Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

Summary Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world. Aim. To determine the interaction profile for the combination of retigabine (RTG) and oxcarbazepine (OXC) in both, the model of tonic-clonic seizures, the maximal electroshock (MES)-induced seizure model and chimney test (motor performance) in adult male albino Swiss mice. Methods. Isobolographic analysis (type I) was applied to characterize interactions for the combination of RTG with OXC with respect to its anticonvulsant and acute side (neurotoxic) effects, as determined in the MES and chimney tests, respectively. Results. The combination of RTG with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in the MES test in mice. Similarly, the combination of RTG with OXC at the fixed-ratio of 1:1 produced additive interaction with a tendency towards sub-additivity in the chimney test in mice. Measurement of total brain concentrations of both AEDs revealed that RTG did not affect total brain concentrations of OXC and inversely, OXC had no impact on RTG’s total brain concentrations, confirming pharmacodynamic interaction between the drugs. Conclusions. The additive pharmacodynamic interactions in both the MES and chimney tests in mice were observed for the combination of RTG with OXC.

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Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

Pharmacology ◽

10.1159/000480019 ◽

2017 ◽

Vol 101 (1-2) ◽

pp. 22-28 ◽

Cited By ~ 5

Author(s):

Jarogniew J. Luszczki ◽

Mirosław Zagaja ◽

Barbara Miziak ◽

Maria W. Kondrat-Wrobel ◽

Katarzyna Zaluska ◽

...

Keyword(s):

Dose Response ◽

Treatment Plan ◽

Linear Regression Analysis ◽

Fixed Ratio ◽

Maximal Electroshock ◽

Type I ◽

Additive Interaction ◽

Pharmacoresistant Epilepsy ◽

Isobolographic Analysis ◽

Chimney Test

Background/Aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice. Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs. Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction. Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy.

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Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis

Pharmacological Reports ◽

10.1007/s43440-020-00117-y ◽

2020 ◽

Vol 72 (5) ◽

pp. 1288-1296 ◽

Cited By ~ 1

Author(s):

Jarogniew J. Łuszczki ◽

Maria Kondrat-Wróbel ◽

Mirosław Zagaja ◽

Sławomir Karwan ◽

Hubert Bojar ◽

...

Keyword(s):

Seizure Activity ◽

Fixed Ratio ◽

Mechanisms Of Action ◽

Clinical Settings ◽

Maximal Electroshock ◽

Type I ◽

Pharmacodynamic Interaction ◽

Isobolographic Analysis ◽

Mes Test ◽

Patients With Epilepsy

Abstract Background Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians’ experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug–drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice. Materials and methods The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1. Results The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. Conclusion The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.

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Additive interactions of pregabalin with lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis for non-parallel dose–response relationship curves

Epilepsy Research ◽

10.1016/j.eplepsyres.2010.07.009 ◽

2010 ◽

Vol 91 (2-3) ◽

pp. 166-175 ◽

Cited By ~ 14

Author(s):

Jarogniew J. Luszczki ◽

Damian Filip ◽

Stanislaw J. Czuczwar

Keyword(s):

Dose Response ◽

Maximal Electroshock ◽

Type I ◽

Response Relationship ◽

Dose Response Relationship ◽

Isobolographic Analysis ◽

Seizure Model ◽

Additive Interactions

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Additive interaction for three-drug combination of carbamazepine, lacosamide and lamotrigine against maximal electroshock-induced seizures – a type I isobolographic analysis

European Journal of Clinical and Experimental Medicine ◽

10.15584/ejcem.2017.4.1 ◽

2018 ◽

Vol 15 (4) ◽

pp. 303-309 ◽

Cited By ~ 2

Author(s):

Maria Kondrat-Wróbel ◽

◽

Jarogniew J. Łuszczki ◽

Keyword(s):

Drug Combination ◽

Maximal Electroshock ◽

Type I ◽

Additive Interaction ◽

Isobolographic Analysis

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Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic–clonic seizure model in mice

Pharmacological Reports ◽

10.1007/s43440-020-00164-5 ◽

2020 ◽

Author(s):

Jarogniew J. Łuszczki ◽

Dominika Podgórska ◽

Justyna Kozińska ◽

Marek Jankiewicz ◽

Zbigniew Plewa ◽

...

Keyword(s):

Drug Interactions ◽

Antiepileptic Drugs ◽

Second Generation ◽

Drug Combinations ◽

Maximal Electroshock ◽

Type I ◽

Swiss Mice ◽

Total Brain ◽

Seizure Model ◽

The Impact

Abstract Background Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug–drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. Aim To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. Materials and method The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. Results The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. Conclusions The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

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Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice

Neurochemical Research ◽

10.1007/s11064-020-03175-z ◽

2020 ◽

Author(s):

Magdalena Drabik ◽

Mariusz Głuszak ◽

Paula Wróblewska-Łuczka ◽

Zbigniew Plewa ◽

Marek Jankiewicz ◽

...

Keyword(s):

Clonic Seizure ◽

Tonic Clonic Seizure ◽

Synergistic Interaction ◽

Protective Effects ◽

Additive Interaction ◽

Protective Index ◽

Total Brain ◽

Neurotoxic Effects ◽

Clonic Seizures ◽

Seizure Model

AbstractProtective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as TD50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.

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Synergy, Additivity, and Antagonism between Cisplatin and Selected Coumarins in Human Melanoma Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22020537 ◽

2021 ◽

Vol 22 (2) ◽

pp. 537

Author(s):

Paula Wróblewska-Łuczka ◽

Aneta Grabarska ◽

Magdalena Florek-Łuszczki ◽

Zbigniew Plewa ◽

Jarogniew J. Łuszczki

Keyword(s):

Cell Lines ◽

Melanoma Cell ◽

Melanoma Cells ◽

Human Melanoma ◽

Type I ◽

Antiproliferative Effects ◽

Isobolographic Analysis ◽

Natural Substances ◽

Additive Interactions ◽

Melanoma Cell Lines

(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and CDDP-related toxicity, is highly desired. Coumarins have many biological properties, including anticancer and antiproliferative effects. (2) An in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on two human melanoma cell lines (FM55P and FM55M2) examined the antitumor properties of CDDP and five naturally occurring coumarins (osthole, xanthotoxin, xanthotoxol, isopimpinellin, and imperatorin). The antiproliferative effects produced by combinations of CDDP with the coumarins were assessed using type I isobolographic analysis. (3) The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol. These compounds were characterized by the lowest median inhibitory concentration (IC50) values relative to the FM55P and FM55M2 melanoma cells. Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions, while the combination of CDDP and xanthotoxol exerted additive interactions. Combinations of CDDP with xanthotoxin, isopimpinellin, and imperatorin showed antagonistic and additive interactions in two melanoma cell lines. (4) The combination of CDDP and osthole was characterized by the most desirable synergistic interaction. Isobolographic analysis allows the selection of potential candidates for cancer drugs among natural substances.

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