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DOI: http://dx.doi.org/10.20534/ESR-17-3.4-20-22
Dzharashtieva Dzan-Pago, Bulgakova Anastasia, Shevchenko Pert, Karpov Sergey,
Vishlova Irina Stavropol State Medical University, Russia Department of neurology, neurosurgery and medical genetics
E-mail: [email protected]
Modern methods of pharmacotherapy of generalized forms of epilepsy
Abstract: epilepsy is a chronic polietiologic disease, manifested by repeated unprovoked, seizures or other seizures, loss of consciousness and is accompanied by changes in personality [8]. Among the forms of epilepsy is one of the most common and dangerous forms of generalized seizures [1]. In recent years, ideas about generalized epilepsy have undergone significant changes: the features of focality in generalized epilepsy and the typical features of idiopathic generalized epilepsy with focal seizures. The relevance lies in the fact that the affinity of these forms is confirmed by genetic studies when one genetic disease, there are a variety of focal and generalized phenotypes in different members of the same family. This, of course, requires the search of new anticonvulsant agents for the successful treatment of various forms of epilepsy, including generalized, contributing to improve the quality of life. Keywords: epilepsy, generalized seizures, focal seizures, quality of life, drug with wide spectrum of action.
Purpose: to analyze the literature of the modern methods of pharmacotherapy in generalized forms of epilepsy.
Material and methods: analysis of data on the incidence of epilepsy among adult population of the Stavropol territory on 2010-2016. Using data on the number ofpatients in percentage, we can observe maximum growth by 2015, and begin decline by 2016.
2010 2011 2012 2013 2014 2015 2016 Figure 1.
Using data from diagnoses that were first installed, we can ob- Results: the incidence of epilepsy is between 50 and 70 per
serve the wave-like change of the data, with maximum values in 100 000 population, the prevalence is 5-10 cases per 1000 people. 2014, a downward trend in 2015 and 2016. It is believed that 1 or more seizures in the course oflife carry about
Modern methods of pharmacotherapy of generalized forms of epilepsy
5% of the population. The prevalence of epilepsy among children is high and in different age populations from 0.3% to 2% (average of 0.7-1.0%) [1; 2]. Generalized seizures - seizures initial clinical and electrophysiological symptoms may indicate involvement in the pathological process of both brain hemispheres. Generalized epi-
1000
500
leptic seizures in most cases are characterized by loss of consciousness. For generalized seizures include typical and atypical absence seizures, clonic, tonic, klonico-tonic and atonic seizures, as well as mioclonii [5].
778
J 485 466 614 bUS 495
mill
2010 2011 2012 2013 2014 2015 2016
Figure 2.
Basic principles of therapy of epilepsy: individual approach; continuity and duration of treatment; complexity of treatment (etiological, pathogenetic and symptomatic); the continuity of treatment [7]. Treatment should begin with monotherapy; the treatment begins with small dose and gradually increase it until cessation of seizures or symptoms of overdose. In case of insufficient clinical effect of treatment to clarify diagnosis, to check the regularity of drug intake (compliance), and achieving the maximum tolerated dose. As a rule, 70% of patients properly selected monotherapy provides adequate control of seizures [5; 6]. Only in cases of ineffectiveness of properly selected monotherapy (after at least two consecutive times of use of drugs in monotherapy), you can use rational poly-therapy (we are talking about drugs of first choice, which is adequate for a specific type of epileptic seizures). In its implementation it is necessary to follow certain rules. Rational polytherapy comes from the concepts of pharmacodynamics, i. e. drug interactions with a substrate of neurons, at the level of neuronal membranes and synaptic formations, which give it its particular therapeutic effect or side effects. It is theoretically feasible to combine drugs with the same mechanism of action, it is advisable to use drugs with complementary properties [10]. With continued seizures monotherapy appropriate timely administration of the second drug. Long-term treatment with two drugs is carried out exclusively at failing an adequate monotherapy. Treatment with three drugs is recommended only after failure of two adequate therapy drugs.
If not precisely defined form of treatment of epilepsy start with a drug with wide spectrum of action — Depakine-Chrono, Depakine chronosphere [3]. Success and drug-free remission for 2-5 years can be questioned on the gradual abolition of the drug. The ineffectiveness of valproate to specify the form of epilepsy and find a more specific drug. Valproaty are the drugs of broad-spectrum, i. e. they have high clinical efficacy in various forms of epileptic seizures [6; 7]. At the same time, the maximum effect is seen when exposed to generalized tonic-clonic seizures and absence seizures. The most commonly used derivative of valproic acid in the treatment of epilepsy are sodium valproate (Depakine, Depakine-Chrono), valproic acid (konvuleks) in the form of the calcium salt ofvalproic acid (convulsofin).
The mechanism of action of valproate is associated with GABA inhibition and increased postsynaptic inhibition, and blockade of the PA - and SA-channels T-type. Depakine is well absorbed. Its bioavailability exceeds 90%. To increase the drug accumulates in plasma within 2-4 h. At the same time, it is noticed that the absorption of valproate when taken after a meal, especially after copious consumption of fatty foods, slows down somewhat. Depakine 7090% bound to plasma proteins. The half-life is 8-20 hours, Frequen-
cy of administration 1-3 times daily (depending on the release forms of the drug). The time to reach a stable concentration in 5-7 days. Therapeutic concentration in blood corresponds to 50-150 ^g/ml. the Average daily dose is 20-30 mg/kg of body weight. The benefit of valproate compared with other traditional antiepileptic drugs (AEDs) is a less pronounced effect on cognitive function. Treatment ofvalproate patients to keep mental performance, professional activity, the children will not worsen indicators of learning. Scientific Committee on drugs at the American Academy of Pediatrics also confirm the absence of negative impact ofvalproate used in the medium therapeutic doses on cognitive function and school performance. To dose-dependent side effects include drowsiness, nystagmus, vertigo, ataxia, tremor, headache, hallucinations, increase or loss of weight, increased or decreased appetite, hair loss, menstrual irregularities (oligo - or amenorrhea). In most cases, these symptoms regressed when the dose ofvalproate. Interesting is the fact that weight gain often occurs if the valproate treatment starts at the age of 20 years than after that age, regardless of the length of treatment. Valproate can inhibit hematopoiesis, causing thrombocytopenia, leukopenia, inhibit platelet aggregation, increasing bleeding. In this regard, care should be taken to appoint valproaty with anticoagulants or acetylsalicylic acid. They include acute effects develop in a few weeks or months of starting treatment. Symptoms of acute and chronic poisonings are myasthenia gravis, Hypo - or areflexia, convulsions, cardiovascular and respiratory disorders, cerebral edema, metabolic acidosis, hypernatremia, confusion, coma. Treatment is aimed at eliminating hypovolemia. For the relief of the depressive effects of valproate on the nervous system can be used naloxone [3; 6; 9]. Perampanel (Ticona, "eisai") is the latest antiepileptic drug (AEDs) Registered for use in the adjunctive treatment in patients 12 years and older with focal and secondary generalized seizures. Perampanel was licensed in the US and Europe in 2012 [4; 11]; registered in 2013 and in 2014 entered the Russian pharmaceutical market. Perampanel is a fundamentally different mechanism of action antiepileptic, unlike other AEDs: non-competitive inhibition of the receptor ionotropic AMPA (a-amino-3-hydroxy-5-methyl-4-isoxa-zolidinone acid) glutamate (major stimulating neurotransmitter in the Central nervous system (CNS)) the drug leads to a decrease in the excitability of neurons. Perampanel is a potent highly selective non-competitive inhibitor of ionotropic AMPA receptors in postsynaptic membranes of neurons at the level of the neocortex and hippocampus [11]. According to many authors, perampanel is the first aed with a specific action on the metabolism of glutamate (glutamate-mediated excitation in CNS) efficacy and tolerability for refractory focal seizures were proven in clinical phase III studies [4]. Today, there are a number of empirical studies that have examined
the use of perampanel in clinical practice as adjunctive treatment for patients with refractory partial epilepsy. The data indicate that perampanel is effective and well tolerated, including in patients with resistant epilepsy and other diseases. Major adverse events perampanel applications include drowsiness and dizziness, rarely-ataxia, aggressiveness, nausea and irritability. Better tolerability, in patients receiving 1 or 2 main probes [11].
In generalized seizures primary generalized tonic-clonic, absence seizures (especially in combination with generalized seizures within the syndromes of idiopathic generalized epilepsy), myoclonic drugs of choice are valproaty; carbamazepine and phenytoin con-traindicated in absence seizures and myoclonic seizures [5]. Simple absence seizures drugs of choice are valproaty and ethosuximide. Atypical absence seizures atonic and tonic seizures often resistant to treatment. In some cases, it may be effective one of the following drugs: phenytoin, valproate, lamotrigine, clonazepam, ethosuxi-mide, phenobarbital, acetazolamide and corticosteroids or their combination. In myoclonic seizures the drug of choice is sodium valproate, also used clonazepam, lamotrigine. In case of insufficient efficacy or poor tolerability traditional AEDs the use of new anticonvulsants (e. g., lamotrigine or topiramate).
Cancellation of PEP should be gradual with regard to mandatory forms of epilepsy and its prognosis, the possibility of recurrence of seizures, individual and age characteristics of the patient (to take into account both medical and social factors). Abolition of anti-epileptic therapy is conducted, as a rule, not less than 2-3 years after the complete cessation of seizures (recommended up to 5 years), under the control of EEG studies [9].
Conclusions: Modern approach makes it the preferred choice of drug with wide spectrum of action (help for all types of seizures and forms of epilepsy) taking into account its efficiency, speed of titration, dosage forms, side effects and cost. Among drugs with broad spectrum of activity (valproate, VPA, levetiracetam, lamotrigine, topiramate) as first choice for the initial treatment of generalized epilepsies of priority are the original form of WPA with controlled release of active substance is Depakine Chrono and Depakine chro-nosphere. Thus, valproaty are currently the most used and effective antiepileptic drugs for the treatment of epilepsy, as well as on the basis of available published data sovremenik perampanel is a promising drug for the treatment of partial and secondary generalized seizures with high efficacy and favorable tolerability.
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