Effect of sildenafil, a selective phosphodiesterase 5 inhibitor, on the anticonvulsant action of some antiepileptic drugs in the mouse 6-Hz psychomotor seizure model.

Sildenafil, a selective phosphodiesterase 5 inhibitor (PDE5), has been recently reported to have both pro- and anticonvulsant action in various experimental models of seizures and epilepsy. Furthermore, it affects anticonvulsant action of some antiepileptic drugs (AEDs) in mice seizure tests and both pharmacodynamic and pharmacokinetic interactions were noted. The present study was carried out to investigate influence of sildenafil on the threshold for 6 Hz-induced psychomotor seizures in mice. Effect of sildenafil on activity of some AEDs, i.e., phenobarbital (PB), clonazepam (CZP), ethosuximide (ETS), valproic acid (VPA), tiagabine (TGB), oxcarbazepine (OXC) and levetiracetam (LEV), in 6 Hz test was also examined. Moreover, combination of sildenafil with LEV was investigated in terms of influence on motor coordination (determined by the chimney test), muscular strength (evaluated in the grip-strength test) and long-term memory (assessed in the passive avoidance task) in mice. To determine the type of pharmacological interaction between sildenafil and LEV, free plasma and total brain concentrations of this AED were determined by LC-MS/MS method. Sildenafil at a dose ranging from 10 to 40 mg/kg statistically increased psychomotor seizure threshold in mice. Moreover, sildenafil enhanced the anticonvulsant action of all the studied AEDs in this test. Interactions between this PDE5 inhibitor and PB, CZP, ETS, TGB and OXC seem to be pharmacodynamic. Since sildenafil increased free plasma and total brain concentration of LEV, interactions between these drugs have pharmacokinetic nature. This kind of interaction was also noted between sildenafil and VPA. Neither LEV (2.32 mg/kg) nor its co-administration with sildenafil (40 mg/kg) produced any significant changes in motor coordination, muscular strength and long-term memory in mice.

Nieoczym D ，Socała K ，Jedziniak P ，Olejnik M ，Wlaź P ... -  《-》

Effect of sildenafil on the anticonvulsant action of classical and second-generation antiepileptic drugs in maximal electroshock-induced seizures in mice.

The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

Nieoczym D ，Łuszczki JJ ，Czuczwar SJ ，Wlaź P ... -  《-》

Sildenafil influences the anticonvulsant activity of vigabatrin and gabapentin in the timed pentylenetetrazole infusion test in mice.

Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to affect convulsant activity in some animal models of seizures and epilepsy. Moreover, its influence on the protective activity of some antiepileptic drugs (AEDs) was also noted. The aim of the present study was to investigate the effect of sildenafil on the anticonvulsant potential of gabapentin (GBP) and vigabatrin (VGB) in the timed intravenous (i.v.) pentylenetetrazole (PTZ) test in mice. The chimney test, the passive avoidance task and the grip strength test were used to estimate some possible side effects caused by the studied AEDs and their combinations with sildenafil. Total brain and free plasma concentrations of GBP and VGB were determined to evaluate the characteristics of interactions. Our studies revealed that GBP (25-100 mg/kg) increases the threshold for the forelimb tonic extension, whereas VGB raises thresholds both, for myoclonic (200-600 mg/kg) and generalized clonic (400-600 mg/kg) seizures in the used model of seizures. GBP at sub-effective dose of 12.5 mg/kg co-administered with sildenafil at doses of 10 and 20 mg/kg significantly increases the threshold for tonic seizures in the i.v. PTZ test in mice. Combination of sub-effective dose of VGB (200 mg/kg) with sildenafil at a dose of 5mg/kg also showed significant anticonvulsant activity against clonic seizures. The studied AEDs and their combinations with sildenafil did not produce any changes in the motor coordination, long-term memory and muscular strength in mice. Sildenafil did not influence total brain and free plasma concentrations of GBP and VGB. Interactions between the studied AEDs and sildenafil were pharmacodynamic in nature and for that reason they are worthy of consideration in the clinical practice.

Nieoczym D ，Socała K ，Luszczki JJ ，Czuczwar SJ ，Wlaź P ... -  《-》

Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.

Wojda E ，Wlaz A ，Patsalos PN ，Luszczki JJ ... -  《-》

Effect of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

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, 0.2s 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 TD(50) and ED(50) 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.

Luszczki JJ ，Czuczwar P ，Cioczek-Czuczwar A ，Dudra-Jastrzebska M ，Andres-Mach M ，Czuczwar SJ ... -  《-》