Effective therapy may require an individual approach and best results are expected when psychological and pharmacological treatments are combined.

Generally, the prevalence of epilepsy does not exceed 0.9% of the population and approximately 70% of epilepsy patients may be adequately controlled with antiepileptic drugs (AEDs). Moreover, status epilepticus (SE) or even a single seizure may produce neurodegeneration within the brain and SE has been recognized as one of acute brain insults leading to acquired epilepsy via the process of epileptogenesis. Two questions thus arise: (1) Are AEDs able to inhibit SE-induced neurodegeneration? and (2) if so, can a probable neuroprotective potential of particular AEDs stop epileptogenesis? An affirmative answer to the second question would practically point to the preventive potential of a given neuroprotective AED following acute brain insults. The available experimental data indicate that diazepam (at low and high doses), gabapentin, pregabalin, topiramate and valproate exhibited potent or moderate neuroprotective effects in diverse models of SE in rats. However, only diazepam (at high doses), gabapentin and pregabalin exerted some protective activity against acquired epilepsy (spontaneous seizures). As regards valproate, its effects on spontaneous seizures were equivocal. With isobolography, some supra-additive combinations of AEDs have been delineated against experimental seizures. One of such combinations, levetiracetam + topiramate proved highly synergistic in two models of seizures and this particular combination significantly inhibited epileptogenesis in rats following status SE. Importantly, no neuroprotection was evident. It may be strikingly concluded that there is no correlation between neuroprotection and antiepileptogenesis. Probably, preclinically verified combinations of AEDs may be considered for an anti-epileptogenic therapy.

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Apart from enzyme inducers, valproate (an even enzyme inhibitor) may also negatively affect BMD. However, the untoward effects of AEDs may depend upon their doses and duration of treatment. Although the problem of supplementation of vitamin D and calcium in epileptic patients on AEDs is controversial, there are recommendations to do so.

Epilepsy is a common neurologic disease, affecting about 1-2% of the population. In around 30% of patients with epilepsy, their seizures are not satisfactorily controlled and drug-resistant epilepsy constitutes a real therapeutic challenge. Consequently, there are efforts aimed at the inhibition of epileptogenesis, a process of converting a normal into an epileptic brain. Data on this problem have been mainly obtained in post-status epilepticus rodent models in which spontaneous seizure activity and behavioral disturbances develop over time. Among antiepileptic drugs, diazepam at high dose of 20mg/kg given during status epilepticus, significantly inhibited the development of spontaneous seizures and also, a strong neuroprotective effect was evident. Also gabapentin and valproate (over a period of 40 days) proved effective in the inhibition of spontaneous seizure activity and reduction of behavioral deficit. However, there are also data that valproate (over 28 days) significantly improved the behavioral performance without affecting the occurrence of spontaneous seizures. A number of antiepileptic drugs, carbamazepine, lamotrigine, levetiracetam, phenobarbital, and topiramate were completely ineffective. Among non-antiepileptic drugs, some promise show rapamycin, losartan and combinations of anti-inflammatory drugs, targeting different inflammatory pathways. Inhibition of epileptogenesis may become a valuable therapeutic approach provided that there are reliable markers of this process. Actually, such markers begin to emerge.

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

Considering that there are around 30% of patients with epilepsy resistant to monotherapy, the use of synergistic combinations of antiepileptic drugs is of particular importance. This review shows most beneficial as well as irrational combined treatments both from an experimental and clinical point of view. Areas covered: Preferably, experimental data derived from studies evaluating synergy, additivity, or antagonism by relevant methods, in terms of anticonvulsant or neurotoxic effects and pharmacokinetic data have been considered. Although there have been no randomized clinical trials on this issue, the clinical data have been analyzed from studies on considerable numbers of patients. Case-report studies have been not considered. Expert commentary: The experimental data provide a strong support that co-administration of lamotrigine with carbamazepine is negative, considering the anticonvulsant and neurotoxic effects. Clinical reports do not entirely support this conclusion. Other experimentally documented negative combinations comprise lamotrigine+ oxcarbazepine and oxcarbazepine+ phenytoin. From the experimental and clinical point of view, a combination of lamotrigine+ valproate may deserve recommendation. Other most positive experimental and clinical combinations include carbamazepine+valproate, phenytoin+phenobarbital, carbamazepine+gabapentin, carbamazepine+topiramate, levetiracetam+valproate, levetiracetam+carbamazepine. Certainly, experimental data have some limitations (non-epileptic animals, acute administration of antiepileptic drugs) so all experimental recommendations need a careful clinical evaluation.

SummaryBackground. Search for beneficial combinations of antiepileptic drugs (aEDs) that can be used in patients with pharmacoresistant epilepsy, is still conducted both empirically and rationally, based on molecular mechanisms of aEDs' action. this study was aimed at characterizing the interaction profiles for the combination of two aEDs (i.e., retigabine [RtG] and phenytoin [PHt]) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male albino Swiss mice. Material and methods. type I isobolographic analysis was used to determine interactions for the combination of RtG with PHt (at three fixed-ratios of 1:3, 1:1 and 3:1) with respect to its anticonvulsant and acute neurotoxic effects in the MES and chimney tests, respectively. total brain concentrations of RtG and PHt were estimated to exclude any pharmacokinetic interaction between aEDs. Results. the combination of RtG with PHt at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in both, the MES and chimney tests. RtG and PHt did not affect each other their total brain concentrations in mice, confirming pharmacodynamic interaction between the investigated drugs. Conclusions. the combination of RtG with PHt was neutral suggesting that this two-drug combination might occur favorable in some patients with refractory epilepsy.Keywords: drug interactions, isobolographic analysis, phenytoin, retigabine Streszczenie Wprowadzenie. Poszukiwanie korzystnych kombinacji leków przeciwpadaczkowych (lPP), które mogą być zastosowane u pacjentów z padaczką lekooporną, jest wciąż przeprowadzane zarówno empirycznie jak i racjonalnie, w oparciu o molekularne mechanizmy działania lPP. celem badania było scharakteryzowanie profilów interakcji kombinacji dwóch leków (tj. retigabiny [RtG] i fenytoiny [PHt]) w teście drgawek wywoływanych maksymalnych wstrząsem elektrycznym (MES) i w teście komina (koordynacja ruchowa) u dorosłych samców myszy szczepu albino Swiss. Materiał i metody. typ I analizy izobolograficznej był zastosowany aby wyznaczyć typy interakcji dla kombinacji RtG z PHt (w trzech stałych proporcjach dawek 1:3, 1:1 i 3:1) w odniesieniu do jej działań przeciwdrgawkowych i ostrych działaniach niepożądanych (neurotoksycznych) odpowiednio w testach MES i komina. całkowite stężenia mózgowe RtG i PHt były oceniane, aby wykluczyć interakcje farmakokinetyczną pomiędzy lPP. Wyniki. wyniki wskazują, że kombinacja RtG z PHt w stałych proporcjach dawek 1:3, 1:1 i 3:1 wykazuje interakcje addytywne w obu testach MES i komina. RtG i PHt nie wpływały wzajemnie na swe całkowite stężenia mózgowe u myszy, potwierdzając interakcję farmakodynamiczną pomiędzy badanymi lekami. Wnioski. Przedkliniczny profil dla kombinacji RtG z PHt jest neutralny, sugerując, że ta dwulekowa kombinacja mogłaby okazać się korzystna u niektórych pacjentów z padaczką lekooporną.