Effective Anticonvulsant Agent Research Articles

Synthesis, Molecular Docking, and Anticonvulsant Activity of 1,3,4-Oxadiazole Derivatives

AbstractA novel series of 1,3,4-oxadiazoles (O1–4) were synthesized and physical characterization was done by spectroscopic data (infrared, mass, proton nuclear magnetic resonance). To ascertain the synthesized compound's likely binding mechanism and affinity toward the protein target (Protein Data Bank ID: 3R7X), molecular docking was performed. The synthesized compounds were subjected to in silico analysis using Schrodinger suite 2020–4 and absorption, distribution, metabolism, and excretion screening. Some of the synthesized compounds were subjected to in vivo evaluation of anticonvulsant activity by maximal electroshock seizure and pentylenetetrazol model. The synthesized 1,3,4-oxadiazole analogs may be developed as lead compounds and effective anticonvulsant agents for the pharmaceutical industry based on computational and in vivo data.

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.

Discovery of Potent Carbonic Anhydrase Inhibitors as Effective Anticonvulsant Agents: Drug Design, Synthesis, and In Vitro and In Vivo Investigations.

Two sets of benzenesulfonamide-based effective human carbonic anhydrase (hCA) inhibitors have been developed using the tail approach. The inhibitory action of these novel molecules was examined against four isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules disclosed low to medium nanomolar range inhibition against all tested isoforms. Some of the synthesized derivatives selectively inhibited the epilepsy-involved isoforms hCA II and hCA VII, showing low nanomolar affinity. The anticonvulsant activity of selected sulfonamides was assessed using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) in vivo models of epilepsy. These potent CA inhibitors effectively inhibited seizures in both epilepsy models. The most effective compounds showed long duration of action and abolished MES-induced seizures up to 6 h after drug administration. These sulfonamides were found to be orally active anticonvulsants, being nontoxic in neuronal cell lines and in animal models.

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after,to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivoand in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Topiramate Improves Neuroblast Differentiation of Hippocampal Dentate Gyrus in the D-Galactose-Induced Aging Mice via Its Antioxidant Effects.

Some anticonvulsant drugs are associated with cognitive ability in patients; Topiramate (TPM) is well known as an effective anticonvulsant agent applied in clinical settings. However, the effect of TPM on the cognitive function is rarely studied. In this study, we aimed to observe the effects of TPM on cell proliferation and neuronal differentiation in the dentate gyrus (DG) of the D-galactose-induced aging mice by Ki-67 and doublecortin (DCX) immunohistochemistry. The study is divided into four groups including control, D-galactose-treated group, 25 and 50mg/kg TPM-treated plus D-galactose-treated groups. We found, 50mg/kg (not 25mg/kg) TPM treatment significantly increased the numbers of Ki-67+ cells and DCX immunoreactivity, and improved neuroblast injury induced by D-galactose treatment. In addition, we also found that decreased immunoreactivities and protein levels of antioxidants including superoxide dismutase and catalase induced by D-galactose treatment were significantly recovered by 50mg/kg TPM treatment in the mice hippocampal DG (P<0.05). In conclusion, our present results indicate that TPM can ameliorate neuroblast damage and promote cell proliferation and neuroblast differentiation in the hippocampal DG via increasing SODs and catalase levels in the D-galactose mice.

Molecular Modeling and In Silico Evaluation of Novel Pyridazinones Derivatives as Anticonvulsant Agents

Context: Virtual screening techniques or computational methods are used for the drug discovery and development. Objective: In search for the safer and effective anticonvulsant agents, docking study on pyridazinone derivatives was performed to potentiate GABA mediated chlorine channel opening. Methods: A total of eighteen compounds were screened for their anticonvulsant activity using molecular docking inside the ligand binding domain of PDB ID 2Q1Q using Molegro Virtual docker. QikProp 3.4 & molinspiration software were also used to evaluate drug likeliness and to perform comparative bioactivity analysis for all the pyridazinone derivatives. Results: Out of eighteen compounds, (I) showed highest Mol dock score and (XVIII) formed maximum number of hydrogen bond interactions. Oxygen atom of the Nitro group on the biphenyl ring of compound (XV) formed a strong hydrogen bond with Thr199 with a distance 2.33?. Mol dock score of diazepam (standard drug) was -101.5306. Conclusions: Based on the results of mol dock score and number of hydrogen bond interactions, compounds (XVIII) and (XIII) observed to be the most potent compounds.

5% CO2 inhalation suppresses hyperventilation-induced absence seizures in children

Hyperventilation can cause respiratory alkalosis by exhaling CO2, and is often used to confirm diagnosis of absence epilepsy. CO2 has long been known for its anticonvulsant properties since the 1920s. In this pilot study, we aimed to determine whether inhaling medical carbogen containing 5% CO2 and 95% O2 can suppress hyperventilation-induced absence seizures and spike-and-wave discharges (SWDs). We examined 12 patients whose absence seizures were induced by hyperventilation using video electroencephalographic recording for at least 4h. The patients were asked to hyperventilate for 3 min while breathing the following gases: (1) room air (12 patients); (2) carbogen (12 patients); and (3) 100% O2 (8 patients). Eight out of twelve patients were also examined in room air through pretreatment with carbogen for 3 min before the 3 min hyperventilation. Compared with hyperventilation in room air, hyperventilation supplemented with 5% CO2 had the following effects: (a) decrease in the number and duration of seizures; (b) prolonged appearance of epileptic discharges; and (c) reduction in the number and duration of SWDs (P<0.001). However, pretreatment with 5% CO2 and 100% O2 supplement did not yield similar effects. We demonstrated that 5% CO2 could suppress hyperventilation-induced absence seizures and SWDs, supporting the claim that 5% CO2 is an effective anticonvulsant agent. Our pilot study provides clinical basis that 5% CO2 inhalation could be a therapeutic approach for hyperventilation-related seizures.

(4S,5R,6R)-para-mentha-1,8-dien-5,6-diol is a new highly effective anticonvulsant agent

(4S,5R,6R)-para-mentha-1,8-dien-5,6-diol is a new highly effective anticonvulsant agent

CYP2C9 Amino Acid Residues Influencing Phenytoin Turnover and Metabolite Regio- and Stereochemistry

Phenytoin has been an effective anticonvulsant agent for over 60 years, although its clinical use is complicated by nonlinear pharmacokinetics, a narrow therapeutic index, and metabolically based drug-drug interactions. Although it is well established that CYP2C9 is the major cytochrome P450 enzyme controlling metabolic elimination of phenytoin through its oxidative conversion to (S)-5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), nothing is known about the amino acid binding determinants within the CYP2C9 active site that promote metabolism and maintain the tight stereocontrol of hydroxy metabolite formation. This knowledge gap was addressed here through the construction of nine active site mutants at amino acid positions Phe100, Arg108, Phe114, Leu208, and Phe476 and in vitro analysis of the steady-state kinetics and stereochemistry of p-HPPH formation. The F100L and F114W mutants exhibited 4- to 5-fold increases in catalytic efficiency, whereas the F100W, F114L, F476L, and F476W mutants lost >90% of their phenytoin hydroxylation capacity. This pattern of effects differs substantially from that found previously for (S)-warfarin and (S)-flurbiprofen metabolism, suggesting that these three ligands bind within discrete locations in the CYP2C9 active site. Only the F114L, F476L, and L208V mutants altered phenytoin's orientation during catalytic turnover. The L208V mutant also uniquely demonstrated enhanced 6-hydroxylation of (S)-warfarin. These latter data provide the first experimental evidence for a role of the F-G loop region in dictating the catalytic orientation of substrates within the CYP2C9 active site.

Effect of Long-Term Therapy with Sodium Valproate on Nail and Serum Trace Element Status in Epileptic Children

Antiepileptic drugs could cause changes in the trace element status of the body. Valproic acid (VPA) is a very effective anticonvulsant agent widely used in the management of various forms of epilepsy. Nail trace element content is a reliable index of trace element nutritional status of the body. To determine whether some of the side effects of antiepileptic drugs could be the result of zinc (Zn) depletion within tissues, Zn concentrations as well as copper (Cu) concentrations in nail and serum in 59 children having various types of epilepsy receiving valproate and 31 controls were assessed. Although serum Zn level in epileptic patients was found to be decreased, there was no difference in nail samples when compared to controls. There was a statistically significant increase in nail Cu level in epileptic patients when compared to controls. On the other hand, serum Cu levels were not different between the groups. Although none of our patients showed any symptoms of Cu elevation and Zn depletion, we should pay attention to potential body trace element changes in patients with epilepsy under VPA treatment. In conclusion, our results indicate that serum trace metal homeostasis might be affected by VPA therapy, but not by the convulsive disorder itself.

Depressive effect of nicardipine on penicillin-induced epileptiform activity in rats

It is believed that calcium ions have very important role in the formation of epilepsy. Calcium ion flux into the cell leads to secretion of excitatory neurotransmitters. During epileptic seizures, routine balance of excitation and inhibition is altered towards the excitation. In present study, the effect of nicardipine on penicillin-induced epilepsy was investigated. The left cerebral cortex was exposed by craniotomy in anaesthetized rats. The epileptic focus was produced by injection of penicillin G potassium (500 units) into the somatomotor cortex. Microinjection of nicardipine into the same area caused an inhibition for 4-5 minutes in electrocorticograms (ECoG). The results of this study suggest that nicardipine may be an effective anticonvulsant agent in treatment of epilepsy by preventing calcium flux into the cell.

Depressive effect of nicardipine on penicillin‐induced epileptiform activity in rats

It is believed that calcium ions have very important role in the formation of epilepsy. Calcium ion flux into the cell leads to secretion of excitatory neurotransmitters. During epileptic seizures, routine balance of excitation and inhibition is altered towards the excitation. In present study, the effect of nicardipine on penicillin-induced epilepsy was investigated. The left cerebral cortex was exposed by craniotomy in anaesthetized rats. The epileptic focus was produced by injection of penicillin G potassium (500 units) into the somatomotor cortex. Microinjection of nicardipine into the same area caused an inhibition for 4-5 minutes in electrocorticograms (ECoG). The results of this study suggest that nicardipine may be an effective anticonvulsant agent in treatment of epilepsy by preventing calcium flux into the cell.

Exacerbation of epileptic seizures by carbamazepine: Report of 10 cases

Carbamazepine (CBZ) is an effective anticonvulsant agent. Current literature reports describe several cases of seizure exacerbation and/or EEG worsening due to CBZ with a high prevalence in children and adolescents; we report 10 new cases. Nine patients had epilepsy; one showed delayed psychomotor development and frequent EEG paroxysmal abnormalities. Four patients were on monotherapy, six on polytherapy. All but one had therapeutic CBZ plasma concentrations. Seizures increased in frequency in nine, and in eight patients new seizure types appeared, mostly absences. Cognitive functions/behaviour worsened in eight; EEG recordings showed slowing background activity and increased paroxysmal abnormalities, in six cases diffuse/generalized spike waves were seen and in two continuous spike wave discharges. The mean time of clinical EEG worsening was 1-2 days after introduction of CBZ at therapeutic doses. After CBZ withdrawal clinical EEG improvement was evident in a few days. The underlying pathogenetic mechanism is not yet understood. However, the pathophysiology of seizure exacerbation might be related to the interaction between age-related alterations in the balance of excitation and inhibition in the developing thalamocortical circuitry and the essential activity of CBZ that tends to induce interictal discharges.

LU 73068, a new non‐NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L‐701,324 in the kindling model of epilepsy

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.

Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives.

Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

Developmental toxicity of valproic acid

Valproic acid is a very effective anticonvulsant agent widely used in the management of various forms of epilepsy. Administration of the drug during pregnancy results in increased incidence of congenital abnormalities in both humans and experimental animals. In recent years, a significant number of research efforts have attempted to define the contributory role of valproic acid to the impairment of normal prenatal growth and development. The present report summarizes current knowledge that has emerged from clinical and research studies. The specific topics include: the placental transfer of valproic acid; the teratogenic potential; structure-teratogenicity and dose-response relationships; species and strain differences; biochemical changes evoked by the drug in the fetus.

Clinical pharmacokinetics of valproic acid--1988.

Sodium valproate (valproic acid) has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent. Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies. Valproic acid is available in different oral formulations such as solutions, tablets, enteric-coated capsules and slow-release preparations. For most of these formulations bio-availability approaches 100%, while the absorption half-life varies from less than 30 minutes to 3 or 4 hours depending on the type of preparation used. Once absorbed, valproic acid is largely bound to plasma proteins and has a relatively small volume of distribution (0.1 to 0.4 L/kg). Its concentration in CSF is approximately one-tenth that in plasma and is directly correlated with the concentration found in tears. At therapeutic doses, valproic acid half-life varies from 10 to 20 hours in adults, while it is significantly shorter (6 to 9 hours) in children. Valproic acid undergoes extensive liver metabolism. Numerous metabolites have been positively identified and there is reasonable evidence that several of them contribute to its pharmacological and toxic actions. In fact, several valproic acid metabolites have anti-convulsant properties, while many of the side effects it may cause (e.g. those related to hyperammonaemia or liver damage) are most often observed in patients previously treated with phenobarbitone. This could indicate that induction of liver enzymes is responsible for the formation of toxic valproic acid metabolites.

Liquid chromatographic optimization of reaction conditions for the synthesis of 2,2-dimethyl-N-benzylmalonamide, a new anticonvulsant.

Reversed-phase liquid chromatographic (RP/LC) procedures are used to optimize the reaction conditions for the large scale preparation of 2,2-dimethyl-N-benzylmalonamide, 1. In acute studies using mice and rats, compound 1 is a very effective anticonvulsant agent. Large quantities of 1 (ca. 300 g) are needed for detailed studies of its chronic effects. LC monitoring of the synthesis of intermediate products and 1 result in the optimum use of reagents, increased product yields, and decreased reaction times.

Seizure control following administration of anticonvulsant drugs in the quaking mouse

The effectiveness of a variety of clinical anticonvulsant drugs was evaluated in the quaking mutant mouse model of epilepsy. In this model, tonic-clonic seizures are easily elicited by handling and the effects of administration of carbamazepine (CBZ), phenytoin (DPH), phenobarbital (PB), diazepam, valproic acid (VPA) and ethosuximide were quantitatively evaluated. Chronic oral administration of CBZ, DPH and PB reduced the frequency of seizures and this was positively correlated with plasma levels of the drugs. The plasma levels of the 10,11-epoxide metabolite of CBZ were found to be approximately 3–5 times that of the parent compound with chronic oral administration. Acute intraperitoneal administration of the other drugs revealed VPA to be an effective anticonvulsant agent, whereas ethosuximide and diazepam were ineffective at dosage levels that are normally effective in mice as determined by classical testing methods such as electroshock and chemoshock. The results of the present study suggest that the quaking mouse may be a simple, reliable and inexpensive animal model for the evaluation of agents effective against focal motor seizures in humans.

Copper complexes: a physiologic approach to the treatment of ‘inflammatory diseases’

Copper is an ‘essential’ metalloelement and as such it is required for life. Since none of the essential metalloelements can be synthesized in vivo it is required that they be obtained in the diet, If, following absorption, copper is not utilized immediately in the synthesis of copper-dependent enzymes it is either stored in the liver or excreted in a homeostatic fashion. It is well established that copper-dependent enzymes are required for cellular utilization of oxygen; dismutation of superoxide; cross-linking of collagen and elastin; synthesis of dihydroxyphenylalanine, melanin, norepinephrine, and epinephrine; metabolism of monoamines; and mobilization of stored iron for hematopoeisis. Other biochemical processes which are less well understood concerning the involvement of copper are: modulation of prostaglandin synthesis, lysosomal membrane permeability, modulation of histamine activity, angiogenesis, enhancement of synaptic vesicle attachment to neuronal plasma membranes, uptake and release of monoamines by synaptosomes, and activation of brain adenylate cyclase. A 2 to 3 fold increase in plasma or serum copper concentration is observed as a general response to infectious, inflammatory, and stress related diseases. It is well documented that blood copper concentrations increase in arthritic diseases, seizures, and neoplastic diseases and it is likely that there is a similar elevation with ulcers and diabetes. These elevations are viewed as a general acute phase physiologic response which facilitates remission. In the event that this physiologic response is impaired remission does not occur. Copper-containing components in blood are: ceruloplasmin which contains 6 atoms of copper and has a molecular weight of 132,000, a copper-albumin complex with a molecular weight of 69,000, and a variety of amino acid complexes with molecular weights in the range of 300 to 400. While there is always a highly significant correlation between the plasma copper increase and the increase in ceruloplasmin, further studies are needed to determine the relative change in concentration of each of the copper-containing components in the physiologic response to disease. This same increase in plasma copper concentration occurs in a variety of animal models of inflammation. Since treatment of these inflammations with exogenous low-molecular-weight copper complexes produces antiinfammatory effects the use of copper complexes may be viewed as a physiological approach to treatment. Low-molecular-weight copper complexes have been shown to have antiarthritic effects in man. In addition to being effective antiinflammatory agents copper complexes have been shown to be effective antiulcer, anticonvulsant, anticancer, and antidiabetic agents. This seeming diverse variety of pharmacologic effects are unified with the hypothesis that copper complexes facilitate or promote tissue repair processes involving copper-dependent enzymes and that arthritis, ulcers, seizures, neoplasia, and diabetes are diseases of specific tissues in disrepair. The corollary to this hypothesis is that the loss or reduction of copper-dependent enzyme mediated processes leads to tissue disfunction which may be re-established with copper complex therapy. Evidence will be presented to show that non-toxic doses of copper complexes have antiinflammatory activity in recognized models of inflammation and that copper complexes of antiinflammatory drugs are more effective than the parent drugs. Data will also be presented to show that copper complexes have antiulcer activity and that copper complexes of antiinflammatory drugs, which are well known ulcerogens, are also potent antiulcer agents. This observation supports the view that copper complexes of antiinflammatory drugs are less toxic than the parent drugs and suggests that complexation may have a role in ulcerogenesis. Anticonvulsant activity of copper complexes in two recognized models of seizure will be presented to show that complexes of non-anticonvulsant and convulsant ligands are effective anticonvulsant agents. In addition, data obtained with a copper complex of an antiepileptic drug suggests that the active form of these drugs may be their copper complexes. Recognition that neoplastic cells have reduced superoxide dismutase (SOD) activity and that copper complexes have SOD-like activity lead to the investigation of copper complexes as anticancer agents. Data will be presented to show that small molecular weight copper complexes inhibit solid Ehrlich tumor growth and increase survival. Following the observation that SOD inhibited streptozotocin-induced diabetes, small molecular weight copper complexes were studied and found to inhibit streptozotocin-induced diabetes as well. This observation will be presented in support of a possible role for copper complexes in the treatment of diabetes.