Levetinol, 30 pcs., 500 mg, film-coated tablets
The adverse event profile presented below is based on the results of an analysis of placebo-controlled clinical trials of levetiracetam for all indications (total number of patients: 3416). These data are supplemented by information on the use of levetiracetam in open-label extension clinical studies, as well as post-marketing data. The most commonly reported adverse reactions were nasopharyngitis, drowsiness, headache, weakness and dizziness. The safety profile of levetiracetam generally does not differ depending on age (adults and children), and does not depend on approved indications for use (various types of epilepsy).
Adverse reactions identified in clinical studies and as part of post-registration monitoring (in adults, adolescents and children over 1 month) are presented below by system-organ class and frequency. Frequency gradation: very often (>1/10), often (>1/100 and <1/10), infrequently (>1/1000 and <1/100), rarely (>1/10,000 and <1/1000 ) and very rare (<1/10,000).
Infections and infestations: very often: nasopharyngitis; rarely - infections.
From the blood and lymphatic system: infrequently - thrombocytopenia, leukopenia; rarely - pancytopenia, neutropenia.
Metabolic and nutritional disorders: often - anorexia; infrequently - loss or increase in body weight.
Mental disorders: often - depression, hostility or aggression, sleep disturbance, nervousness, irritability; uncommon - suicide attempts, suicidal thoughts, psychotic disorders, behavioral disturbances, hallucinations, anger, confusion, emotional lability, mood changes, agitation; rarely - completed suicide, personality disorder, thinking disorder.
From the nervous system: very often - drowsiness, headache; often - convulsions, imbalance, dizziness, lethargy, tremor; uncommon - amnesia, memory impairment, impaired motor coordination or ataxia, paresthesia, attention disorder; rarely - choreoathetosis, dyskinesia, hyperkinesia.
From the side of the organ of vision: infrequently - diplopia, visual impairment.
On the part of the organ of hearing and balance: often - vertigo.
From the respiratory system, chest and mediastinal organs: often - cough.
From the gastrointestinal tract: often - abdominal pain, diarrhea, dyspepsia, vomiting, nausea; rarely - pancreatitis.
From the liver and biliary tract: infrequently - violation of liver function tests; rarely - liver failure, hepatitis.
From the skin and subcutaneous tissues: often - rash; uncommon - alopecia, eczema, itching; rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
From the musculoskeletal and connective tissues: infrequently - muscle weakness, myalgia.
General disorders and disorders at the injection site: often - asthenia or fatigue.
Injuries, poisonings and complications of procedures: infrequently - injuries.
With simultaneous use of topiramate and levetiracetam, the risk of developing anorexia increases.
In some cases of alopecia, it has reversed after discontinuation of levetiracetam.
Children:
A total of 645 patients aged 4-16 years were treated in placebo-controlled and open-label extension studies, 233 of whom received levetiracetam in placebo-controlled studies. For both age ranges, additional data are available on post-marketing experience with levetiracetam.
The safety profile of levetiracetam generally does not differ depending on age (adults and children), and does not depend on approved indications for use (various types of epilepsy). With the exception of behavioral and psychiatric adverse reactions, which occurred more frequently in children than in adults, the safety profile of levetiracetam in children was comparable to that in adults in placebo-controlled studies. In children aged 4-16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood changes (common, 2.1%), emotional lability (common, 1.7%) , aggression (common, 8.2%), conduct disorder (common, 5.6%) and lethargy (common, 3.9%) were reported more often than in other age ranges.
The cognitive and neuropsychological effects of levetiracetam in children 4–16 years of age with partial-onset seizures were assessed in double-blind, placebo-controlled safety profile studies using a noninferiority design. Levetiracetam has been shown to be no different (no less safe) from placebo in terms of changes from baseline in the Leiter-R Attention and Memory scale and the Memory Screen Composite scale. in patients undergoing 'per protocol' analysis. The results of the study of behavioral and emotional functions confirming that aggressive behavior occurs during the use of levetiracetam were obtained using a standardized method using a validated instrument - the Achenbach Child Behavior Checklist. However, in patients taking levetiracetam long-term in open-label studies, behavioral and emotional dysfunctions did not occur, in particular, the level of aggressive behavior did not differ from baseline.
Symptoms of overdose: drowsiness, agitation, aggression, depression of consciousness, respiratory depression and coma. After an acute overdose, it is necessary to rinse the stomach or induce vomiting. No antidote for levetiracetam has been found. Treatment is symptomatic and may include hemodialysis. Dialysis activity against levetiracetam is 60%, against the main metabolite - 74%.
Levetinol®
Levetiracetam, the active substance of the drug Levetinol®, is a pyrrolidone derivative ((2S)-2-(2-oxopyrrolidin-1-yl) butanamide) whose chemical structure differs from known antiepileptic drugs.
Mechanism of action
The mechanism of action of levetiracetam is not fully understood, but it is obvious that it differs from the mechanism of action of known antiepileptic drugs.
In vitro experiments
and
in vivo
showed that levetiracetam does not affect basic cell characteristics and normal transmission.
In vitro studies
showed that levetiracetam affects the intraneuronal concentration of Ca2+ ions, partially inhibiting the Ca2+ current through N-type channels and reducing the release of calcium from intraneuronal stores. In addition, levetiracetam partially restores currents through GABA- and glycine-dependent channels reduced by zinc and β-carbolines.
One of the proposed mechanisms is based on proven binding to the synaptic vesicle glycoprotein SV2A, contained in the gray matter of the brain and spinal cord. It is believed that in this way an anticonvulsant effect is realized, which is expressed in counteracting the hypersynchronization of neural activity.
Levetiracetam also acts on GABA receptors and glycine receptors, modulating these receptors through various endogenous agents. Does not alter normal neurotransmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculline and excitation of glutamate receptors.
Pharmacodynamic effects
The activity of the drug has been confirmed against both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction). Levetiracetam induces protection against seizures in a variety of animal models.
Adjunctive therapy for partial seizures with or without secondary generalization in adults, adolescents and children over 1 month of age with epilepsy
:
In adults, the effectiveness of levetiracetam was shown in 3 double-blind, placebo-controlled studies. It was shown that the proportion of patients who demonstrated a 50% or greater reduction in the frequency of partial seizures per week from baseline when taking continuous levetiracetam doses of 1000 mg, 2000 mg or 3000 mg in two doses for 12-14 weeks was 27.7%. , 31.6% and 41.3%, respectively, and 12.6% in patients taking placebo.
Pediatric population
The effectiveness of levetiracetam in patients aged 4 to 16 years was established in a double-blind, placebo-controlled study of 14 weeks duration, including 198 patients. The dose of levetiracetam was 60 mg/kg/day in two divided doses.
44.6% of patients taking levetiracetam and 19.6% of patients taking placebo showed a 50% or greater reduction in the frequency of partial seizures per week from baseline. During the treatment period, 11.4% of patients were seizure-free for at least 6 months and 7.2% were seizure-free for at least one year.
The effectiveness of levetiracetam in patients aged one month to 4 years was established in a double-blind, placebo-controlled study of 116 patients with a treatment duration of 5 days. The dose of levetiracetam as an oral solution for infants from one to 6 months was 20 mg/kg/day in two divided doses, followed by titration to 40 mg/kg/day, for infants and children from 6 months to 4 years - 25 mg/day. kg/day in two doses, followed by titration to 50 mg/kg/day.
The initial efficacy assessment was determined by the response rate (percentage of patients with a 50% or greater reduction in the frequency of partial seizures per day from baseline) using an anonymous reader during 48-hour video electroencephalography. The efficacy rate is based on an analysis of 109 patients who underwent electroencephalography for at least 24 hours. Responders were 43.6% of patients taking levetiracetam and 19.6% of patients taking placebo. Over the course of long-term treatment, 8.6% of patients were seizure-free for at least 6 months and 7.8% for at least 1 year.
Monotherapy for partial seizures with or without secondary generalization in patients over 16 years of age with newly diagnosed epilepsy
The efficacy of levetiracetam as monotherapy was comparable to that of controlled-release carbamazepine in a parallel group, double-blind study of 576 patients over 16 years of age with newly diagnosed epilepsy with unprovoked partial seizures or generalized tonic-clonic seizures. Patients were randomly selected to receive controlled-release carbamazepine 400–200 mg/day or levetiracetam 1000–3000 mg/day. Duration of treatment was up to 121 weeks depending on response.
Seizure freedom at 6 months was observed in 73% of patients taking levetiracetam and 72.8% of patients taking controlled-release carbamazepine. The consensus absolute difference between treatments was 0.2% (95% confidence interval, 7.8–8.2). More than half of the patients were seizure-free at 12 months (56.6% of patients on levetiracetam and 58.5% on controlled-release carbamazepine, respectively).
When the study was conducted in clinical practice, concomitant antiepileptic drugs could be discontinued in a limited number of patients who responded to adjunctive levetiracetam therapy (36 of 69 adult patients).
Additional therapy of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy
The effectiveness of levetiracetam was established in a double-blind, placebo-controlled study lasting 16 weeks in patients over 12 years of age with idiopathic generalized epilepsy with various myoclonic seizure syndromes. Most patients had juvenile myoclonic epilepsy. The dose of levetiracetam was 3000 mg/day in two divided doses. 58.3% of patients taking levetiracetam and 23.3% of patients taking placebo had at least a 50% reduction in myoclonic seizures over a week. During continuous long-term treatment, 28.6% of patients were free of myoclonic seizures for at least 6 months and 21% of patients for at least 1 year.
Additional therapy for primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years of age with idiopathic generalized epilepsy
The effectiveness of levetiracetam was established during a 24-week, double-blind, placebo-controlled study that included adults, adolescents and a limited number of children with idiopathic generalized epilepsy with primary generalized tonic-clonic seizures, with various syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy or epilepsy with generalized tonic-clonic seizures on awakening).
In this study, the daily dose of levetiracetam was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children in two divided doses. 72.2% of patients taking levetiracetam and 45.2% of patients taking placebo showed a 50% or greater reduction in seizure frequency within a week in patients with primary generalized tonic-clonic seizures.
During continuous long-term treatment, 47.4% of patients were free of tonic-clonic seizures for at least 6 months, and 31.5% of patients were free of tonic-clonic seizures for at least 1 year.
Levetinol Solution, bottle, 300 ml, 100 mg/ml, for oral administration
Pharmacological properties
Antiepileptic drug, pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide).
Its chemical structure differs from known antiepileptic drugs. The mechanism of action of levetiracetam is not fully understood, but it is obvious that it differs from the mechanism of action of known antiepileptic drugs. In vitro studies have shown that levetiracetam affects the intraneuronal concentration of Ca2+ ions, partially inhibiting Ca2+ current through N-type channels and reducing the release of calcium from intraneuronal stores. In addition, levetiracetam partially restores currents through GABA- and glycine-dependent channels reduced by zinc and β-carbolines.
One of the proposed mechanisms is based on proven binding to the synaptic vesicle glycoprotein SV2A, contained in the gray matter of the brain and spinal cord. It is believed that in this way an anticonvulsant effect is realized, which is expressed in counteracting the hypersynchronization of neural activity. Does not alter normal neurotransmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculline and excitation of glutamate receptors. The activity of levetiracitam has been confirmed against both focal and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal reaction).
Pharmacokinetics
After oral administration, levetiracetam is well absorbed from the gastrointestinal tract. Absorption is complete and linear, so plasma concentrations can be predicted based on the administered dose of the drug in mg/kg body weight. The degree of absorption does not depend on the dose and time of food intake. Bioavailability is approximately 100%.
After administration at a dose of 1 g, Cmax in blood plasma is reached after 1.3 hours and is 31 mcg/ml, after repeated administration (2 times/day) – 43 mcg/ml.
Plasma protein binding of levetiracetam and its main metabolite is less than 10%. Vd of levetiracetam is about 0.5-0.7 l/kg. The equilibrium state is achieved after 2 days when taken 2 times a day.
The formation of the primary pharmacologically inactive metabolite occurs without the participation of cytochrome P450 isoenzymes in the liver. Levetiracetam does not affect the enzymatic activity of hepatocytes.
In adults, T1/2 from blood plasma is 7±1 hours and does not change depending on the dose, route of administration or repeated administration. The average clearance is 0.96 ml/min/kg. 95% of the dose is excreted by the kidneys. The renal clearance of levetiracetam and its inactive metabolite is 0.6 ml/min/kg and 4.2 ml/min/kg, respectively.
In elderly patients, T1/2 increases by 40% and is 10-11 hours, which is associated with a decrease in renal function in this category of patients. In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with CC. In end-stage renal failure in adult patients, T1/2 is 25 hours between dialysis sessions and 3.1 hours during dialysis. During a 4-hour dialysis session, up to 51% of levetiracetam is removed.
During the 4-hour dialysis process, 51% of levetiracetam is removed from the body.
In patients with mild to moderate liver dysfunction, there are no significant changes in the clearance of levetiracetam. In severe liver dysfunction with concomitant renal failure, the clearance of levetiracetam is reduced by more than 50%.
The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg/kg/day. Cmax is reached after 0.5-1 hour. T1/2 in children after a single oral dose of 20 mg/kg body weight is 5-6 hours. The total clearance of levetiracetam in children is approximately 40% higher than in adults and is directly related to from body weight.
Levetinol tablet p/o 1000 mg N30 (Geropharm)
The active ingredient of Levetinol® is levetiracetam. It is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidinacetamide) and differs in chemical structure from other similar anticonvulsants. The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of other similar anticonvulsants. In vitro and in vivo experiments showed that this active substance does not affect the basic properties of the cell and normal nerve transmission. The results of the in vitro study showed that, by partially reducing N-type calcium currents and reducing the release of calcium ions from the intracellular depots of neurons, levetiracetam changes the concentration of calcium ions inside neurons. In addition, it partially eliminates the decrease in GABA and glycine channel currents caused by zinc and β-carbolines. In addition, in vitro studies have shown that levetiracetam binds to specific areas of the rat brain. This site is synaptic vesicle protein 2A, which is thought to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and its analogues, which bind to synaptic vesicle protein 2A, exhibit anticonvulsant activity in an audiogenic mouse model of epilepsy, with the stronger the binding, the higher the activity. These data imply that binding of levetiracetam to synaptic vesicle protein 2A mediates its anticonvulsant effect. Levetiracetam has anticonvulsant effects in many animal models of partial and primary generalized seizures without concomitant proconvulsant effects. The main metabolite of levetiracetam is inactive. Levetiracetam exhibits anticonvulsant activity in partial and generalized epilepsy in humans (epileptiform burst/photoparoxysmal response), which confirms its wide spectrum of pharmacological action. Pharmacokinetics Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and interindividual variation. After long-term use, there is no change in clearance. There is no evidence of sex, race, or diurnal differences. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable. Due to complete and linear absorption, plasma concentrations can be predicted by the dose of levetiracetam, expressed in mg/kg body weight. Therefore, monitoring the plasma concentration of levetiracetam is not required. In adults and children, a high correlation has been shown between the concentration of levetiracetam in plasma and saliva (the saliva/plasma ratio ranges from 1-1.7 for oral tablets and for oral solution 4 hours after taking the latter ).Adults and adolescents Absorption After oral administration, levetiracetam is rapidly absorbed. Absolute bioavailability after oral administration is close to 100%. Cmax is reached after 1.3 hours. The equilibrium state is achieved after 2 days when taking the drug 2 times / day. Cmax is usually 31 and 43 mcg / ml after, respectively, a single dose of 1000 mg and taking 1000 mg of the drug 2 times / day. The amount of absorption does not depend on doses and from food intake. Distribution There are no data on distribution in humans. Levetiracetam and its main metabolite are weakly bound to plasma proteins (Vd of levetiracetam is about 0.5-0.7 l / kg, which approximately corresponds to the volume of water in the body. Metabolism Levetiracetam is poorly metabolized in the human body. The main metabolic pathway (24% of the dose) is enzymatic hydrolysis of the acetamide group. Liver cytochrome P450 isoenzymes are not involved in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive. 2 were also found minor metabolite. The first is formed due to hydroxylation of the pyrrolidone ring (1.6% of the dose), the second - by opening of the pyrrolidone ring (0.9% of the dose).Other unidentified metabolites account for only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite in vivo has not been detected. Levetiracetam and its main metabolite do not inhibit the main human liver cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylases y in vitro. Levetiracetam also does not affect the glucuronidation of valproic acid in vitro. In cultured human hepatocytes, levetiracetam had little or no effect on the activity of the CYP1A2, SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induced the activity of the CYP2B6 and CYP3A4 isoenzymes. In vivo drug interaction data with oral contraceptives, digoxin, and warfarin indicate that significant enzyme induction is not expected in vivo. Therefore, the interaction of levetiracetam with other substances is unlikely. Elimination T1/2 in adults is 7 ± 1 and does not depend on the dose, route of administration or duration of use. The average total clearance is 0.96 ml/min/kg. The main route of elimination is excretion in the urine (about 95% of the dose, of which 93% is excreted within 48 hours). Excretion in feces is only 0.3% of the dose. The total excretion of levetiracetam and its main metabolite is 66% and 24% of the administered dose, respectively, during the first 48 hours. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg, respectively. which indicates the excretion of levetiracetam through glomerular filtration followed by tubular reabsorption, and the main metabolite through, along with glomerular filtration, active tubular secretion. Elimination of levetiracetam correlates with CC. Elderly patients T1/2 in the elderly increases by 40% (up to 10-11 hours) , which is due to decreased renal function in this population group. Renal failure The apparent clearance of levetiracetam and its main metabolite depends on QC. In this regard, in patients with moderate and severe renal failure, it is recommended to adjust the maintenance dose of the drug depending on QC. In adult patients with end-stage renal failure, T1/2 is 25 hours between hemodialysis sessions and 3.1 hours during the procedure itself. B During a typical four-hour hemodialysis session, about 51% of levetiracetam is removed. Liver dysfunction In patients with mild to moderate hepatic impairment, the clearance of levetiracetam changes slightly. In most patients with severe liver failure, the clearance of levetiracetam is reduced by more than 50%, which is due to concomitant renal failure. Children aged 4-12 years After a single dose of the drug at a dose of 20 mg/kg T1/2 in children 6-12 years old is 6 hours Body weight-adjusted apparent clearance is 30% higher than that observed in adults with epilepsy. After long-term administration of the drug at a dose of 20-60 mg/kg/day, absorption of levetiracetam in children 4-12 years old is rapid. Cmax is achieved within 0.5-1 hour. Cmax and AUC are linear and proportional to the dose. Terminal T1/2 is 5 hours. Apparent clearance is 1.1 ml/min/kg.
Experience with the use of levetiracetam in combination therapy of focal epilepsy
The 2006 International League Against Epilepsy's core practice recommendation for epilepsy therapy is stated as follows: “The final choice of drug for an individual patient should include knowledge of the drug's effectiveness, taking into account other variables such as safety and tolerability, pharmacokinetics, available dosage forms and cost” [3 , 4]. Today, the cost of treating a patient with epilepsy, especially antiepileptic drugs, is one of the important components in determining treatment tactics (drug choice). One of the modern antiepileptic drugs (AEDs) prescribed for the treatment of various forms of epilepsy is Levetinol (levetiracetam), but information about its effectiveness and safety was scattered and insufficient for the doctor to make an informed choice when prescribing this AED in clinical practice. The purpose of this observation was to study the effectiveness and tolerability of Levetinol (levetiracetam) in a polytherapy regimen in patients with focal epilepsy and ongoing seizures. Materials and methods 30 patients with focal forms of epilepsy took part in the observation: 15 men and 15 women aged from 19 to 76 years with the presence of seizures differing in type and etiology (20 patients with symptomatic focal epilepsy, 10 people with cryptogenic focal epilepsy ) (Table 1). The diagnosis of epilepsy was established in accordance with the International Classification of Epilepsy (1989, New Delhi, USA). The type of epileptic seizures was determined according to the International Classification of Epileptic Seizures (ILAE, 1981). The observation was carried out in epileptology offices of the Moscow outpatient network. Statistical analysis was carried out using the Statistica 6 program. To determine the statistical significance of differences in effectiveness in groups of patients (reduction of attacks), the χ2 test or Fisher's exact test with p<0.05 was used. Criteria for inclusion in observation: 1. Patients aged 19–76 years. 2. Patients with a verified diagnosis of epilepsy or epileptic syndrome in accordance with the classification of epilepsies and epileptic syndromes (ILAE, 1989). 3. Severe patients with refractory epilepsy who have repeatedly changed basic therapy, taking valproate, topiramate, carbamazepine, while maintaining the number of attacks at 4–8 per month. 4. Obtaining informed consent from the patient a few days before Visit 1 or on the day of Visit 1. Criteria for exclusion from observation: 1. Pregnancy. 2. Lactation period. 3. Women of reproductive age who do not use oral and barrier contraceptives. 4. Chronic alcoholism or substance abuse over the past 2 years. 5. Blood pressure diast. less than 60 mm Hg. Art. or more than 105 mm Hg. Art. 6. Heart rate less than 45 beats/min or more than 110 beats/min. 7. Clinically and ECG-confirmed heart rhythm disturbances, including prolongation of the QT interval, defined as 450 ms for men and 470 ms for women. 8. History of anaphylactic reactions. 9. History of blood diseases. 10. Non-epileptic or psychogenic seizures. 11. Status epilepticus over the past 12 months. Observation design. The observation consisted of 3 visits lasting 1 month: 1st visit – starting, inclusion in observation, 2nd visit – intermediate, after 2 weeks. after the prescription of Levetinol - included an assessment of the effectiveness and safety of Levetinol and, in case of insufficient effectiveness - increasing the dose, 3rd visit - end of observation, after 1 month. after the start of observation. At each visit, a clinical assessment of the effectiveness of therapy was performed and possible adverse reactions were recorded based on the adverse events questionnaire; At visits 1 and 3, the HADS (Hospital Anxiety and Depression Scale) scale was filled out and health and general quality of life were assessed using the QOLIE 10 scale (Table 2). The observation period was 1 month. Clinical evaluation of effectiveness was carried out based on changes in the frequency of attacks after adding Levetinol to basic therapy. At the 3rd visit, at the end of observation, the distribution of effectiveness for combination therapy with Levetinol was represented by the values indicated in Table 3.
A complete absence of attacks was noted in 6 patients, in 5 cases during basic therapy with valproate and in 1 patient when combined with topiramate. It should be noted that with the exception of one patient in whom remission occurred already at the 2nd visit, the remaining patients experienced a decrease in the frequency of attacks, which in most cases was associated with a dose adjustment of Levetinol (the average effective dose of Levetinol at the time of completion of the study in this group patients was 2083 mg/day).
The number of patients with a 75% reduction in attacks was 8 people with an average effective dose of Levetinol of 1437.5 mg/day. All patients in this group showed a reduction in the dose of basic therapy already at the 2nd visit. It is worth considering that in 2 out of 8 patients Levetinol became the third drug in combination therapy (combinations of TPM and CBZ; CBZ and VPA) with its insufficient effectiveness. Of the remaining patients in this group, the observation participants were distributed according to basic therapy as follows: 2 patients took CBZ, 3 patients took VPA, and 1 patient took TPM. By the end of the observation, among patients with a reduction in attacks by 50% (10 people), patients with basic therapy with CBZ (6 people) predominated. The average dose of Levetinol for the entire group was 1250 mg/day. In the vast majority of cases (8 patients), a 50% reduction in attacks was recorded already on the 2nd visit, and even with an increase in the dose, there was no improvement in the condition. In 6 patients with 25% seizure control at the end of the study, the average dose was 1083 mg/day (Fig. 1). Efficacy analyzes included assessment of the Hospital Anxiety and Depression Scale (HADS) scores, as well as assessment of quality of life. These indicators were assessed twice - at visit 1 and visit 3 and, upon receipt of the results, were compared with the results of the clinical effectiveness of therapy and the presence/absence of adverse events.
The average anxiety score in patients before treatment was 12 points, which is comparable to the average depression score of 11 points (clinically expressed anxiety and depression). At the end of the observation, against the background of combination therapy with Levetinol, the average score for both anxiety and depression in patients with different seizure control decreased and amounted to 7 points, which corresponded to the subclinical manifestation of anxiety and depression (p>0.05) (Fig. 2).
Thus, we can conclude that a decrease in the number of attacks significantly affects indicators of anxiety and depression in the direction of reducing the manifestation of affective disorders. An analysis of changes in the quality of life scale of patients before and after the inclusion of Levetinol in therapy was carried out taking into account the fact that the quality of life is affected by the frequency of attacks, as well as psychological discomfort due to the inclusion of a new drug in polytherapy. The average value of the quality of life assessment before treatment was 5 points (out of 10 possible), which correlated with the subjective assessment of health by the patients themselves (44.3% of 100%). At the end of the study, the average value of the quality of life assessment was 6.9 points and the health assessment was 71.3%, respectively (Fig. 3). Positive dynamics in health assessment correlated with a decrease in the number of attacks. This study showed the high effectiveness of Levetinol. All patients responded to therapy, and the level of drug remission corresponded to international standards for patients with refractory epilepsy. It should be noted that the results obtained turned out to be very encouraging for such a short-term observation (1 month), it is necessary to continue studying Levetinol over longer time intervals.
Unfortunately, due to the limited sample size, we were not able to draw a conclusion about the statistical significance of the change in quality of life after the addition of Levetinol. However, after the inclusion of Levetinol in polytherapy, there was a tendency to improve the quality of life and health of patients. Safety assessments were conducted in all patients included in the study who received at least one dose of the study drug. All adverse events recorded during the observation were expected, i.e., they corresponded to the instructions for use of the drug. To obtain statistically reliable results assessing the safety of the study drug, it is necessary to conduct larger studies.
Thus, based on the results of the observation, we can conclude that it is advisable to prescribe Levetinol to patients with focal forms of epilepsy in order to optimize treatment and achieve a higher effect in the treatment of a patient with epilepsy.
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