Anticonvulsant Agents Research Articles

The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database.

A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal anti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibiotics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, 'unmasking', dataset analyses were carried out as well. Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications, which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed significant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7-20.3), 14.3 (9.1-22.4) and 58.7 (36.3-95.9). A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.

Design and synthesis of novel cycloalkanecarboxamide parabanic acid hybrids as anticonvulsants

Aiming to develop novel anticonvulsant agents a new series of novel cycloalkanecarboxamide parabanic acid hybrids series 8, 9 and 10 possessing the essential structure requirements for anticonvulsant activity was synthesized starting from cycloalkanones. All final target compounds were primary screened for chemically and electrically induced seizures using pentylenetetrazole “scPTZ” and maximal electroshock seizure “MES” models. In phase I anticonvulsant evaluation compounds 8b and 10b exhibited the highest potency among all the target compounds with 100% protection towards chemically induced seizures. Results of phase II anticonvulsant screening showed that compounds 8b and 10b are more potent than standard drug ethosuximide by about 11 and 9 fold, respectively. Regarding MES test, compounds 8b and 9a-d exhibited 100% protection with ED50 values ranged between 0.107–0.177 mmol/Kg. All final compounds did not display any signs of motor impairment in the neurotoxicity screening test. Also, compounds 8a, 9a-d and 10b were devoid of hepatotoxicity as shown by measurement of serum levels of liver enzymes, albumin as well as total protein. Moreover, the cyclohexyl derivative 10b produced a significant increase of Gamma-aminobutyric acid “GABA” brain’s content of mice compared to control group confirmed its GABAergic modulating activity. Molecular docking, physicochemical and pharmacokinetic properties were carried out for all compounds as well. These outcomes support that cycloalkanecarboxamide parabanic acid hybrid is a promising scaffold to pave the way towards further development of novel class of antiepileptic drugs.

Neuroprotective effects of trigonelline in kainic acid-induced epilepsy: Behavioral, biochemical, and functional insights

Trigonelline, an alkaloid found in the seeds of Trigonella foenum-graecum L. (fenugreek), has been recognized for its potential in treating various diseases. Notably, trigonelline has demonstrated a neuroprotective impact by reducing intrasynaptosomal calcium levels, inhibiting the production of reactive oxygen species (ROS), and regulating cytokines. Kainic acid, an agonist of kainic acid receptors, is utilized for inducing temporal lobe epilepsy and is a common choice for establishing kainic acid-induced status epilepticus, a widely used epileptic model. The neuroprotective effect of trigonelline in the context of kainic acid-induced epilepsy remains unexplored. This study aimed to induce epilepsy by administering kainic acid (10 mg/kg, single subcutaneous dose) and subsequently evaluate the potential anti-epileptic effect of trigonelline (100 mg/kg, intraperitoneal administration for 14 days). Ethosuccimide (ETX) (187.5 mg/kg) served as the standard drug for comparison. The anti-epileptic effect of trigonelline over a 14-day administration period was examined. Behavioral assessments, such as the Novel Object Recognition (NOR) test, Open Field Test (OFT), and Plus Maze tests, were conducted 2 h after kainic acid administration to investigate spatial and non-spatial acquisition abilities in rats. Additionally, biochemical analysis encompassing intrasynaptosomal calcium levels, LDH activity, serotonin levels, oxidative indicators, and inflammatory cytokines associated with inflammation were evaluated. Trigonelline exhibited significant behavioral improvements by reducing anxiety in open field and plus maze tests, along with an amelioration of memory impairment. Notably, trigonelline substantially lowered intrasynaptosomal calcium levels and LDH activity, indicating its neuroprotective effect by mitigating cytotoxicity and neuronal injury within the hippocampus tissue. Moreover, trigonelline demonstrated a remarkable reduction in inflammatory cytokines and oxidative stress indicators. In summary, this study underscores the potential of trigonelline as an anti-epileptic agent in the context of kainic acid-induced epilepsy. The compound exhibited beneficial effects on behavior, neuroprotection, and inflammation, shedding light on its therapeutic promise for epilepsy management.

Pharmacological Evaluation of Signals of Disproportionality Reporting Related to Adverse Reactions to Antiepileptic Cannabidiol in VigiBase.

Cannabidiol is the first cannabis-derived drug approved for the treatment of Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex. In the current study, we performed a descriptive analysis followed by a disproportionality analysis of potential adverse events caused by CBD extracted from the VigiBase® database. Furthermore, the biological plausibility of the association between CBD and the serotonin 5-HT1A receptor as a possible cause of adverse events was analyzed and discussed. Data were extracted from the VigiBase® database using the VigiLyze® signal detection and signal management tool. Adverse events in VigiBase® reports were coded using MedDRA, version 19 of Preferred Terms (PTs). Data were uploaded into SPSS software and analyzed via a disproportionality analysis. Statistically significant disproportionality signals for CBD were found for "weight decreased" (5.19 (95% CI: 4.54-5.70)), "hypophagia" (3.68 (95% CI: 3.22-5.27)), and "insomnia" (1.6 (95% CI: 1.40-1.83)). Positive IC025 values were found for "weight decreased" (2.2), "hypophagia" (1.3), and "insomnia" (0.5), indicating a surplus of reported cases. CBD's interactions with 5-HT1A serotonin receptors may offer a potential biological explanation for the occurrence of insomnia in patients. It is noteworthy that the risk profiles mentioned in the information for prescribing CBD as an antiepileptic agent by regulatory agencies showed disparities specifically related to the adverse event "insomnia".

Study, Docking, In Silico ADME and Bio-Evaluation of Novel Hetero-Aromatic Amino Acid Derivatives as Potential Anti-Epileptic Agents

Study, Docking, In Silico ADME and Bio-Evaluation of Novel Hetero-Aromatic Amino Acid Derivatives as Potential Anti-Epileptic Agents

Effects of defoliant exposure and medication use on the development of Parkinson's disease in veterans.

Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. A retrospective cohort study was conducted using 12years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.

Synthesis, in vivo Biological Evaluation and Molecular Docking Study of Some Newer Oxadiazole Derivatives as Anticonvulsant, Antibacterial and Analgesic Agents.

The compounds containing heterocyclic cores with O, N and/or S atoms are bioactive and valuable molecules in the field of drug discovery and development. There are several applications in different areas for the molecules having oxadiazole moiety in their structures viz. herbicides and corrosion inhibitors, electron-transport materials, polymers and luminescent materials. Hence, demand for new anticonvulsant, antibacterial and analgesic agents has turned into an imperative assignment in the area of medicinal chemistry to improve therapeutic efficacy as well as safety. In the journey of new anticonvulsive, antibacterial and analgesic molecules with better potency, some newer Oxadiazole analogues were attained by a sequence of synthetic steps with the substituted acrylic acids. IR and 1H-NMR spectral data were used for the structure elucidation of obtained chemical compounds. In this perspective, the anticonvulsant, antibacterial and analgesic activities were evaluated for synthetically obtained newer chemical moieties. Furthermore, a molecular docking study was performed to elucidate the binding modes of synthesized ligands in the active pockets of Cox-1/2 enzymes, DNA Gyrase and GABA inhibitors. It has been observed that all the synthetic molecules showed good analgesic activity while A1 molecule demonstrated better analgesic activity. In the case of anticonvulsant and antibacterial activity among other ligands, C1 molecule possessed profound anticonvulsant activity whereas B1 molecule showed maximum antibacterial activity and molecular docking study also endorsed the same consequences. It might be recognized from the present study that prepared compounds are distinctive in lieu of their structure and noticeable biological activity. In the quest for a newer group of anticonvulsant, antibacterial and analgesic molecules, these compounds might be useful for the society.

Molecular Mechanisms of Valproic Acid Action on Signalling Systems and Brain Functions

Valproic acid (valproate, VA) has been widely used as an antiepileptic agent for several decades, as well as in the treatment of bipolar affective disorder. For many years, the ability of VA to stop epileptic seizures of a different nature has been associated with increased GABAergic neurotransmission, inhibition of glutamatergic neurotransmission and a general decrease in CNS hyperactivity by acting on ion channels, however precise mechanisms of VA anticonvulsant effects are still not clear. Over time, the effects of VA on other neurotransmitter systems, enzymes and intracellular signalling pathways have been revealed, however they do not explain the effectiveness of the drug as an anticonvulsant and mood stabilizer, but only expand its pharmacological profile. Over the past 10 years, the focus of interest in valproate research has changed due to its ability to alter gene expression both by inhibiting histone deacetylases and by changing levels of DNA methylation. These new studies reveal alternative mechanisms of valproate action rather than trying to test and confirm hypotheses previously put forward.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

Impact of noscapine on halting the progression of pentylenetetrazole induced kindling epilepsy in mice.

Epilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurgeto drug-resistant epilepsy. The study repurposedthe drug 'noscapine'mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent.

Anticonvulsant Properties of 1-Diethylamino-3-phenylprop-2-en-1-one.

There is a need for novel antiepileptic agents whose modes of action differ from those of current antiepileptic drugs. The objective of this study was to determine whether 1-diethylamino-3-phenylprop-2-en-1-one (2) could prevent or at least diminish convulsions caused by different mechanisms. This amide afforded protection in the maximal electroshock and subcutaneous pentylenetetrazole screens when given intraperitoneally to both mice and rats. A number of specialized tests in mice were conducted and are explained in the text. They revealed (2) to have efficacy in the 6 Hz psychomotor seizure test, the corneal kindling model, the mouse temporal epilepsy screen and a peripheral neuronal transmission test using formalin. Three screens in rats were undertaken, which revealed that (2) blocked chloride channels, inhibited peripheral neuronal transmission (tested using sciatic ligation and von Frey fibres) and afforded protection in the lamotrigine-resistant kindled rat model. The biodata generated reveal that (2) is an important lead molecule in the quest for novel structures to combat epilepsy.

Seizure Incidence in Patients under Clozapine

Clozapine can cause potentially fatal side effects, including seizures. In the absence of therapeutic alternatives, well-coded guidelines are required for the management of this adverse effect in order to maintain treatment. Our aim is to determine the incidence of seizures associated with clozapine use in our hospital, to study the factors associated with this side effect, and to establish a clear, unified attitude based on a review of the literature. Among 483 patients treated with clozapine, 11 cases of seizures were reported, with a rate of 2.27% and an incidence of 1.62 cases per 1000 person-years. 80% of these patients presented tonic-clonic seizures, preceded by myoclonus in 2 cases, and the average seizure onset dose was estimated at 560mg/day. The course of action varied from one psychiatrist to another. Clozapine was discontinued in the case of one patient after the first episode, and doses were reduced in 8 patients from 28 to 75% of the therapeutic dose reached before. Six patients received additional antiepileptic agent.

Post-operative Treatment Chronic Subdural Hematoma with or without Dexamethasone: a Systematic Review

Abstract Introduction: Discovering If the post-operative patient is given dexamethasone or without dexamethasone, it can cause recurrence of Chronic Subdural Hematoma patients. This systematic review aims to summarize the research on the link between dexamethasone and recurrent chronic subdural hematoma. Methods: We present systematic reviews reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and adhere to a structured review protocol. We searched PubMed, ScienceDirect, and British Medical Journal databases using the following search strategy from inception to March 2023. Results: Four studies were included for further analysis. CSDH can be treated as medical, surgical, or both medical surgeries. Medical treatment for post-traumatic and post-operative prophylaxis of seizures and for preventing edema and ischemia. Anticonvulsant agents can be cut off after a few weeks if post-operative seizures do not appear at all. Surgery has been shown to be most effective in the treatment of cSDH. The evacuation of subdural collections forms the basis of the surgery in cSDH. After treatment, residual subdural fluid collections are standard. The most critical and dangerous complications of surgical treatment of acute post-operative bleeding. Discussion: Chronic subdural hematoma is an event of head bleeding that occurs for more than three weeks. It can be examined using CT (Computed Tomography). Often occurs in parents. The operation was carried out using the burr-hole method, and post-operative treatment can be given using dexamethasone. Recurrent bleeding may occur in patients with chronic subdural hematoma.

STATISTICAL OPTIMIZATION AND ASSESSMENT OF DIVALPROEX SODIUM EXTENDED RELEASE TABLET

The purpose of the current experimental research was to optimize the quantities of macromolecules such as Eudragit L/100-55 and HPMC-K-100M for the development of extended release tablets of divalproex sodium, an anti-convulsant or epileptic agent used in the effective management of bipolar disorders, mania, seizures, convulsions, tremors/epilepsy. Divalproex sodium ER tablets were formulated with the help of Eudragit L/100-55 and HPMC-K-100M in variable compositions and variable amounts as per 32 factorial design technique. Tablets were prepared by direct compression technique. Quantities of polymers required for exhibiting extended release of active agent from the tablet were chosen as independent variables, in similar manner time required for drug release was chosen as dependent variable (t10%, t50%, t75%, t90%). Nine formulations were created in accordance with the plan, formulated, and tested for quality control criteria. It is obvious from the data that all formulations exceed the compendial restrictions. Kinetic parameters were established, and the data from the dissolution investigation suited kinetic models very well. For the responses, polynomial equations were created and validated. The optimum formulation of SOD5, which contains 31.25 mg of Eudragit L/100-55 &amp; 31.25 mg of HPMCK-100M, exhibits resemblance to the commercial product of f2=85.91 and f1=2.25 (DIVALEX). SOD5 is made in a zero-order fashion, and the mechanism of drug release was found to be non - Fickian in nature (n = 0.645)

Protective effects of topiramate on acetic acid-induced colitis in rats through the inhibition of oxidative stress.

Ulcerative colitis is an intestinal inflammatory condition characterized by a rise in inflammatory mediator production and oxidative stress. Topiramate is an anticonvulsant agent with effectiveness on a wide range of seizures, which is anti-oxidative. This study aims to examine the protective effects of topiramate on acetic acid-induced ulcerative colitis in rats. Rats were randomly divided into four groups as follows: control, acetic acid, acetic acid + topiramate, and acetic acid + dexamethasone groups. Topiramate (100 mg/kg/day) or dexamethasone (2 mg/kg/day) was administered for six consecutive days, and ulcerative colitis was induced on the first day of the study by transrectal administration of 4% acetic acid. Four hours after the last dose of treatments, animals of each group were sacrificed, and colon tissues were removed for further macroscopic, histopathologic, and biochemical analyses. Treatment with topiramate markedly decreased colonic lesions and macroscopic scores as well as the improvement of histopathologic changes. Topiramate also effectively decreased the levels of malondialdehyde and upregulated the activity of anti-oxidative enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Our results reveal that the administration of topiramate ameliorates acetic acid-induced colitis in rats via anti-oxidative properties, and further studies may introduce it as an effective therapeutic candidate to decrease ulcerative colitis severity.

Evaluation of the Effect of Gabapentin in the Management of Uremic Pruritus in Hemodialysis Patients

Background: Gabapentin is an antiepileptic agent that has analgesic properties in neuropathic pain. Given that few studies have assessed the effect of the low dose of gabapentin on uremic pruritus, this study aimed to evaluate the effect of gabapentin on pruritus of hemodialysis patients.&#x0D; Materials and Methods: This clinical trial study was conducted on dialysis patients who were referred to Shafa Hospital, Kerman. In this regard, 40 patients consumed 100 mg of gabapentin for one week. Then patients did not take any medication within the washout period and consumed a 100 mg placebo for one week. Assessment of pruritus severity was done by visual analog scale (VAS). Hematocrit, calcium, phosphor, creatinine, and albumin were evaluated. These measurements were done before and after treatments with placebo and gabapentin.&#x0D; Results: The main places of pruritus location in dialysis patients were the back (90 %), abdomen (80%), shoulder (80%), and head (70%). The mean pruritus severity before treatment, and after treatment with placebo and gabapentin, was 8.3± 1.5, 6.73 ± 1.17, and 4.58 ± 1.50, respectively. Significant difference was seen before and after treatment, in terms of pruritus severity (p&lt;0.1). In addition, there was a significant difference between gabapentin and placebo groups, regarding the severity of pruritus (p&lt;0.1). No significant difference was seen before and after treatment, regarding biochemical parameters (p&gt;0.05).&#x0D; Conclusion: According to the findings, it seems that gabapentin can be an effective and safe treatment for pruritus in patients on hemodialysis. The therapeutic approach chosen for these patients is based on the neuropathic hypothesis.

PROTECTIVE EFFECT OF ANTI-EPILEPTIC AGENT Q808 ON NEURONAL DAMAGE IN A RAT MODEL OF TEMPORAL LOBE EPILEPSY

The detailed effect of Q808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine) which has been demonstrated to have anti-epileptic activity, on the protection from neuronal damage in temporal lobe epilepsy (TLE) still remains unclear. The purpose of this study was to evaluate the protective effects of Q808 on neuronal damage by exploring its mechanism of hippocampal neuronal apoptosis in a rat model of TLE. Fifty rats were divided equally into five groups. The normal group [Formula: see text] served as the normal non-seizure and untreated group. To induce the TLE model, pilocarpine (20[Formula: see text]mg/kg) was intraperitoneally administered to the other 40 rats; 33 rats successfully developed TLE status. Subsequently, the TLE group [Formula: see text], VPA group [Formula: see text], Q808-L group [Formula: see text], and Q808-H group [Formula: see text] were, respectively, treated with 5[Formula: see text]ml normal saline, 1[Formula: see text]ml/kg valproate, 0.5[Formula: see text]ml/kg Q808, and 1[Formula: see text]ml/kg Q808 solution once daily for 28 days. The Morris water maze test was performed to evaluate the effects of Q808 on cognitive impairment in the TLE model. Hematoxylin-eosin (HE) staining was performed to determine histopathological changes in the hippocampus, immunohistochemistry was performed to determine the expression of caspase-3 in the hippocampus, and western blotting was performed to determine the expression levels of apoptosis-related proteins, including Apaf-1, caspase-9, and caspase-3. Q808 decreased the expression levels of the apoptosis-related proteins in the TLE hippocampal tissue, and higher doses are more effective. Besides, Q808 did not impair spatial cognition and memory. Furthermore, the results indicated that Q808 treatment inhibited neuronal cell death, and significantly decreased the expression levels of apoptotic factors, including Apaf-1, caspase-9, and caspase-3. Q808 prevented neuronal damage in the hippocampus of TLE rats by targeting the intrinsic apoptotic pathway of neurons.

Developmental Toxicity Study of DL-4-Hydroxy-4-Phenylhexanamide (DL-HEPB) in Rats.

Antiepileptic drugs affect embryonic development when administered during pregnancy, generating severe alterations, such as as cleft lip, spina bifida, heart abnormalities, or neuronal alterations. The compound DL-4-hydroxy-4-phenylhexanamide (DL-HEPB), a phenyl alcohol amide structurally different from known anticonvulsants, has shown good anticonvulsant effects in previous studies. However, its effects on intrauterine development are unknown. So, the purpose of this study was to determine the potential of DL-HEPB to produce alterations in conceptus. Pregnant Wistar rats were orally exposed to 0, 50, 100, and 200 mg/kg of DL-HEPB during organogenesis, and their food consumption and weight gain were measured. On gestation day 21, pregnant females were euthanized to analyze the fetuses for external, visceral, and skeletal malformations. A significant decrease in food consumption and body weight was observed in mothers, without any other manifestation of toxicity. In fetuses, no external malformations, visceral, or skeletal abnormalities, were observed under the dose of 100 mg/kg, while the dose of 200 mg/kg caused malformations in low frequency in brain and kidneys. In view of the results obtained, DL-HEPB could be a good starting point for the design of new highly effective anticonvulsant agents, with much lower developmental toxicity than that shown by commercial anticonvulsants.

Exploring the Antiepileptic Potential of Amaranthus spinosus: An Experimental Study in Albino Mice

About 60% of the world population relies on herbal medicine, and 80% depend almost entirely on it for their primary healthcare. Many of these herbs are rich in phytochemicals, thus valuable as potential sources of drugs. Amaranthus spinosus is a vegetable and ornamental plant used in African folklore to treat several illnesses. This study aimed to investigate the antiepileptic potential of the methanol leaf extract of Amaranthus spinosus in albino mice. Preliminary phytochemical screening and acute toxicity studies were conducted using standard methods. Anticonvulsant studies were conducted using chemo-shock models (pentylenetetrazole (PTZ) - and strychnine (STR)-induced seizures) in mice. Phytochemical screening has revealed the presence of terpenoids, tannins, saponins, alkaloids, anthraquinones, carbohydrates, cardiac glycosides, and flavonoids. Additionally, the acute toxicity studies of the extract revealed that the extract is safe in mice at 2000 mg/kg. The extract at 400 and 800 mg/kg produced a significant (p&lt;0.05) delay in the mean onset of seizures, decreased the duration of seizures induced by PTZ in a dose-dependent manner, and protected the mice. The extract showed insignificant protection against strychnine-induced seizures in mice. This could serve as a scientific basis for further evaluation of the plant’s potential in managing epilepsy, which can lead to the discovery of an effective antiepileptic agent with fewer side effects.

Modulating Hyperpolarization-Activated Cation Currents through Small Molecule Perturbations: Magnitude and Gating Control.

The hyperpolarization-activated cation current (Ih) exhibits a slowly activating time course of the current (Ih) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the Ih magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the Ih amplitude but also reduced the strength of voltage-dependent hysteresis (Hys(V)) associated with Ih. Cilobradine, similar to ivabradine, inhibited the amplitude of Ih; however, it also suppressed the amplitude of delayed-rectifier K+ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on Ih in a concentration-dependent fashion. Suppression of Ih amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the Ih amplitude as well as to depress Hys(V)'s strength of Ih. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the Ih magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the Ih magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of Ih. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the Ih amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on Ih.