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Zhe-shan Quan - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the anticonvulsant activity of 6 4 chlorophenyoxy tetrazolo 5 1 a phthalazine in various experimental seizure models in mice
Pharmacological Reports, 2010Co-Authors: Xianqing Deng, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neuroToxicity of QUAN-0808 was investigated using the rotarod neuroToxicity test in mice. QUAN-0808 exhibited higher activity (Median effective Dose, ED 50 = 6.8 mg/ kg) and lower neuroToxicity (Median Toxic Dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low neuroToxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
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Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice
Pharmacological reports : PR, 2010Co-Authors: Xian-yu Sun, Xianqing Deng, Cheng-xi Wei, Zhi-gang Sun, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neuroToxicity of QUAN-0808 was investigated using the rotarod neuroToxicity test in mice. QUAN-0808 exhibited higher activity (Median effective Dose, ED 50 = 6.8 mg/ kg) and lower neuroToxicity (Median Toxic Dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low neuroToxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
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Characterization of the anticonvulsant activity of doxepin in various experimental seizure models in mice
Pharmacological Reports, 2009Co-Authors: Lei Zhang, Hu-ri Piao, Zhe-shan QuanAbstract:Abstract In this paper, the anticonvulsant characteristics of doxepin were evaluated in numerous experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, isoniazid (ISO)-, 3-mercaptopropionic acid (3-MP)-, bicuculline (BIC)-, thiosemicarbazide (THIO)-, and strychnine (STR)-induced seizures. In addition, the acute adverse-effect profile of doxepin with respect to impairment of motor coordination was assessed with a mouse rotarod test. The evaluation of the time-course and Doseresponse relationships for doxepin provided evidence that the peak maximum anticonvulsant activity and acute adverse effects occurred 5 min after intraperitoneal ( ip ) administration. The results also revealed that doxepin had excellent anticonvulsant activity against maximal electroshock-induced seizures in mice with a Median effect value (ED 50 ) of 6.6 mg/kg. The assessment of acute adverse effects in the rotarod test revealed that doxepin induced acute neuroToxicity, and its Median Toxic Dose (TD 50 ) was 26.4 mg/kg. Additionally, doxepin showed anticonvulsant activity in several chemically-induced seizure models, including ISO, 3-MP, BIC, and THI. Based on this study, we can conclude that the antidepressant drug doxepin may be useful for treatment of depression in patients with epilepsy due to its short time to peak maximum anticonvulsant activity after ip administration (5 min) and remarkable anticonvulsant activity (6.6 mg/kg).
Stanisław J. Czuczwar - One of the best experts on this subject based on the ideXlab platform.
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Anticonvulsant and acute adverse effect profiles of picolinic acid 2-fluoro-benzylamide in various experimental seizure models and chimney test in mice.
Fundamental & clinical pharmacology, 2007Co-Authors: Jarogniew J. Luszczki, Mariusz J. Swiader, Ryszard Paruszewski, Waldemar A. Turski, Katarzyna Swiader, Stanisław J. CzuczwarAbstract:The objective of this study was to evaluate the anticonvulsant properties of picolinic acid 2-fluoro-benzylamide (Pic-2F-BZA) in numerous experimental seizure models [maximal electroshock (MES), bicuculline (BIC), pentylenetetrazole (PTZ), pilocarpine (PILO), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced seizures]. Moreover, the acute adverse-effect profile of the agent with respect to impairment of motor performance was assessed in animals subjected to the chimney test. Results indicate that Pic-2F-BZA in time- and Dose-dependent manners produced both the anti-electroshock action and acute adverse effects in the MES and chimney tests in mice respectively. The experimentally derived Median effective Dose (ED(50) value) in the MES test was 24.2 mg/kg (at 5 min after i.p. administration), whereas the Median Toxic Dose (TD(50) value) in the chimney test was 71.7 mg/kg. Furthermore, Pic-2F-BZA produced clear-cut antiseizure effects in all chemically induced seizure models and its ED(50) values amounted to 19.9 mg/kg for KA-, 39.5 mg/kg for AMPA-, 56.2 mg/kg for PTZ-, 76.4 mg/kg for BIC-, 160.1 mg/kg for PILO- and 165.2 mg/kg for NMDA-induced seizures. Based on this study, one can conclude that Pic-2F-BZA, because of its broad spectrum of anticonvulsant action and the short time to peak of its maximum anticonvulsant effects (5 min after its i.p. administration), deserves more attention as a potential antiepileptic drug for status epilepticus patients.
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Anticonvulsant and acute neuroToxic characteristics of nicotinic acid benzylamide : a preclinical study
Pharmacological reports : PR, 2006Co-Authors: Mariusz J. Swiader, Stanisław J. Czuczwar, Jarogniew J. Łuszczki, Ryszard Paruszewski, Waldemar A. TurskiAbstract:The aim of this study was to evaluate time-course and Dose-response relationships of nicotinic acid benzylamide (Nic-BZA) with regard to its anticonvulsant activity in the maximal electroshock (MES)-induced seizures and acute neuroToxic effects in terms of motor coordination impairment in the chimney test in mice. The experimental determination of both Median effective Dose (ED 50 ) and Median Toxic Dose (TD 50 ) allowed for the calculation of protective index (PI) values characterizing a preclinical profile of Nic-BZA. Results indicated that Nic-BZA produced the time-dependent and clear-cut anticonvulsant activity in the MES test and its ED 50 values ranged between 35.7 and 84.0 mg/kg (after the ip administration of the agent at 5 and 60 min, respectively), and between 72.0 and 152.1 mg/kg (at 5 and 60 min, respectively, following the po administration of Nic-BZA). In the chimney test, the TD 50 values for Nic-BZA, after its ip administration ranged between 188.5 and 509.9 mg/kg, whereas following its po administration the TD 50 values for Nic-BZA were between 552 and 1222.1 mg/kg. The PI values for Nic-BZA, calculated at various times after its ip and po administrations (ranging between 3.56 and 17), revealed that the agent has a favorable profile, when considering its both anticonvulsant and acute neuroToxic effects in this preclinical study. Based on this study, one can conclude that Nic-BZA might occur advantageous as a potential antiepileptic drug for breaking seizure attacks in patients with epilepsy.
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Isobolographic and Subthreshold Analysis of Interactions among Felbamate and Four Conventional Antiepileptic Drugs in Pentylenetetrazole‐induced Seizures in Mice
Epilepsia, 2004Co-Authors: Kinga K. Borowicz, Jarogniew J. Luszczki, Stanisław J. CzuczwarAbstract:Summary: Purpose: Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in Lennox–Gastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)-induced convulsions in mice, a model of myoclonic seizures in humans. Methods: Data obtained from PTZ-evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both Median Toxic Dose (TD50) and protective index (PI) for each drug combination. Results: FBM reduced the clonic seizure activity [with an ED50 of 9.7 mg/kg; TD50, 439.1 mg/kg; and PI, 45.3]. FBM at the Dose of 10 mg/kg, but not 7.5 mg/kg, significantly reduced PTZ-induced convulsions in mice. In the subthreshold method, FBM (7.5 mg/kg) did not affect the protective activity of conventional AEDs used in the study. However, when applied at 10 mg/kg, it enhanced the protective activity of PB and ESM, but not that of VPA or CZP. The nature of these interactions could not be precisely estimated with this method. The exact profile of drug interactions was determined with the use of isobolography. In terms of seizure inhibition, antagonism was found between FBM and VPA applied at the fixed-Dose ratio of 3:1. Synergy was detected between FBM and PB (1:3). Combinations of FBM with VPA (1:3, 1:1), PB (1:1, 3:1), and ESM or CZP (1:3, 1:1, 3:1) led to additive interactions. As regards motor impairment, the combinations of FBM with VPA (1:3) or CZP (1:1, 3:1) were synergistic. Remaining combinations exhibited pure additivity. Pharmacokinetic events may influence FBM/ESM and FBM/CZP interactions, because FBM lowered the brain concentration of ESM and increased that of CZP. Conclusions: The profitable benefit index was found only for the combination of FBM with PB (1:3). Conversely, the combinations of FBM with either VPA (1:3) or CZP (1:1, 3:1) do not seem promising for the therapy of refractory myoclonic convulsions. Isobolographic analysis provides more reliable clues to be considered by the clinicians willing to introduce AED combinations for the therapy of epilepsy.
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Interactions Between Oxcarbazepine and Conventional Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis
Epilepsia, 2003Co-Authors: Jarogniew J. Luszczki, Kinga K. Borowicz, Mariusz J. Swiader, Stanisław J. CzuczwarAbstract:Summary: Purpose: The aim of this study was to determine the types of interactions between oxcarbazepine (OCBZ) and conventional antiepileptic drugs (AEDs) against maximal electroshock-induced seizures (MES test) in mice, by using a method of isobolographic analysis. Methods: Adverse effects of combinations were evaluated in the chimney test (motor performance), also using the isobolographic method, which allowed determination of the Median Toxic Dose (TD50) values for individual combinations; thus the protective indices could be determined. Results: OCBZ and phenytoin (PHT) at the fixed-ratio combination of 1:1 were significantly infraadditive (antagonistic) with respect to the antiseizure protection against MES and simultaneously additive in terms of side effects in the chimney test. Interestingly, combinations between OCBZ and clonazepam (CZP) in the MES test proved antagonistic or synergistic, depending on the proportion of both AEDs in the mixture. Low Doses of OCBZ with high Doses of CZP exerted antagonism. Conversely, high Doses of OCBZ combined with low Doses of CZP resulted in a synergistic interaction. Remaining combinations between OCBZ and phenobarbital, valproate, or carbamazepine were purely additive, either as regards the anticonvulsant activity against MES or in terms of motor impairment in the chimney test. Conclusions: The results of this study indicate that interaction of OCBZ and CZP at fixed-ratio combination of 1:1 might be profitable from a clinical point of view. Conversely, combinations of OCBZ with PHT may not be clinically efficient.
H. Steve White - One of the best experts on this subject based on the ideXlab platform.
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Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice
Epilepsia, 2016Co-Authors: Melissa Barker-haliski, Fabiola Vanegas, Matthew J. Mau, Tristan K. Underwood, H. Steve WhiteAbstract:Summary Objective Some antiseizure drugs (ASDs) are associated with cognitive liability in patients with epilepsy, thus ASDs without this risk would be preferred. Little comparative pharmacology exists with ASDs in preclinical models of cognition. Few pharmacologic studies exist on the acute effects in rodents with chronic seizures. Predicting risk for cognitive impact with preclinical models may supply valuable ASD differentiation data. Methods ASDs (phenytoin [PHT]; carbamazepine [CBZ]; valproic acid [VPA]; lamotrigine [LTG]; phenobarbital [PB]; tiagabine [TGB]; retigabine [RTG]; topiramate [TPM]; and levetiracetam [LEV]) were administered equivalent to maximal electroshock Median effective Dose ([ED50]; mice, rats), or Median Dose necessary to elicit minimal motor impairment (Median Toxic Dose [TD50]; rats). Cognition models with naive adult rodents were novel object/place recognition (NOPR) task with CF-1 mice, and Morris water maze (MWM) with Sprague-Dawley rats. Selected ASDs were also administered to rats prior to testing in an open field. The effect of chronic seizures and ASD administration on cognitive performance in NOPR was also determined with corneal-kindled mice. Mice that did not achieve kindling criterion (partially kindled) were included to examine the effect of electrical stimulation on cognitive performance. Sham-kindled and age-matched mice were also tested. Results No ASD (ED50) affected latency to locate the MWM platform; TD50 of PB, RTG, TPM, and VPA reduced this latency. In naive mice, CBZ and VPA (ED50) reduced time with the novel object. Of interest, no ASD (ED50) affected performance of fully kindled mice in NOPR, whereas CBZ and LEV improved cognitive performance of partially kindled mice. Significance Standardized approaches to the preclinical evaluation of an ASD's potential cognitive impact are needed to inform drug development. This study demonstrated acute, Dose- and model-dependent effects of therapeutically relevant Doses of ASDs on cognitive performance of naive mice and rats, and corneal-kindled mice. This study highlights the challenge of predicting clinical adverse effects with preclinical models.
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Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy.
Epilepsy research, 2007Co-Authors: Thomas Stöhr, James P. Stables, Harvey J Kupferberg, Daeock Choi, Robert H Harris, Harold Kohn, Nancy Walton, H. Steve WhiteAbstract:This paper comprises a series of experiments in rodent models of partial and generalized epilepsy which were designed to describe the anti-convulsant profile of the functionalized amino acid lacosamide. Lacosamide was effective against sound-induced seizures in the genetically susceptible Frings mouse, against maximal electroshock test (MES)-induced seizures in rats and mice, in the rat hippocampal kindling model of partial seizures, and in the 6Hz model of psychomotor seizures in mice. The activity in the MES test in both mice (4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously reported for most clinically available anti-epileptic drugs. At both the Median effective Dose for MES protection, as well as the Median Toxic Dose for rotorod impairment, lacosamide elevated the seizure threshold in the i.v. pentylenetetrazol seizure test, suggesting that it is unlikely to be pro-convulsant at high Doses. Lacosamide was inactive against clonic seizures induced by subcutaneous administration of the chemoconvulsants pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced seizures in mice and showed full efficacy in the homocysteine model of epilepsy. In summary, the overall anti-convulsant profile of lacosamide appeared to be unique, and the drug displayed a good margin of safety in those tests in which it was effective. These results suggest that lacosamide may have the potential to be clinically useful for at least the treatment of generalized tonic-clonic and partial-onset epilepsies, and support ongoing clinical trials in these indications.
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A neuropharmacological evaluation of felbamate as a novel anticonvulsant.
Epilepsia, 1992Co-Authors: H. Steve White, Harold H. Wolf, Ewart A. Swinyard, G. A. Skeen, R. Duane SofiaAbstract:Summary: Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and clinical potential. FBM was effective against intracere broventricular (i.c.v.) N-methyl-D-aspartate (NMDA)-induced clonus and i.c.v. NMDA- and quisqualic acid (quis)-induced forelimb tonic extension in mice and ineffective against i.c.v. quis-induced clonus in mice. FBM was also effective in preventing the expression of Stage 5 kindled seizures in corneal-kindled rats. The calculated protective indices (rotorod Median Toxic Dose divided by anticonvulsant Median effective Dose) ranged from 28 to 146 for those tests in which FBM displayed activity. With the in vitro tests, FBM did not significantly displace [3H]MK-801 from its binding site. In contrast, FBM was effective in blocking sustained repetitive firing in mouse spinal cord neurons grown in tissue culture (Median inhibitory concentration 67 μg/ml). This effect on repetitive firing suggests indirectly that FBM modulates sodium channel conductance. The results, when compared to similar data for phenytoin, carbamazepine, valproate, and ethosuximide, support the concept that FBM is a relatively nonToxic agent with a unique profile of anticonvulsant action, a broad margin of safety, and a clinical potential that includes at least generalized tonic-clonic and complex partial seizures.
James P. Stables - One of the best experts on this subject based on the ideXlab platform.
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Design & synthesis of N'-[substituted] pyridine-4-carbohydrazides as potential anticonvulsant agents.
European Journal of Medicinal Chemistry, 2010Co-Authors: Laxmi Tripathi, Ranjit Singh, James P. StablesAbstract:Abstract A series of N′-[substituted] pyridine-4-carbohydrazides were designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neuroToxicity. The anticonvulsant activity of the titled compounds was established after intraperitoneal administration in three seizure models, which include MES, scMET and 6 Hz model. The most active compound of the series was N′-[4-(4-fluorophenoxy)benzylidene]pyridine-4-carbohydrazide PCH 6, which showed a MES ED 50 value of 128.3 mg/kg and 6 Hz ED 50 value of 53.3 mg/kg in mice. The Median Toxic Dose (TD 50 ) was 343.6 mg/kg, providing compound PCH 6 with a protection index of 2.67 in the MES test and 6.44 in 6 Hz test. A computational study was also carried out, including calculation of pharmacophore pattern, prediction of pharmacokinetic properties and docking studies.
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Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy.
Epilepsy research, 2007Co-Authors: Thomas Stöhr, James P. Stables, Harvey J Kupferberg, Daeock Choi, Robert H Harris, Harold Kohn, Nancy Walton, H. Steve WhiteAbstract:This paper comprises a series of experiments in rodent models of partial and generalized epilepsy which were designed to describe the anti-convulsant profile of the functionalized amino acid lacosamide. Lacosamide was effective against sound-induced seizures in the genetically susceptible Frings mouse, against maximal electroshock test (MES)-induced seizures in rats and mice, in the rat hippocampal kindling model of partial seizures, and in the 6Hz model of psychomotor seizures in mice. The activity in the MES test in both mice (4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously reported for most clinically available anti-epileptic drugs. At both the Median effective Dose for MES protection, as well as the Median Toxic Dose for rotorod impairment, lacosamide elevated the seizure threshold in the i.v. pentylenetetrazol seizure test, suggesting that it is unlikely to be pro-convulsant at high Doses. Lacosamide was inactive against clonic seizures induced by subcutaneous administration of the chemoconvulsants pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced seizures in mice and showed full efficacy in the homocysteine model of epilepsy. In summary, the overall anti-convulsant profile of lacosamide appeared to be unique, and the drug displayed a good margin of safety in those tests in which it was effective. These results suggest that lacosamide may have the potential to be clinically useful for at least the treatment of generalized tonic-clonic and partial-onset epilepsies, and support ongoing clinical trials in these indications.
Krzysztof Kamiński - One of the best experts on this subject based on the ideXlab platform.
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The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.
International journal of molecular sciences, 2020Co-Authors: Michał Abram, Marcin Jakubiec, Anna Rapacz, Szczepan Mogilski, Gniewomir Latacz, Rafał M Kamiński, Krzysztof KamińskiAbstract:Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (Median effective Dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, Median Toxic Dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatoToxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.
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Design, synthesis, and anticonvulsant activity of N-phenylamino derivatives of 3,3-dialkyl-pyrrolidine-2,5-diones and hexahydro-isoindole-1,3-diones.
Bioorganic & medicinal chemistry, 2008Co-Authors: Krzysztof Kamiński, Jolanta ObniskaAbstract:In the present study on the development of new anticonvulsants, the library of differently substituted N-phenylamino pyr- rolidine-2,5-dione and hexahydro-isoindole-1,3-dione derivatives was synthesized. The anticonvulsant activity of all the compounds was evaluated using the maximal electroshock (MES) and pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neuroToxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in electrical (MES) and/or pentylenetetrazole induced seizure (scPTZ) models. The quantitative in vivo anticonvulsant evaluation of N-phenylamino-3,3-dimethyl-pyrrolidine- 2,5-dione (15), conducted at the time of peak pharmacodynamic activity (TPE), showed the MES ED50 value of 69.89 mg/kg in rats. The Median Toxic Dose (TD50) was 500 mg/kg, providing compound 15 with a protective index (TD50/ED50) of 7.15 in the MES test. � 2008 Elsevier Ltd. All rights reserved.