Effect of 70% Ethanol Extract and its Solvent Fractions of Artemisia afra (Jacq. Ex Willd.) against Pentylenetetrazole-Induced Seizure in Mice

Introduction. Artemisia afra (Jacq. ex Willd.), commonly called African wormwood, is a highly aromatic perennial herb and a well-known medicinal plant, claimed to be effective and safe in the treatment of epilepsy. The whole-plant extract is traditionally used as an antiepileptic agent in Ethiopia. Aim of the Study. The aim of this study was, therefore, to evaluate the anticonvulsant effect of the hydroethanolic extract and solvent fractions of A. afra whole part in mice. Materials and Methods. The effects of A. afra hydroethanolic extract and its solvent fractions were evaluated against pentylenetetrazole- (PTZ-) induced convulsions in mice. The onset and duration of PTZ-induced convulsions were determined with hydroethanolic A. afra extract and its solvent fractions. Data were analyzed using a one-way analysis of variance (ANOVA) followed by post hoc Tukey’s multiple comparisons test. p < 0.05 was considered statistically significant. Results. The hydroethanolic extract of A. afra, with all the three doses of 250, 500, and 1000 mg/kg, showed a significant delay (504.833 ± 62.835 ∗ s; p < 0.05 ∗ ; 551.833 ± 47.69 ∗ ∗ s; p < 0.01 ∗ ∗ ; and 808.333 ± 64.8 ∗ ∗ ∗ s; p < 0.001 ∗ ∗ ∗ , respectively) in the mean onset of convulsion and a decrease (17.000 ± 1.88 ∗ ∗ ∗ s, p < 0.05 ∗ ; 13.000 ± 1.8 ∗ ∗ s, p < 0.01 ∗ ∗ ; and 7.833 ± 1.07 ∗ ∗ ∗ s, p < 0.001 , respectively) in the mean duration of convulsion against PTZ-induced convulsion in a dose-dependent manner compared to the control (92.833 ± 13.006 s; 34.167 ± 3.683 s), and its anticonvulsant activity was significantly less compared to that of diazepam (1001.167 ± 68.430 s; 4.500 ± 0.619 s). The solvent fractions, however, did not show anticonvulsant activity against PTZ-induced convulsion. Conclusion. Crude extract of A. afra has an anticonvulsant effect in mice. This might be attributed to the synergistic effects of two or more active ingredients present in the herb.

A valproátterápia túlélésre gyakorolt hatása gliomás betegekben

Összefoglaló. Bevezetés: A gliomák, ezen belül a glioblastoma kezelése továbbra is megoldatlan onkológiai problémát jelent. A szekunder szimptómás epilepsziabetegség megjelenése pozitív prognosztikai faktornak tekinthető a korai diagnosztizálás és az antiepileptikumok potenciális tumorellenes hatásának köszönhetően. A valproát túlélést hosszabbító hatása már több mint 20 éve az alap- és klinikai kutatások tárgyát képezi. Napjainkban ismert citotoxikus, proapoptotikus, antiangiogenetikus és hiszton-deacetiláz-gátló hatásmechanizmusa. Célkitűzés: Kutatásunk célja a valproát túlélést hosszabbító hatásának vizsgálata egy hazai gliomás betegcsoportban. Módszer: Egycentrumos, retrospektív klinikai vizsgálatot végeztünk. A vizsgálatba 122 felnőtt beteget vontunk be, akiknél 2000 januárja és 2018 januárja között supratentorialis glioma miatt műtét történt, és rohamtevékenység miatt antiepileptikumot (valproát, levetiracetám, karbamazepin) szedtek. Egyúttal gyógyszert nem szedő kontrollcsoportot is kialakítottunk. A populációt vizsgálati és kontrollcsoportokra osztottuk 28 : 52 arányban. Leíró statisztikai, Kaplan–Meier- és log-rank analízist végeztünk. Eredmények: A vizsgált szövettani kategóriák túlélési analízise az irodalmi adatokkal megegyező értékeket mutatott. A progressziómentes (PFS: p = 0,031) és a teljes (OS: p = 0,027) túlélés tekintetében is szignifikáns eltérés mutatkozott a különböző antiepileptikumot szedő betegcsoportok között, amely még kifejezettebbé vált a valproátot és az egyéb antiepileptikumot szedő betegek túlélési idejének összehasonlítása során (PFS: p = 0,006; OS: p = 0,015). Következtetés: Vizsgálatunkban a valproát betegeink PFS- és OS-idejének meghosszabbodását eredményezte. Az irodalmi adatok és kutatásunk alapján megfontolandónak tartjuk a valproát első vonalban történő alkalmazását onkoterápiában részesülő, epilepsziás, agyi gliomás betegekben. Orv Hetil. 2021; 162(24): 960–967. Summary. Introduction: Gliomas still prove to be a serious oncological problem. The presence of epilepsy may present a favorable prognosis due to early diagnosis and the potential antitumor effects of antiepileptic drugs. The survival prolongation effect of valproate has been studied for more than 20 years, nowadays its proapoptotic, anti-angiogenetic, cytotoxic and histone deacetylase inhibitory effects are well known. Objective: Our goal was to investigate the survival-enhancing effects of valproate in a Hungarian patient cohort of primary brain tumors. Method: A single-center based retrospective clinical trial was designed. In our study, we included 122 patients harboring supratentorial glioma who underwent surgery and experienced seizures between 2000 January and 2018 January. The patients were grouped by the antiepileptic therapies and survival analysis was performed. Results: The Kaplan–Meier curves of the histological categories showed the survival values consistent with the data of the literature. The progression-free (PFS: p = 0.031) and the overall (OS: p = 0.027) survival of the antiepileptic drug categories were significantly different. It was performed by comparing the valproate group and the population formed by the other groups which also showed a significant increase in the survival values (PFS: p = 0.006; OS: p = 0.015). Conclusion: Our results show that valproate increases the PFS and OS period of glioma patients in comparison to other antiepileptic drugs. Our data suggest that the use of valproic acid should be considered as a first-line antiepileptic agent in certain well-selected epileptic patients with glioma as a supplement to the oncotherapy. Orv Hetil. 2021; 162(24): 960–967.

PROMISING DIRECTIONS FOR THE APPLICATION OF PIPERIDINE DERIVATIVES AS STRUCTURAL COMPONENTS OF NEUROTROPIC DRUGS

Piperidine is one of the most common heterocycles, and its derivatives are found in many pharmacological groups, including neurotropic drugs. These compounds are numerous among analgesics, and, in addition to “classical” promedol, fentanyl and its derivatives, the paper presents the results of studying new compounds with analgesic activity and piperidine cycle. Reviews of such piperidine antipsychotics as haloperidol and risperidone have been considered, and new compounds showing antipsychotic activity through their effects on dopamine and serotonin receptors have been elucidated. The data on the influence of methylphenidate on the brain in case of attention deficit/ hyperactivity disorder (ADHD) have been analyzed, which help to understand the disturbances occurring in this disease. Tiagabine has been considered as an antiepileptic agent reducing the number of seizures in resistant forms of partial epilepsy, as well as the activation of microglia and may be effective in neurodegenerative diseases. The last section is devoted to drugs for the treatment of Alzheimer’s disease (AD), namely donepezil, its modifications, and some new compounds potentially capable of inhibiting AD progression through the inhibition of Aβ42 protein synthesis.

Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response

OBJECTIVES Neonatal seizures are common complications. Phenobarbital is the agent of choice but leads to adverse neurologic outcomes. There has been increased use of newer agents like levetiracetam. The objective of this study was determining the rate of seizure resolution in neonates treated with phenobarbital or levetiracetam. METHODS This was a retrospective, single-center, cohort study from June 1, 2012–June 1, 2018 evaluating seizure resolution in neonates following first-line treatment with phenobarbital versus levetiracetam. Data were collected via review of the patient's charts in the electronic medical record. The primary outcome was seizure resolution without addition of a second antiepileptic agent. Logistic regression was used to assess the impact of pertinent variables. RESULTS Each group included 73 patients. The mean gestational age was 36.01 and 37.91 weeks for the phenobarbital and levetiracetam groups, respectively (p = 0.011). The phenobarbital group had higher rates of intraventricular hemorrhage at baseline. The median birth weight was 2750 and 3002 grams in the phenobarbital and levetiracetam groups, respectively (p = 0.10). Forty-five neonates (61.6%) achieved seizure resolution with phenobarbital compared with 30 neonates (41.1%) with levetiracetam (p = 0.01). In neonates who did not receive a benzodiazepine, seizure resolution was similar between groups (51–52%). In neonates who received a benzodiazepine, seizure resolution rate was 94.1% (16/17 neonates) for phenobarbital and 18.2% (4/22 neonates) for levetiracetam. CONCLUSIONS These findings suggest seizure resolution with levetiracetam, and phenobarbital may be impacted by benzodiazepine administration. If no benzodiazepine is used, these agents demonstrated similar efficacy. Further research into the pharmacodynamic interaction with benzodiazepines is necessary.

Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

KEPPRA (Levetiracetum) VS EPIVAL (Sodium Valporate) to control generalized tonic clonic seizures.

Objective: This present study is design to assess the efficacy and frequency of side effects with a newer anti-epileptic agent levertiracetum while comparing an older anti-epileptic, Sodium Valproate, in the patients with generalized tonic colonic epilepsy. Material & Methods: Patients with GTC epilepsy had been allocated in two groups, A and B, Group A was given Sodium valproate while group B was given levertiracetum. Study Design: Randomized Control Trial. Setting: Fatima Memorial Hospital, Lahore and Allied Hospital, Faisalabad. Period: December, 2017 to December, 2018. Results: Seventy five subjects were taking levertiracetum from three months out of which 56(74.7%)were seizures free, 15(20%) were seizure free on higher dose,6(8%) were with dizziness ,vertigo and 9(12%) were with somnolence. Fifty-four individuals were seizures free with normal dose of sodium valproate from last 3 months, and 16(21%) were seizures free on higher doses among which 53(70%) were with side effects of weight gain and 69(92%) were with hand tremors and this was the most prominent side effects among individuals who were taking sodium valproate. Conclusion: Generalized tonic colonic epilepsy is one of the most common forms of epilepsy and with the advent of newer anti-epileptic drugs like levertiracetum, such seizures can be controlled in with lesser side effects as compared to older antiepileptic agent Sodium Valproate.

Molecular-Docking Study of quinazolin-4(3H)-one derivatives against GABAa Receptor Signifies the Novel Approach to Epilepsy Treatment

Nowadays, a lot of new active substances as antiepileptic agents have been developed. One of the protein targets of antiepileptic is selective GABA. Selective GABA is the regulator of CNS activity. In this research, quinazolinone derivatives were used to design the antiepileptic agent through a selective GABA activation. The potential activity of quinazolinone derivatives could be increased by substitution in position 3 of quinazolinone. Molecular docking of selective GABA activation was required to predict their antiepileptic activity. The molecular docking of quinazolinone derivatives was carried out using Autodock viva Ver.1.1.2. Twenty quinazolinone derivatives were docked into GABAa with PDB code 4cof. The interaction was evaluated based on the docking score. Diazepam was used as the reference standard for this research. Twenty quinazolinone derivatives showed the approximate docking score -7.1 to -9.3 kcal/mol. All twenty quinazolinone derivatives which value that have greater docking score compared to diazepam used as a standard compound. Derivative Q-18 had higher binding energy than other quinazolinone derivatives because it has the smallest docking score. All new quinazolinone derivatives are feasible to be synthesize and performed their in vitro evaluation.