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Tapani Keränen and Hanna Kuusisto

. Pharmacotherapy, 2007, 278: 1202-1205. Mancl E.E., Gidal B.E.: The effect of carbapenem antibiotics on plasma concentrations of valproic acid. Ann. Pharmacother., 2009, 43: 2082-2087. Omoda K., Murakami T., Yumoto R., Nagai J., Maeda Y., Kiribayashi Y., Takano M.: Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human. J. Pharm. Sci., 2005, 8: 1685-1693. Park M.K., Lim K.S., Kim T.E., Han H.K., Yi S.J., Shin K.H. et al.: Reduced valproic acid serum

Open access

Walter Fröscher, Timo Kirschstein and Johannes Rösche

(Anticonvulsant therapy for brain tumor-related epilepsy). Fortschr. Neurol. Psychiat., 2014, 82: 678-690. Gefroh-Grimes H.A., Gidal B.E.: Antiepileptic drugs in patients with malignant brain tumor: beyond seizures and pharmacokinetics. Acta Neurol. Scand., 2016, 133: 4-16. Gerstner T., Teich M., Bell N., Longin E., Dempfle C.-E., Brand J. et al.: Valproate-associated coagulopathies are frequent and variable in children. Epilepsia, 2006, 47: 1136-1143. Glantz M.J., Cole B.F., Forsyth P.A., Recht L.D., Wen P.Y., Chamberlain M.C. et

Open access

Mirosław Jasiński, Magdalena Chrościńska-Krawczyk and Stanisław J. Czuczwar


Background. Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.

Aim. To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.

Methods. The following adenosine receptor agonists were used: A1 – cyclohexyladenosine, A2A – CGS 21 680, A3 – N6-benzyl-NECA and A1 (preferentially) and A2 – 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50 values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1 and A2 antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.

Results. Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).

Conclusion. The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.

Open access

José Pimentel


Background. Monotherapy is the choice regimen to treat newly diagnosed epilepsies. However, if it fails, several strategies may be followed.

Aim. To discuss the treatment options when an initial monotherapy regimen fails.

Methods. We reviewed the relevant literature on the topic by using PubMed.

Review and Discussion. Approximately 64% of people with epilepsy (PWE) de novo are free of seizures with the first appropriate antiepileptic drug (AED) in monotherapy. The type (first versus second generation) of the first AED to use depends on the physician's personal choice provided that it is a first-line AED. There is a tendency to prefer a substitution rather than a combination of a failed first AED when it was produced associated with an idiosyncratic reaction, was poorly tolerated at a moderate dose, or produced no improvement in seizure control. In contrast, there is some evidence to prefer secondary polytherapy whenever the PWE tolerate its first AED but with a suboptimal response. In this case, and particularly mainly if a first generation AED was used as a first-line treatment, I prefer to choose a new generation AED given their more favourable pharmacokinetic and pharmacodynamic profiles. A very often used strategy is transitional polytherapy between two regimens of monotherapy.

Conclusion. Any therapeutic decision should take into account factors such as seizure type or syndrome, possibility of drug side effects, comorbidities, comedications, age, teratogenic potential, and compliance. Whatever the option to be taken, the PWE, his family or the caregivers should take part in the decision making.

Open access

Pavel Vlasov, Vladimir Karlov, Irina Zhidkova, Aleksandr Chervyakov, Oleg Belyaev, Iosif Volkov, Diana Dmitrenko, Antonina Karas, Tatiana Kazennykh, Olga Miguskina, Anna Moskvicheva, Elena Paramonova and Irina Ponomareva

effects of adjunctive perampanel for partial-onset seizures: A randomized trial. Epilepsia, 2016, 57: 243-251. Mula M., Kanner A.M., Schmitz B., Schachter S.: Antiepileptic drugs and suicidality: An expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia, 2013, 54: 199-203. Patsalos P.N.: Drug Interactions With the Newer Antiepileptic Drugs (AEDs) - Part 1: Pharmacokinetic and Pharmacodynamic Interactions Between AEDs. Clinical Pharmacokinetics, 2013a, 52: 927

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Walter Fröscher and Alois Rauber

–417. Neligan A., Bell G.S., Sander J.W., Shorvon S.D.: How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res., 2011, 96: 225–230. Patsalos P.N.: Drug interactions with the newer antiepileptic drugs (AEDs) – Part 1. Pharmacokinetic and pharmacodynamic interactions between AEDs . Clin. Pharmacokinet., 2013, 52: 927–966. Pedersen B., Rasmussen J.B.: Lacosamide treatment – added value of plasma levels? Epilepsia, 2013, 54, Suppl 3: 171. Sattler A., Schaefer M., May T.W., Rambeck B

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Mirosław Zagaja, Barbara Miziak, Katarzyna Załuska, Paweł Marzęda, Bartłomiej Drop, Karolina Załuska-Patel, Grażyna Ossowska, Stanisław J. Czuczwar and Jarogniew J. Łuszczki

models. Epilepsy Research, 1991, 8: 79–94. Löscher W., Nolting B.: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices. Epilepsy Research, 1991, 9: 1–10. Łuszczki J.J., Andres M.M., Czuczwar P., Cioczek-Czuczwar A., Ratnaraj N., Patsalos P.N. et al.: Pharmacodynamic and pharmacokinetic characterization of interactions between levetiracetam and numerous antiepileptic drugs in the mouse maximal electroshock seizure model: an isobolographic analysis . Epilepsia, 2006

Open access

Matti Sillanpää

. Lancet, 1958, 2: 175–178. Kudriakova T.B., Sarota L.A., Rozova G.I., Gotkov V.A.: Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites . Br. J. Clin. Pharmacol., 1992, 33: 611–615. Larsson K., Eeg-Olofsson O.: A population based study of epilepsy in children from a Swedish county . Eur. J. Paediatr. Neurol., 2006, 10: 107–113. Leach J.P., Lauder R., Nicolson A., Smith D.F.: Epilepsy in the UK: Misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project . Seizure, 2005, 14: 514

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Magdalena Chrościńska-Krawczyk, Magdalena Wałek, Bożydar Tylus and Stanisław J. Czuczwar

pharmacokinetic/pharmacodynamic interactions – an update . Pharmacol. Rep., 2011, 63: 271–292. Leach J.P., Brodie M.J.: New antiepileptic drugs – an explosion of activity . Seizure, 1995, 4: 5–17. Lee C.Y., Fu W.M., Chen C.C., Su M.J., Liou H.H.: Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus . Epilepsia, 2008a, 49: 588–597. Lee J.H., Hwang Y.S., Shin J.J., Kim T.H., Shin H.S., Park S.K.: Surgical complications of epilepsy surgery procedures: experience of 179 procedures in a single institute . J. Korean