA blood concentration range (P<0.05). The abnormal incidence of liver function indexes of high blood drug concentration was lower in the concentration group and higher in the treatment concentration group, and there were differences (P<0.05). Conclusion Abnormal liver function in the high blood drug concentration treatment groupis quite common, and the dose of the drug should be adjusted in time to avoid liver damage caused by the VPA.
Valproic acid can reduce the frequency of seizures through various mechanisms and is widely used in clinical practice as a monotherapy or adjunctive treatment for various types of epilepsy and epileptic syndromes. In addition, valproic acid has significant therapeutic effects on comorbidities associated with epilepsy, such as migraines and psychiatric disorders. It can also be effective in terminating status epilepticus and is commonly used as a broad-spectrum antieseizure medication in clinical settings. However, valproic acid has side effects such as teratogenicity, infertility, and menstrual disorders. Additionally, when used in combination with other drugs, the interactions between medications should be carefully considered. Therefore, in clinical practice, it is necessary to strictly adhere to the indications and dosage regimens for the use of valproic acid. This article provides a comprehensive review of the use of valproic acid in different types of seizures, epileptic syndromes, comorbidities associated with epilepsy, post-craniotomy cases, status epilepticus, and special populations. It also summarizes the combination therapy of valproic acid with other drugs, providing a basis for the rational use of valproic acid and individualized drug treatment selection for epilepsy patients.
ObjectiveTo explore the protective effects of sodium valproic acid (VPA) on oxidative stress injury of osteoblasts induced by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and its mechanism. Methods Osteoblasts were isolated from the skulls of 10 newborn Sprague Dawley rats and cultured by tissue block method, and the 1st generation cells were identified by alkaline phosphatase (ALP) and alizarin red staining. The 3rd generation osteoblasts were cultured with 2-18 μmol/L CCCP for 2-18 minutes, and cell counting kit 8 (CCK-8) was used to detect the cell survival rate. An appropriate inhibitory concentration and culture time were selected for the preparation of osteoblasts oxidative stress injury model based on half maximal concentration principle. The cells were cultured with 0.2- 2.0 mmol/mL VPA for 12-72 hours, and CCK-8 was used to detect cell activity, and appropriate concentration was selected for further treatment. The 3rd generation cells were randomly divided into 4 groups, including blank control group (normal cultured cells), CCCP group (the cells were cultured according to the selected appropriate CCCP concentration and culture time), VPA+CCCP group (the cells were pretreated according to the appropriate VAP concentration and culture time, and then cultured with CCCP), VPA+CCCP+ML385 group (the cells were pretreated with 10 μmol/L Nrf inhibitor ML385 for 2 hours before VPA treatment, and other treatments were the same as VPA+CCCP group). After the above treatment was complete, the cells of 4 groups were taken to detect oxidative stress indicators [reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA)], cell apoptosis rate, ALP/alizarin red staining, and the relative expressions of osteogenic related proteins [bone morphogenetic protein 2 (BMP-2), RUNX2], anti-apoptotic family protein (Bcl2), apoptotic core protein (Cleaved-Caspase-3, Bax), channel protein (Nrf2) by Western blot. Results The osteoblasts were successfully extracted. According to the results of CCK-8 assay, the oxidative stress injury model was established by 10 μmol/L CCCP cultured for 10 minutes and 0.8 mmol/mL VPA cultured for 24 hours was selected for subsequent experiments. Compared with blank control group, the activity and mineralization capacity of osteoblasts in CCCP group decreased, the contents of ROS and MDA increased, the activity of SOD decreased, and the apoptosis rate increased. Meanwhile, the relative expressions of BMP-2, RUNX2, and Bcl2 decreased, and the relative expressions of Cleaved-Caspase-3, Nrf2, and Bax increased. The differences were significant (P<0.05). After further VPA treatment, the oxidative stress damage of osteoblasts in VPA+CCCP group was relieved, and the above indexes showed a recovery trend (P<0.05). In VPA+CCCP+ML385 group, the above indexes showed an opposite trend (P<0.05), and the protective effects of VPA were reversed. Conclusion VPA can inhibit the CCCP-induced oxidative stress injury of osteoblasts and promote osteogenesis via Keap1/Nrf2/Are pathway.
Objective To investigated the influence of the CYP2C9 polymorphism on lipid profile and blood concentration in epileptic children with VPA. Methods This study collected the information of healthy children and epilepsy children who were treated with VPA in the First Affiliated Hospital of Putian University during June, 2018 to March, 2021. The serum lipids of 184 cases were collected and compared between epilepsy group before and after treatment with VPA with the control group. The polymorphism of CYP2C9 gene in children with epilepsy was detected, and lipid and VPA concentration were compared after classification. Results There was no significant difference in lipid between the control group and the epilepsy group before treatment (P>0.05); The TC, HDL, LDL, TC/HDL, LDL/HDL were statistically different in VPA treatment group from the control group (P<0.05), and there were statistical differences in TG, LDL, TC/HDL, LDL/HDL between the trial group before the initiation and VPA treatment (P<0.05); There is no correlation between VPA blood concentration and lipid (P>0.05). VPA concentration, TC, HDL, LDL, TC/HDL and LDL/HDL in CYP2C9 wild-type were statistically different from heterozygous mutant. Conculsions CYP2C9 polymorphism and long-term use of VPA caused the changes in serum lipid levels in epilepsy children.
ObjectiveTo explore the inhibition action of valproic acid to inflammatory cells and smooth muscle cells then to find out that valproic acid (VPA) can repress rat thoracic aortic aneurysm or not.
MethodsThe model of rat thoracic aortic aneurysm was built through the method of soaking the adventitia of artery using porcine pancreatic elastase (PPE). The rats were divided into three groups:a normal saline blank control group (a C group), an adventitia soaked PPE group (a P group), and adventitia soaked PPE plus intraperitoneal injection by injecting intraperitioneal VPA 200 mg/kg for seven days (a PV group).The animals of the three groups were all using vascular ultrasound to detect blood vessel diameter. Animals were killed after operation to observe the general morphology of vascular aneuysm and do the immunohistochemial, morphological, protein analysis of interleukin 1 (IL-1), interleukin 6 (IL-6), smooth muscle 22 alpha (SM22α), matrix metallopeptidase 2 (MMP-2), MMP-9 and Western blot by drawing animals on the 14th day.
ResultsThe vessels diameter in the PV group was narrower than that in the P group (P value<0.05). HE staining, immunohistochemistry and Western blot displayed that the cells in the P group were in disorder arrangement and interstitial disorder while the cells in the PV group maintained better albumin layer. The protein expressions of IL-1, IL-6, MMP-2, and MMP-9 in the PV group decreased except that SM22α increased.
ConclusionVPA can inhibit phenothpic transforming of aneurysm inflammatory cells and smooth muscle cells, reduce the levels of cell proliferation, decrease the secretion of matrix metalloproteinases, and depress tumor growth of rat thoracic aorta.
