S J Czuczwar

Medical University of Lublin, Lyublin, Lublin Voivodeship, Poland

Are you S J Czuczwar?

Claim your profile

Publications (258)660.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test.
    European journal of pharmacology 10/2013; · 2.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In ~30% of epileptic patients, full seizure control is not possible, which is why the search for novel antiepileptic drugs continues. Retigabine exhibits a mechanism of action that is not shared by the available antiepileptic drugs. This antiepileptic enhances potassium currents via Kv7.2-7.3 channels, which very likely results from destabilization of a closed conformation or stabilization of the open conformation of the channels. Generally, the pharmacokinetics of retigabine are linear and the drug undergoes glucuronidation and acetylation. Results from clinical trials indicate that, in the form of an add-on therapy, retigabine proves an effective drug in refractory epileptic patients. The major adverse effects of the add-on treatment are dizziness, somnolence, and fatigue. This epileptic drug is also considered for other conditions - neuropathic pain, affective disorders, stroke, or even Alzheimer's disease.
    Therapeutics and Clinical Risk Management 01/2012; 8:7-14. · 1.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) plays a variety of physiological and pathological roles in mammalian cells. In the central nervous system NO may behave as a second messenger, neuromodulator, and neurotransmitter, which may suggest an essential role of this gaseous molecule in epilepsy and epileptogenesis. The aim of this review is to survey the current literature in terms of experimental and clinical evidence of anti- or proconvulsive properties of NO and its implications in the anticonvulsive action of antiepileptic drugs. Up-to-date multiple NO synthase (NOS) inhibitors and donors of NO were used in a plethora of seizure models (e.g. electrically and pharmacologically-evoked convulsions, amygdala-kindled seizures). Reported results vary depending on the seizure model, kind and doses of pharmacological tools used in experiments, and route of drug administration. The most thoroughly tested NOS inhibitor was 7- nitroindazole (7-NI), which presented anticonvulsive properties in most known models of seizures. The clear-cut proconvulsant action of 7-NI was observed only in kainate-, nicotine-, and soman-induced convulsions in rodents. This NOS inhibitor enhanced the anticonvulsant action of almost all available classic and second-generation antiepileptic drugs except tiagabine, felbamate, and topiramate. The effect of NG-nitro-L-arginine methyl ester was not so unambiguous. In pentylenetetrazole, pictotoxin, and N-methyl-Daspartate seizure models the inhibitor exhibited dose-dependent bidirectional action. NG-nitro-L-arginine methyl ester potentiated the efficacy of diazepam and clonazepam, diminished that of valproate and phenobarbital, but did not affect the anticonvulsant action of phenytoin and ethosuximide. On the other hand, NG-nitro-L-arginine, was anticonvulsant in nicotine-, glutamate-, and hyperbaric O2- evoked seizures, and proconvulsant in pilocarpine-, kainate-, bicuculline-, aminophylline-, and 4-aminopyridine-induced convulsions. NG-nitro-L-arginine remained without effect on the anticonvulsant action of both classic (valproate, phenobarbital, diazepam) and new generation (oxcarbazepine, felbamate, and ethosuximide) antiepileptic drugs. The action of ethosuximide was even impaired. Summing up, in the present state of knowledge the only reasonable conclusion is that NO behaves as a neuromodulator with dual - proconvulsive or anticonvulsive - action.
    CNS & neurological disorders drug targets 11/2011; 10(7):808-19. · 3.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the influence of acute (single) and chronic (once daily for 7 consecutive days) treatments with atorvastatin and fluvastatin on the anticonvulsant potential of three antiepileptic drugs: carbamazepine, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of both statins on the adverse effect potential of three antiepileptic drugs were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). To evaluate the pharmacokinetic characteristics of interaction between antiepileptic drugs and statins, the total brain concentrations of antiepileptic drugs were estimated with the fluorescence polarization immunoassay technique. Results indicate that atorvastatin at doses up to 80mg/kg in chronic experiment attenuated the anticonvulsant potential of carbamazepine by increasing its ED(50) value against maximal electroconvulsions. Acute fluvastatin (80mg/kg) enhanced the anticonvulsant potential of carbamazepine and valproate by decreasing their ED(50) values. Acute fluvastatin (80mg/kg) also markedly increased the total brain carbamazepine concentration by 61% in a pharmacokinetic reaction. Atorvastatin (acute and chronic) and fluvastatin (chronic) in combinations with valproate impaired long-term memory in mice. Both statins in combinations with all three antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on this preclinical study, one can conclude that chronic administration of atorvastatin reduces the anticonvulsant action of carbamazepine and acute fluvastatin can enhance the anticonvulsant potency of the carbamazepine and valproate. The former interaction was pharmacokinetic in nature.
    European journal of pharmacology 10/2011; 674(1):20-6. · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.
    European journal of pharmacology 09/2011; 670(1):114-20. · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (AEDs: clonazepam [CZP], ethosuximide [ETS], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model. WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED(50) values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P<0.05). WIN (5 and 10mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively. Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against PTZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2011; 35(8):1870-6. · 3.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN--a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5 mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment.
    Pharmacology Biochemistry and Behavior 04/2011; 98(2):261-7. · 2.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurosteroids were initially defined as steroid hormones locally synthesized within the nervous tissue. Subsequently, they were described as steroid hormone derivatives that devoid hormonal action but still affect neuronal excitability through modulation of ionotropic receptors. Neurosteroids are further subdivided into natural (produced in the brain) and synthetic. Some authors distinguish between hormonal and regular neurosteroids in the group of natural ones. The latter group, including hormone metabolites like allopregnanolone or tetrahydrodeoxycorticosterone, is devoid of hormonal activity. Both hormones and their derivatives share, however, most of the physiological functions. It is usually very difficult to distinguish the effects of hormones and their metabolites. All these substances may influence seizure phenomena and exhibit neuroprotective effects. Neuroprotection offered by steroid hormones may be realized in both genomic and non-genomic mechanisms and involve regulation of the pro- and anti-apoptotic factors expression, intracellular signaling pathways, neurotransmission, oxidative, and inflammatory processes. Since regular neurosteroids show no affinity for steroid receptors, they may act only in a non-genomic mode. Multiple studies have been conducted so far to show efficacy of neurosteroids in the treatment of the central and peripheral nervous system injury, ischemia, neurodegenerative diseases, or seizures. In this review we focused primarily on neurosteroid mechanisms of action and their role in the process of neurodegeneration. Most of the data refers to results obtained in experimental studies. However, it should be realized that knowledge about neuroactive steroids remains still incomplete and requires confirmation in clinical conditions.
    Frontiers in Endocrinology 01/2011; 2:50.
  • Jarogniew J Luszczki, Damian Filip, Stanislaw J Czuczwar
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.
    Epilepsy research 10/2010; 91(2-3):166-75. · 2.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.
    Epilepsy research 08/2010; 90(3):188-98. · 2.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to characterize the anticonvulsant effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ--an endogenous parkinsonism-preventing substance) in combination with four second-generation antiepileptic drugs (AEDs: lamotrigine [LTG], oxcarbazepine [OXC], pregabalin [PGB], and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of MeTHIQ with LTG, OXC, PGB and TPM at the fixed-ratio of 1:1 from the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain concentrations of MeTHIQ and TPM. In the mouse MES model, MeTHIQ administered singly had its DRRC parallel to those for OXC and TPM, and simultaneously, non-parallel to those for LTG and PGB. With type I isobolography for parallel DRRCs, the combination of MeTHIQ with TPM at three fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction, whereas the combination of MeTHIQ with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interaction. Similarly, the type I isobolography for non-parallel DRRCs revealed that the combination of MeTHIQ with LTG and PGB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength were affected. Total brain concentrations of MeTHIQ and TPM revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratios of 1:3, 1:1 and 3:1. In conclusion, the synergistic interaction of MeTHIQ with TPM at the fixed-ratios of 1:3, 1:1 and 3:1 against MES-induced seizures was pharmacodynamic in nature and thus, it is worthy of consideration in further clinical settings. The combinations of MeTHIQ with LTG, OXC and PGB were neutral in the mouse MES model.
    Epilepsy research 05/2010; 89(2-3):207-19. · 2.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the influence of arachidonyl-2′-chloroethylamide (ACEA — a highly selective cannabinoid type 1 [CB1] receptor agonist) on the protective action and acute adverse effects of carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, and topiramate in the maximal electroshock seizure model and chimney test in mice.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the studied antiepileptic drugs with respect to motor coordination was assessed in the chimney test. Additionally, long-term memory and skeletal muscular strength were measured along with free plasma (non-protein bound) and total brain antiepileptic drug concentrations. To inhibit the rapid metabolic degradation of ACEA by the fatty-acid amide hydrolase, phenylmethylsulfonyl fluoride (PMSF) was used at a constant ineffective dose of 30 mg/kg.Results indicate that ACEA (2.5 mg/kg, i.p.) co-administered with PMSF (30 mg/kg, i.p.), significantly enhanced the anticonvulsant activity of phenobarbital, but not that of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, or topiramate in the maximal electroshock seizure test in mice. Moreover, ACEA (2.5 mg/kg) with PMSF (30 mg/kg) had no significant impact on the acute adverse effects of all examined antiepileptic drugs in the chimney test in mice. The protective index values (as quotients of the respective TD50 and ED50 values denoted from the chimney and maximal electroshock seizure tests, respectively) for the combinations of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) with carbamazepine, oxcarbazepine, phenobarbital, and topiramate were greater than those denoted for the antiepileptic drugs administered alone. Only, the protective index values for the combination of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) with lamotrigine and phenytoin were lower than those determined for the antiepileptic drugs administered alone. Pharmacokinetic experiments revealed that ACEA (2.5 mg/kg) and PMSF (30 mg/kg) affected neither free plasma (non-protein bound) nor total brain concentrations of phenobarbital in mice. Moreover, ACEA and PMSF in combination with carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, and topiramate did not alter long-term memory or skeletal muscular strength in experimental animals.In conclusion, the enhanced anticonvulsant action of phenobarbital by ACEA and PMSF, lack of pharmacokinetic interaction and no acute adverse effects between the examined compounds, make the combination of ACEA and PMSF with phenobarbital of pivotal importance for further experimental and clinical studies. The combinations of ACEA and PMSF with carbamazepine, lamotrigine, oxcarbazepine, phenytoin, and topiramate are neutral from a preclinical viewpoint.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2010; · 3.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs. The aim of this study was to investigate the influence of acute and chronic treatment with intraperitoneal milnacipran (MLN), a selective serotonin/noradrenaline reuptake inhibitor, on the protective activity of valproate, carbamazepine (CBZ), phenytoin, or phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by an alternating current (50 Hz, 25 mA) delivered via ear-clip electrodes. Motor coordination and long-term memory were evaluated in the chimney test and passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs (AEDs) were assessed by immunofluorescence. Given acutely, MLN at 10 mg/kg increased the convulsive threshold. Acute MLN applied at the subprotective dose of 5 mg/kg enhanced the anticonvulsant effects of CBZ and PB. Chronic treatment with MLN (5-30 mg/kg once daily for 2 weeks) did not affect either the electroconvulsive threshold or the anticonvulsant action of all studied conventional antiepileptic drugs. Since the antidepressant did not affect brain concentrations of antiepileptics used in the study, the revealed interactions seem to be of pharmacodynamic nature. Moreover, acute and chronic MLN, AEDs, and their combinations did not produce significant motor and long-term memory impairment. Acute, but not chronic, treatment with MLN can increase the effectiveness of some AEDs against MES-induced seizures in mice. It seems that MLN may also be considered as a candidate drug for clinical trials in patients with epilepsy and depressive disorders.
    Psychopharmacology 10/2009; 207(4):661-9. · 4.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.
    Seizure 08/2009; 18(9):607-14. · 2.00 Impact Factor
  • Jarogniew J Luszczki, Sergey L Kocharov, Stanislaw J Czuczwar
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the influence of N-(anilinomethyl)-p-isopropoxyphenylsuccinimide (AMIPPS) on the protective action of carbamazepine, phenobarbital, phenytoin, and valproate in the mouse maximal electroshock seizure model. Results indicate that AMIPPS administered separately (i.p., at doses of 75 and 150 mg/kg), significantly elevated the threshold for electroconvulsions in mice. Moreover, AMIPPS (37.5mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate, but not that of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. AMIPPS (18.75 mg/kg) had no impact on the antiseizure action of phenobarbital and valproate against maximal electroshock seizure-induced seizures in mice. Pharmacokinetic experiments revealed that AMIPPS significantly increased total brain valproate concentrations and it had no impact on total brain concentrations of phenobarbital in mice. In conclusion, the enhanced antielectroshock action of phenobarbital by AMIPPS and lack of pharmacokinetic interaction make the combination of AMIPPS with phenobarbital of pivotal importance for further experimental and clinical studies. Although AMIPPS potentiated the anticonvulsant action of valproate in the maximal electroshock seizure test, the caution is advised when combining these drugs due to the risk of pharmacokinetic interactions. The combinations of AMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.
    Neuroscience Research 08/2009; 64(3):267-72. · 2.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine and compare the anticonvulsant and acute adverse (neurotoxic) effects of imperatorin and osthole (two natural coumarin derivatives) with valproate (a classical antiepileptic drug) in the maximal electroshock seizure and chimney tests in mice. The anticonvulsant and acute adverse effects of imperatorin, osthole and valproate were determined at 15, 30, 60 and 120 min after their systemic (i.p.) administration. The evaluation of time-course and dose-response relationships for imperatorin, osthole and valproate in the maximal electroshock seizure test revealed that the compounds produced a clear-cut antielectroshock action in mice and the experimentally derived ED(50) values for imperatorin ranged between 167 and 290 mg/kg, those for osthole ranged from 253 to 639 mg/kg, whereas the ED(50) values for valproate ranged from 189 to 255 mg/kg. The evaluation of acute neurotoxic effects in the chimney test revealed that the TD(50) values for imperatorin ranged between 329 and 443 mg/kg, the TD(50) values for osthole ranged from 531 to 648 mg/kg, while the TD(50) values for valproate ranged from 363 to 512 mg/kg. The protective index (as a ratio of TD(50) and ED(50) values) for imperatorin ranged between 1.13 and 2.60, for osthole ranged from 0.83 to 2.44, and for valproate ranged between 1.72 and 2.00. In conclusion, both natural coumarin derivatives deserve more attention from a preclinical point of view as compounds possessing some potentially favorable activities in terms of suppression of seizures, quite similar to those reported for valproate.
    Epilepsy research 05/2009; 85(2-3):293-9. · 2.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.
    European journal of pharmacology 02/2009; 605(1-3):87-94. · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: At least 20 - 30% of epileptic patients do not sufficiently respond to monotherapy. Some of them can benefit from drug combinations; hence, animal data may provide some useful novel clues for rational polytherapy. To review combinations of antiepileptic drugs, evaluated with the help of isobolographic analysis, in terms of their efficacy and adverse effects. A literature search, on the basis of experimental studies, with no time limit was carried out. Preclinical data indicate that a synergy occurred for the combinations of valproate + phenytoin, valproate + ethosuximide, lamotrigine + valproate, gabapentin + valproate, gabapentin + carbamazepine, topiramate + carbamazepine, topiramate + valproate, topiramate + oxcarbazepine, levetiracetam + topiramate, levetiracetam + oxcarbazepine, oxcarbazepine + gabapentin, tiagabine + gabapentin and lamotrigine + topiramate. On the other hand, lamotrigine combined with carbamazepine or oxcarbazepine resulted in a clear-cut antagonism. Interestingly, a combination of oxcarbazepine + clonazepam produced variable responses, including synergy, additivity or antagonism, depending on the dose ratio of these drugs. In no case did pharmacokinetic factors contribute to the final analysis of the effects of drug combinations. Pharmacokinetic factors can contribute to the final effect of drug combinations,such as when stiripentol is added to valproate, or clobazam is added to valproate. It may be concluded that the rational treatment of drug-resistant epilepsy needs to consider the results of preclinical studies.
    Expert Opinion on Drug Metabolism &amp Toxicology 02/2009; 5(2):131-6. · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one] – a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED50 values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies.
    European Journal of Pharmacology. 01/2009;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The anticonvulsant activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ--an endogenous parkinsonism-preventing substance) administered alone and in combination with four conventional antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and valproate) was determined in the mouse maximal electroshock-induced seizure model. The types of interactions of MeTHIQ with the antiepileptic drugs were characterized using isobolographic analysis. The isobolographic analysis revealed that the combination of MeTHIQ with phenobarbital at the fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction in the maximal electroshock-induced seizure test. In contrast, the combinations of MeTHIQ with carbamazepine, phenytoin and valproate exerted additive interaction for all three fixed-ratios (1:3, 1:1 and 3:1) tested in the maximal electroshock-induced seizure test. In conclusion, MeTHIQ produces a clear-cut anticonvulsant effect in the maximal electroshock-induced seizure test in mice. The supra-additive interaction of MeTHIQ with phenobarbital against maximal electroshock-induced seizures makes their combination of pivotal importance from a clinical viewpoint.
    European journal of pharmacology 01/2009; 602(2-3):298-305. · 2.59 Impact Factor

Publication Stats

4k Citations
660.09 Total Impact Points

Institutions

  • 1981–2013
    • Medical University of Lublin
      • • Department of Pathophysiology
      • • Department of Neurology
      • • Laboratory of Class III Isotopes
      • • Department of Toxicology (Pharmacy)
      Lyublin, Lublin Voivodeship, Poland
  • 1996–2005
    • National Institutes of Health
      • Branch of Toxicology and Pharmacology
      Maryland, United States
    • Agricultural University in Lublin
      Lyublin, Lublin Voivodeship, Poland
  • 1999–2000
    • Instytut Medycyny Wsi
      Lyublin, Lublin Voivodeship, Poland
  • 1985–1986
    • Freie Universität Berlin
      • Department of Veterinary Medicine
      Berlin, Land Berlin, Germany
    • Max Planck Institute for Experimental Medicine
      Göttingen, Lower Saxony, Germany