Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile

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.

Therapeutic Drug Monitoring of Carbamazepine: A 20-Year Observational Study

Background: Carbamazepine (CBZ) is a first-generation anticonvulsant drug. Hence, in certain cases, therapeutic drug monitoring (TDM) supports pharmacotherapy. Methods: The presented research was based on a retrospective analysis including 710 ambulatory and hospitalized patients treated with CBZ between the years 1991 and 2011. The method used for the determination of the CBZ concentration was fluorescence polarization immunoassay (FPIA) performed using an Abbott GmbH TDx automatic analyzer, with the therapeutic range for carbamazepine being 4–12 µg/mL. Results: The therapeutic range was observed more often in patients between 3 and 17 years of age compared with the population ≥18 years of age (73.5% vs. 68.8%). The therapeutic level was exceeded less frequently in the population between 3 and 17 years of age despite them being given a significantly higher dose per kilogram of body weight than in the population ≥18 years of age (13.64 mg/kg vs. 10.43 mg/kg, p < 0.0001). Patients ≥18 years of age were statistically significantly more likely to be in the group with a suspected drug overdose (73.9% vs. 26.1%), and suicide attempts only occurred in elderly patients (100.0% vs. 0.0%, p = 0.003). Conclusion: The results of the TDM of CBZ showed that only 71% of all samples were at the therapeutic level. To ensure the maximum efficacy and safety of the therapy, it is necessary to monitor the concentration of CBZ regardless of sex and age.

Lamotrigine Induced DRESS Syndrome in a Child: A Case Report and Literature Review

Lamotrigine is an important anticonvulsant drug. Its use, however, has been limited by the risk of potentially life-threatening dermatological reactions, such as a drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we report the case of a 7-year-6-month-old girl with a history of epilepsy who developed a skin rash with dyspnoea after 2 weeks of lamotrigine treatment, with DRESS ultimately being diagnosed. After discontinuation of the offending drug and the initiation of systemic glucocorticosteroids, the DRESS symptoms were relieved and the patient was discharged in a stable condition. Anticonvulsant drugs such as lamotrigine are among the factors that induce DRESS in children. When a patient displays skin rash and systemic organ involvement following the initiation of an anticonvulsant drug, DRESS should not be overlooked as a diagnosis, and immunosuppressant drugs should be considered as an option for treating DRESS patients.

MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy

One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1α is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1α on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1α expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1α was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1α expression. Intervention using miR-221-3p mimics reduced HIF-1α expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p/HIF-1α as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets.

A Review on Analytical Method for Determination of Lamotrigine in Bulk and Pharmaceutical Dosage Form

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy & bipolar disorder/major affective disorder (manic depression). Lamotrigine is and antiepileptic drug of phenyltriazine class. For epilepsy it is used to treat the partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with the Lennox-Gastuat syndrome and are chemically unrelated to the other anticonvulsants. Lamotrigine is a phenyltriazine that has comparatively few side-effects and it does not requires blood monitoring/observance in monotherapy. It additionally acts as a mood stabilizer. Common side-effects of lamotrigine include, nausea, sleepiness, headache, vomiting, trouble/bother with co-ordination and rash. Serious side-effects include in, lack of red blood cells, accumulated in risk of suicide, Stevens-Johnson syndrome and allergy. It issues that use of lamotrigine throughout pregnancy or breastfeeding it’s going to lead/result in harm/damage.

Valproic Acid and Breast Cancer: State of the Art in 2021

Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.

Epileptiform state of rats and the protective effect of antiepileptic drugs: Dilantin, Depakin, and Zarontin

The aim of the study is to investigate the direction of changes in the epileptiform state of the rat organism under the influence of antiepileptic drugs, and also to reveal the possibility of using simple criteria for the comparative assessment of the severity of their protective actions using the hardware complex «Bioscope». Materials and methods. Three series of experiments were carried out using anticonvulsants: Dilantin, Depakine, and Zarontin. In each series of experiments, the integrative state of animals was recorded in normal conditions, after administration of an anticonvulsant drug and after administration of corazole against the background of the effect of an anticonvulsant drug. For a comparative assessment of the effectiveness of the protective action of the antiepileptic drug, spectral distributions of the signals of the «Bioscope» were constructed and the power of the signals was compared in normal conditions and after administration of drugs. Results. For the relief of epileptiform states, Dilantin and Depakin are most effective - after the introduction of corazole against the background of these drugs, a higher correlation was observed between the values of the power of their spectrum compared with the norm. The injection of Dilantin has been shown to significantly change the nature of the «Bioskop» signals, while after the introduction of Depakin this does not happen. Zarontin was found to have a lower efficacy in relieving epileptiform states of the body compared to Dilantin and Depakin. Conclusion. The study revealed the feasibility of using the hardware complex «Bioscope» for the purpose of rapid assessment of the protective effect of antiepileptic drugs in epileptiform states of the body. At the same time, the possibility of using simple criteria for a comparative assessment of the severity of the protective action of drugs is shown.

Development and Validation of HPLC Determination of related Substances in A Novel Anticonvulsant agent Epimidin

1-(4-methoxyphenyl)-5-[2-[4-(4-methoxyphenyl)piperazin-1-yl]-2-oxo-ethyl]pyrazolo[3,4-d]pyrimidin-4-one has been reported as a promising new anticonvulsant drug candidate with a code name “Epimidin”. A new HPLC method for the related substances determination of potential active pharmaceutical ingredient has been developed and validated. The method uses ACE C18 column (250x4.6mm, 5µm) and gradient elution. Mobile phase consisted of a mixture of methanol R (mobile phase A) and phosphate buffer solution with triethanolamine, adjusted to pH 7.0 (mobile phase B). During the analysis, the ratio of mobile phases was changing according to a gradient mode at a flow rate of 1ml/min. The DAD detection was set at 240nm. The method was validated according to the ICH guidelines and requirements of State Pharmacopoeia of Ukraine. Drug substance was thoroughly explored for stability assessments under various stress conditions such as high temperature, as well as the influence of strong acid and base and oxidizing agents. The obtained solutions were analyzed by HPLC and LC/MS. It has been shown that the substance Epimidin was not resistant to the action of peroxide, alkali and acid decomposition – the mentioned stress conditions lead to the formation of unidentified impurities.