Synthesis,in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED₅₀) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED₅₀ values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA_A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.

Anticonvulsant Efficacy in Sturge-Weber Syndrome

ObjectiveWe analyzed individuals with epilepsy due to Sturge-Weber syndrome to determine which anticonvulsants provided optimal seizure control and which resulted in the fewest side effects.MethodsOne-hundred-eight records from a single center were retrospectively analyzed for Sturge-Weber syndrome brain involvement, epilepsy, Sturge-Weber syndrome neuroscores, and currently used anticonvulsants.ResultsOf the fourteen anticonvulsants that had been employed, the most often used agents were oxcarbazepine or carbamazepine, and levetiracetam. Individuals whose seizures at the most recent visit were fully controlled (seizure-free) for 6 months or longer were more likely to have ever tried, or currently used, oxcarbazepine or carbamazepine than those with uncontrolled seizures. Thirty-nine of 69 individuals (56.5%) were seizure-free with oxcarbazepine or carbamazepine history versus 11 of 35 individuals (31.4%) who had not taken these agents (P < 0.05); 38 of 62 patients (61.3%) were seizure-free while currently taking these anticonvulsants versus 12 of 42 (28.6%) not taking them (P < 0.01). Patients with seizure control for 6 months or longer were less likely to have ever tried, or to currently be taking, levetiracetam than those without control. Sixteen of 56 individuals (28.6%) were seizure-free with levetiracetam history versus 34 of 48 (70.8%) without it (P < 0.001); 14 of 43 individuals (32.6%) were seizure-free and currently taking levetiracetam versus 36 of 61 (59.0%) not taking it (P < 0.01). When topiramate was added as second-line medication, five of nine patients (55.6%) experienced decreased seizure severity, and worsening of glaucoma was not reported.ConclusionsCarbamazepine and oxcarbazepine were associated with better seizure control than levetiracetam in this Sturge-Weber syndrome cohort and so may be preferred as the initial therapy. When used as adjunctive therapy, topiramate was effective in this limited analysis without a clear increased incidence of glaucoma.     

Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury: a randomized clinical trial

BACKGROUND: Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries (DILI) in children. Although withdrawal of the caus-ative agent is the only proved treatment for DILI, in some clin-ical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with anti-oxidant actions for the management of DILI. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy. METHODS: This randomized, open-label, clinical trial evalu-ated 55 children with epilepsy who were on antiepileptic treat-ment and experienced DILI. The children were randomized to receive either silymarin (5 mg/kg per day) or folic acid (1 mg per day) for one month and were followed up for three months. RESULTS: Liver enzymes significantly decreased in both groups. The decrease trend in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were stronger in the folic acid group compared to silymarin group (P=0.04 and P=0.007, respectively). At the end of the study patients in the folic acid group had significantly lower ALT (P=0.04), AST (P=0.02), and gamma-glutamyl transferase (GGT) (P<0.001) levels and also higher percentage of normal ALT (30.7% vs 3.4%, P=0.009) and AST (42.3% vs 0%, P<0.001), and GGT (23.1% vs 0%, P=0.008) values compared to the patients in the silymarin group. No rebound elevations in ALT, AST and GGT levels or adverse reactions were noted in neither of the study groups.CONCLUSION: Although both treatments were safe and ef-fective in decreasing liver enzymes, folic acid seems to be supe-rior to silymarin in the management of DILI.     

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA_A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world''s first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.     

Brivaracetam: a new drug in development for epilepsy and neuropathic pain

Background: Epilepsy is a neurological disorder with a worldwide prevalence estimated to be 0.5 – 1.0% of the population. Many potent antiepileptic drugs (AED) have been used for treatment but still about 30% of patients are resistant to current AEDs. Some AEDs are also used for the treatment of neuropathic pain. Objective: The aim of this report is to present preclinical and clinical studies of brivaracetam (UCB-34714), a new drug developed by UCB Pharma. Methods: Published results of preclinical studies in several animal models of epilepsy, neuropathic pain, essential tremor and results of Phase I and II evaluations of brivaracetam have been analysed. Results/conclusion: Brivaracetam represents a new mechanism of action being a ligand of synaptic vesicle protein 2A. It is undergoing Phase III evaluation after a successful Phase II programme in which was effective as an adjunctive treatment in partial-onset epilepsy (50 mg/day). It is well tolerated, without serious adverse side effects.     

4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物的合成及其抗惊厥活性

目的设计合成一系列4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物,并评价其抗惊厥活性和神经毒性。方法以对乙酰氨基酚为起始原料,经烷基化、水解、环合等反应合成1,2,4-三唑-5(4H)-酮类化合物。通过最大电惊厥实验(MES)和神经毒性实验(NT),分别测定目标化合物的抗惊厥活性和神经毒性。结果与结论合成了20个新化合物,其结构经IR、1H-NMR和ESI-MS确证。药理学实验结果表明,所有化合物在不同剂量下都显示出抗惊厥活性。其中,3-乙基-4-(4-戊氧基苯基)-1H-1,2,4-三唑-5(4H)-酮(4e)的活性最强,其半数有效量ED50值为26.9 mg·kg-1,保护指数(PI)为11.0,虽然该化合物的活性低于阳性对照药卡马西平,但其保护指数优于卡马西平(PI=6.4);3-乙基-4-(4-(3-氟苄氧基)苯基)-1H-1,2,4-三唑-5(4H)-酮(4n)的ED50值为61.1 mg·kg-1,但其PI大于17.0,明显优于卡马西平,具有进一步研究的价值。     

Drug‐induced gingival enlargement: Biofilm control and surgical therapy with gallium–aluminum–arsenide (GaAlAs) diode laser—A 2‐year follow‐up

Drug‐induced gingival enlargement has been reported in patients treated with various types of anticonvulsant drugs, and is generally associated with the presence of plaque, gingival inflammation, and a genetic predisposition. Effective treatment includes daily oral hygiene and periodic professional prophylaxis. However, in some patients, surgical removal of the gingival tissue overgrowth becomes necessary. The patient in this case report was mentally impaired and had severe drug‐induced gingival enlargement. This report describes the initial protocol, the gingivectomy, and a 2‐year follow‐up. A diode laser was used as an effective and safe method to remove the patient's overgrown gingival tissue.     

In silico and in vivo investigation of ferrocene‐incorporated acyl ureas and homoleptic cadmium carboxylate derivatives for anticonvulsant,anxiolytic, and sedative potential

In this study different derivatives of ferrocene‐incorporated acyl ureas and homoleptic cadmium carboxylates were investigated for potential anticonvulsant, anxiolytic and sedative properties, using in‐silico and in‐vivo techniques. The molecular docking studies reveled that ferrocene compounds derivative 1‐(4‐bromobenzoyl)‐3‐(4‐ferrocenylphenyl) urea (PB1) and cadmium compounds derivative bis (diphenylacetato) cadmium (II) (DPAA) exhibit binding affinities against various neurotherapeutic molecular targets involved in epilepsy, anxiety, and sedation. Both PB1 and DPAA showed high binding affinities against protein targets like mammalian shaker voltage dependent potassium channel beta subunit complex, calcium release‐activated calcium channel, sodium channel 2A inactivation gate, human sodium/hydrogen exchanger regulatory factor, and gamma amino butyric acid A receptor associated protein. PB1 (2–10 mg/kg) and DPAA (1–5 mg/kg) delayed onset time of pentylenetetrazole‐induced myoclonic jerks and tonic‐clonic seizures in mice while decreased duration of tonic‐clonic seizures, determining the anticonvulsant effect of these compounds. PB1 and DPAA (0.5–1 mg/kg) exhibited anxiolytic effect by increasing time spent and number of animals entries into open arms, while decreasing time spent in dark compartment. Furthermore, PB1 (0.5–1 mg/kg) and DPAA (0.1–1 mg/kg) reduced onset time of sleep and increased duration time of sleep in mice, showing sedative effect. Taken together, our results indicate that aforementioned derivatives of ferrocene and cadmium are potent neurotherapeutic agents possessing anticonvulsant, anxiolytic and sedative properties.     

α-Subunit selective modulators of GABAA receptor function as CNS therapeutics

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the CNS. Many drugs, including the benzodiazepines, exert their effects by modulating the GABA_A receptor complex, but side effects are common and reflect, in part, poor subunit selectivity. The subunits are arranged into heteropentamers and this produces a rich diversity of GABA_A receptor subtypes, which are potential targets for treating a variety of CNS disorders including epilepsy, anxiety and insomnia, as well as for ameliorating deficiencies arising from neurodegeneration, such as cognitive impairment. The identification of new ligands with improved subunit selectivity should reduce or abolish some of the side effects observed with current drugs, such as tolerance, dependence and withdrawal. This article focuses on new ligands that are reported to selectively recognise particular α-subunits of GABA_A receptors and may thereby offer improved treatments for CNS disorders. Only patents and literature since 1998 are necessarily included, although some earlier reports and reviews are also cited. Several publications and patent applications since 1998 disclose new compounds that modulate GABA_A receptor function without mentioning whether they have α-subunit selectivity; these compounds, like those known to interact with sites on other GABA_A subunits (particularly β), are not within the scope of this review.     

An Open-Label Pilot Study of Divalproex Sodium for Posttraumatic Stress Disorder Related to Childhood Abuse

Background: Few effective pharmacotherapeutic strategies have been established for the treatment of symptoms associated with posttraumatic stress disorder (PTSD). Preliminary evidence supports the efficacy of serotonergic agents and anticonvulsants, such as divalproex sodium, for the treatment of PTSD symptoms, particularly in military populations.Objective: The aim of this study was to obtain pilot data on the use of divalproex sodium for the treatment of PTSD among adult civilian outpatients with a history of childhood physical and/or sexual abuse.Methods: Outpatients with a primary psychiatric diagnosis of PTSD received open-label, flexibly dosed divalproex sodium as adjuvant therapy or monotherapy for 8 weeks. Overall and subcluster PTSD features, as well as affective symptoms and clinical global improvement, were monitored using standardized assessment scales.Results: A total of 7 patients (5 women, 2 men; mean age, 44.1 years [range, 29-57 years]) were enrolled. At a mean (SD) peak dosage of 1500 (661) mg/d, significant improvement occurred in overall PTSD symptom severity (P<0.02) and in the diagnostic subclusters of hyperarousal and avoidance (P<0.02 for both). Depressive symptoms also were significantly improved from baseline (P<0.02). Divalproex sodium was well tolerated, except in 1 patient who prematurely discontinued treatment due to cognitive adverse events.Conclusions: These provisional findings support the possible utility of divalproex sodium therapy for adult outpatients with PTSD related to physical and/or sexual abuse during childhood. Controlled trials with larger sample sizes powered to show safety and efficacy are needed to substantiate these initial findings.