The latest treatment for epilepsy. Experience with the use of Perampanel (Ficompa). The latest methods of treating epilepsy Anticonvulsant drugs for epilepsy: list
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" />In a few years, people with drug-resistant epilepsy will be able to take a new drug to suppress seizures only when needed, much like people with headaches take painkillers today.
Worldwide, approximately 50 million people suffer from epilepsy.
Of these, only 70% respond well to antiepileptic drugs (AEDs).
After 2-5 years of successful treatment, drugs can be discontinued in 70% of children and 60% of adults without subsequent exacerbations. However, millions of patients who do not respond to drug therapy must, in some cases, undergo surgical treatment.
Researchers from University College London in the UK are confident that a new anticonvulsant drug that can be taken "as needed" will be a real lifesaver for the 30% of patients who do not respond to standard medications.
The new treatment, which has so far only been tested in rodents, makes nerve cells more sensitive to certain substances in the brain that are normally inactive.
The lead author of the study, the developer of the new therapy, Professor Dimitri Kullmann from the Institute of Neuroscience at University College London, explains how his drug works: “First, we inject a modified virus into the area of the brain where seizure activity begins. The virus instructs brain cells to produce a protein that is activated by the substance CNO (clozapine-N-oxide). This substance can be taken in tablet form. The activated protein suppresses the excessive excitability of the cells responsible for seizures, but only in the presence of CNO."
Today, severe epileptic seizures are treated with drugs that suppress the excitability of all brain cells, and this leads to serious side effects. If the dose required by the patient is very high, then patients have to be hospitalized.
“If we could transfer our new method into clinical practice, which we hope to do over the next decade, we could treat such patients with CNO tablets on an as-needed basis, after having given one single injection of the virus for the entire time,” says Professor Kullmann .
Many people with drug-resistant epilepsy experience episodes of petit mal seizures. The professor envisages taking the new drug in these situations, as well as in cases where the patient feels an approaching severe attack.
Factors that increase the risk of seizure activity in this group of patients include illness, lack of sleep, certain periods of the menstrual cycle, etc. In these situations, taking CNO is also advisable to prevent the worst-case scenario.
A team of scientists is working on alternative methods of delivering the drug. One of them will be an injection that will quickly and effectively stop an attack that has already begun. Work is also underway on an automatic drug delivery system, in which CNO will be administered according to the same principle as in insulin pumps for diabetics.
“Fully reversible” treatment without permanent side effects
Professor Kullmann claims that the “new method is completely reversible”, so any side effects that may occur while taking the drug will go away once it is stopped.The professor also answered questions about possible side effects associated with the introduction of a modified virus into the body of patients.
He said: “The modified virus has been rendered harmless so it is unable to produce new viruses and spread. The injection is a short surgical procedure in which a small hole is drilled into the patient's skull, a needle is inserted through the lining of the brain, and medication is delivered directly to the problem area. "This operation is much simpler and safer than what patients with drug-resistant epilepsy usually face - they sometimes have to remove several cubic centimeters of brain tissue."
Another advantage of CNO is that this substance has a short lifespan (only a few hours), and only affects areas of the brain tissue treated with the virus. This avoids problems in other areas of the brain that are common with other antiepileptic drugs, and also prevents permanent damage from more invasive treatment.
“Short-acting drugs are rarely used for epilepsy. However, because they affect the entire brain and have a limited role, they are used only as second-line drugs for acute treatment of seizures in a hospital setting. Limitations of short-acting drugs include potentially dangerous respiratory depression. Our approach avoids such complications,” concluded Professor Kullmann.
MOSCOW, December 26 - RIA Novosti. Biologists from Russia monitored how the functioning of memory center cells in rats changes after the onset of an epileptic seizure and created a substance that dulls their severity, according to an article published in the journal Epilepsy Research.
Scientists have created the first potential cure for epilepsyAmerican doctors have created a small protein molecule that suppresses neurons in the temporal lobe of the brain that are responsible for causing epileptic seizures, without killing them, which will allow doctors in the near future to save patients from the most common form of epilepsy.“The use of our drug or its analogues may contribute to the development of a new approach for the treatment of temporal lobe epilepsy. The development of new strategies for the treatment of pharmacologically resistant forms of epilepsy can help reduce the damage caused to brain cells during seizures, and opens up new possibilities for the treatment of this disease,” said Valentina Kichigin from the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences in Pushchino, whose words are quoted by the press service of the institution.
According to statistics from the World Health Organization, today there are approximately 50 million people living in the world suffering from various forms of epilepsy. Approximately 40% of these cases are not treatable, and approximately half of epileptics cannot take medications without experiencing side effects.
Epileptic seizures and all the symptoms associated with them arise as a result of the fact that nerve cells suddenly begin to synchronize their impulses, simultaneously “turning on” and “turning off.” Scientists do not yet know why this happens, and without revealing the reasons for this behavior, a full fight against epilepsy is impossible. Recently, scientists from ITEB RAS discovered that epileptic seizures can occur due to the fact that nerve cells mistakenly believe that there are almost no nutrients left inside them.
Kichigina and her colleagues at the institute studied the roots of one of the most severe forms of epilepsy, the foci of which are located inside the hippocampus, the brain's memory center, located in the temporal lobe of the brain. In some cases, doctors have to remove some of its cells if the seizures cannot be stopped, which deprives the patient of the ability to remember new information.
Russian scientists tried to uncover the roots of this epilepsy and find a way to treat it in less radical ways, observing what happened to the neurons of the hippocampus of rats during an artificial epileptic seizure caused by a powerful neurotoxin - kainic acid.
These observations showed that injection of the toxin into the hippocampus resulted in massive death of so-called pyramidal cells, the main signal processors in the cerebral cortex and memory center, and damage to the surviving cells, especially those parts responsible for the synthesis of new protein molecules and metabolism.
The nature of this damage has led scientists to believe that most of it can be suppressed using one of the neurons' built-in repair systems, which are controlled by so-called cannabinoid receptors. They are special outgrowths on the surface of nerve cells that respond to analogues of the active substances of marijuana that are produced by the brain.
The problem, as the researchers note, is that the concentration of such molecules in the brain is kept at a minimum level by a special enzyme called FAAH, which destroys most of the cannabinoid molecules before they have time to connect with neurons. Guided by this idea, Russian biophysicists injected a special substance, URB597, into the brains of rats, which blocks the action of this protein, about a day after the seizure.
As this experiment showed, URB597 significantly improved the hippocampus and well-being of rats in which the neurotoxin caused relatively mild seizures in which they did not have convulsions. In such cases, the number of dead neurons was reduced by approximately half, and the surviving cells were not damaged.
With the development of more severe seizures and convulsions, the effect of URB597 was noticeably weaker - hippocampal neurons died almost as en masse as in rats from the control group, and not all traces of damage disappeared from the surviving cells.
However, scientists believe that URB597 and other substances that promote the activation of the cannabinoid "self-repair" system of neurons may protect the brains of epileptics from damage and could save thousands of people from having to undergo surgery that would forever send them into endless Groundhog Day.
A new study has confirmed that fewer than two-thirds of patients with newly diagnosed epilepsy are seizure-free at 1 year. The risk-free rate in this new study was essentially unchanged from 64.0% in a smaller study published in 2000.
"Despite the introduction of many new antiepileptic drugs over the past two decades, the overall outcomes of people with newly diagnosed epilepsy have not changed fundamentally," Patrick Kwan, MD, PhD, professor, neurology, Monash University, Melbourne, Australia, told Medscape Medical news.
A "paradigm shift" in treatment and research strategies is needed to improve long-term outcomes for patients with epilepsy, said Dr Kwan, who was at the University of Melbourne during the study.
The original study included 470 patients with newly diagnosed epilepsy at the Western Hospital, Glasgow, Scotland, who were first treated between 1982 and 1998. In the current study, this period continued until 2012.
The new analysis included 1,795 patients, 53.7% men and a mean age of 33 years. About 21.5% had generalized epilepsy and 78.5% had focal epilepsy.
Following diagnosis of epilepsy, clinicians considered seizure type, adverse drug effects, and interaction profiles when selecting an appropriate antiepileptic drug (AED). The majority of patients in the study (98.8%) experienced two or more attacks before starting treatment.
During the first 6 months after initiation of treatment, patients were seen in the epilepsy clinic every 2–6 weeks. Thereafter, they attended follow-up visits at least every 4 months.
Patients were asked to record the number of seizures they had between clinic visits and to describe these events.
Freedom of seizure was defined as the absence of seizures in at least the previous year. The overall 1-year level of freedom of confiscation was 63.7%. The majority of patients who became attack-free (86.8%) achieved this by taking one AED.
This rate of 86.8% is lower than the proportion of patients in the earlier study whose seizures were controlled by monotherapy (90.5%).
In a new study, patients with generalized epilepsy responded better to AED therapy than those with focal epilepsy.
Patients who did not achieve a year of seizure freedom by taking the first AED were more likely to have uncontrolled epilepsy with each additional AED (odds ratio, 1.73; 95% confidence interval, 1.56–1.91, P<0, 001 после корректировки для классификации болезни, возраст и пол). В то время как вторая схема AED могла бы сделать на 11% больше этих пациентов без припасов, пособие было уменьшено более чем на половину для третьего режима. И попробовав четвертый - или более - AED предоставил менее 5% дополнительной вероятности свободы захвата.
There was an increase
The use of new AEDs increased significantly during the study. Early, older drugs such as carbamazepine, valproate and phenytoin were used much more often, but by the end of the study drugs such as valproate, levetiracetam and lamotrigine were more common.
But the proportion of patients who were attack-free was similar for subgroups categorized into the three AED initiation periods (1982 to 1991, 1992 to 2001, and 2002 to 2012).
Newer AEDs are not necessarily better tolerated than older drugs, Dr. Kwan comments. The notion that these newer drugs have fewer side effects is "probably not true," but they may be easier to use because they don't require comprehensive drug monitoring, he said.
From his own practice, Dr. Kwan could see that new epilepsy drugs were not having a "huge impact" on patient outcomes, but he thought the study would show at least some improvement.
However, despite the "dramatic change" in drugs used, with a shift from older to newer agents, he and his colleagues were surprised by how little change there was as a result.
"It wasn't just that there was little change, there was no change," he said.
The researchers analyzed treatment results using the International League Against Epilepsy's 2010 definition of grip freedom. By this definition, freedom of seizure may be the absence of cramps for three times the pretreatment interval between cramps or at least the past year, whichever is greater.
The reason for the update was that some patients experience infrequent seizures, "so being seizure-free for a year may have nothing to do with the medication," Dr. Kwan explained.
This analysis yielded results similar to those obtained using the original definition of seizure freedom at 1 year.
The new study also confirmed that the prognosis of AED treatment was associated with factors such as the number of seizures that occurred before treatment, a family history of epilepsy in first-degree relatives, and a history of recreational drug use.
While the study found that the level of parish freedom has not changed since the onset at the population level, Dr. Kwan noted that this may not be the case at the individual level.
“In terms of the frequency of seizures and their severity in individual patients, new drugs may make a difference and this could have an impact on people's lives, but we did not measure that.”
Epilepsy is a "very complex disorder" that is not simply one disease, making it "very difficult to find a magic bullet" that targets everyone and makes a "huge impact" on outcomes, Dr. Kwan said.
However, it is important to develop more effective treatments for epilepsy, and this requires a change in thinking and perhaps "more risky approaches", he said. He added that this change in thinking must come from "all stakeholders", including funding bodies, research groups and the pharmaceutical industry.
Clinicians should refer patients whose two drugs fail to reach a specialist center, where they can be considered for non-arc therapy, such as recirculation surgery and brain stimulation techniques, Dr. Kwan said.
"Get it early, don't leave it too late," he said. “There is evidence that the earlier you treat these patients, the better the outcome.”
Disconcerting Conclusions
Some of the new findings are sobering and somewhat discouraging, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology, Columbia University Sergius Center, New York, writes in an accompanying editorial. In an interview with Medscape Medical News, Dr. Houser elaborated on what he found so embarrassing.
“Until now, efforts have been made to develop new and effective antiseptic drugs,” he said. “I suspect there have been 20 or more new drugs marketed in the US or Europe in the last 30 years, or both. And during this time, at least with new epilepsy, which is what this study relates to, it seems to us that we are not doing anything better.”
He noted "dramatic changes" in medications over the course of the study, with new drugs largely replacing older ones.
“But in terms of objective outcomes that in terms of epilepsy controls for seizure, there really was no change.”
That the new drugs do not increase the percentage of patients who are seizure free should not be surprising because, for the most part, seizure drugs were developed to try to prevent seizures rather than address the underlying cause, Dr. Houser said.
“People have insults to the brain, such as a stroke or severe head injury, and then develop epilepsy, and the ideal would be to develop something that would prevent any process that would lead to epilepsy. The drugs available to us, as far as we know, only suppress seizures, they do nothing in terms of preventing the process of epileptic development."
Dr. Houser also noted that there is little evidence that tolerability has improved with the advent of new drugs. So while the hope is to find an agent that stops seizures and has no side effects, "it doesn't look like there has been any improvement with drugs in either arena," he said.
It is possible, Dr. Hauser said, that a two-thirds grip freedom level represents a “ceiling” for initial epilepsy control.
However, he agreed that most new drugs have some benefit. For example, they have improved bioavailability and pharmacokinetics, making them easier to administer, he said.
Dr Kwan has received research grants from the National Health and Medical Research Council of Australia, the Australian Research Council, the US National Institutes of Health, the Hong Kong Research Grants Council, the Innovation and Technology Foundation, the Health Sciences and Healthcare Research Foundation, and the Health and Medical Foundation. research. He and/or his institution have also received speaker or consulting fees and/or research grants from Eisai, GlaxoSmithKline, Johnson & Johnson, Pfizer, and UCB Pharma. Dr. Hauser is a member of the Neuropace Epilepsy Sudden Unexpected Death Surveillance Committee and a member of the editorial boards of Acta Neurologica Scandinavia, Epilepsy Research and Neuroepidemiology.
Some fatty acids have powerful antiepileptic effects. Drugs based on them can be used to control this disease in children and adults. These data were obtained during a study of special dietary nutrition in children with severe epilepsy resistant to pharmacological agents. This analysis was carried out by specialists from King's College London (UK), says the journal Neuropharmacology.
Epilepsy affects more than 50 million people worldwide. In a third of them, it is not possible to achieve adequate control over the course of the disease with currently available drugs. A high-fat, low-carbohydrate diet is often prescribed to treat intractable epilepsy. Despite the fact that such nutrition is often effective, this diet is constantly criticized, since its side effects can be very significant. Among them are constipation, hypoglycemia, growth retardation and bone fractures.
British scientists were able to determine which fatty acids have an anticonvulsant effect. On their basis, new drugs can be created. Clinical trials conducted by this group of medical experts have demonstrated that they may not only be safer, with fewer side effects, than current drugs, but also more effective.
Author of the article: doctor, neurologist -
The relevance of the topic of the latest treatment of epilepsy
- More than 75% of patients with epilepsy in the world do not receive adequate anticonvulsant therapy
- Achieving remission is possible in 60–70% of cases
- Resistance is the lack of effect from the use of first-line drugs (carbamazepines, valproates) at maximum tolerated doses in mono- or duotherapy, or a combination of one of them with new generation AEDs (lamotrigine, topiramate, levetiracetam and others).
What approaches to overcome pharmacoresistance?
- Surgery
- Vagus nerve stimulation
- Hormone therapy
- Immunoglobulins
- New AEDs with a new, previously unused mechanism of action
We present 1 clinical case of a drug-resistant form of epilepsy
Patient M., age over 20 years.
Seizures: gelastic (epileptic seizures of laughter), serial (6 – 12/day), almost daily; motor-tonic; versive 1-3/week; VGSP 1-4/year.
Ill since age 10. The diagnosis was made: Tuberous sclerosis.
He was observed by a pediatric epileptologist, geneticist, and psychiatrist.
In treatment I received:
Combinations of AEDs: Depakine + Topamax; depakine + phenobarbital; Depakine + Topamax +
The frequency of attacks remained: VGSP 1 - 2/year, focal attacks from 1-3/week, to series of 6-15/day. There has been an increase in attacks over the past year.
Hospitalization to the neurological department for treatment correction. On the day of admission, a series of gelastic attacks (twice stopped with IV benzodiazepines).
In therapy he received: 175 mg/day, Topamax 150 mg/day, Keppra 1000 mg/day.
The introduction of a new generation of AEDs has begun: Titration of perampanel 2 mg/day with weekly intervals up to 8 mg/day.
At a dose of 4 mg/day, gradual withdrawal of Keppra was started.
Discharged after 21 days. The attacks did not recur
After 1.5 months at a second consultation
No seizures. AEDs taken: Depakine - Chronosphere 1750 mg/day, perampanel 6 mg/day (dysphoria appears at a dose of 8 mg/day), Topamax 100 mg/day. Topamax is being gradually withdrawn.
2 clinical case
Patient D., age over 30 years.
Seizures:
1. dizziness, version of the head to the left, sometimes – tonic tension in the right hand;
2. freezing, staring, automotor;
3. rare VGSP.
The duration of focal attacks is from 30 seconds. up to 1.5 min. Frequency is from 1-2/day to 1-3/month.
Ill since age 12. He connects his illness with a previous head injury and concussion. Hippocampal sclerosis on the left was discovered for the first time 20 years after the onset of attacks using high-field MRI. This congenital pathology was not previously detected on MRI.
About 10 years ago, she suffered from status epilepticus of focal and secondary generalized convulsive seizures during pregnancy. There were hospitalizations for emergency reasons with an increase in attacks.
Treatment: Carbamazepine, Valproate.
Polytherapy: valproate + carbamazepine; valproate + lamotrigine; valproate + topiramate + keppra; topiramate + lamotrigine + valproate.
The introduction of a new generation of AEDs has begun: titration of perampanel to 8 mg/day. Then gradual withdrawal of topiramate, gradual withdrawal of lamotrigine.
Termination of focal attacks at a dose of perampanel 6 mg/day.
There were no epileptic seizures for 2 months.
She received AEDs: perampanel 8 mg/day + valproate 1500 mg/day.
At the patient’s insistence, resection of the left hippocampus and part of the temporal lobe was performed. Intraoperatively, focal cortical dysplasia (FCD) of the left temporal lobe was detected. The postoperative period was complicated by hemorrhage in the surgical area.
A month after surgical treatment, there was a recurrence of focal and secondary generalized attacks. Emergency hospitalization to the neurological department, where the emergency situation was stopped within one day. She was discharged with the same doses of AEDs.
When repeated MRI— FCD was detected in both frontal lobes, postoperative changes in the left temporal lobe.
No seizures for 3 months.
3 clinical case
Patient L., age after 40 years
Seizures: staring, freezing, smacking, wrist automatisms, dystonic positioning of the left hand, there may be ambulatory automatisms, VGSP. The frequency of focal attacks is from 1-2/week to serial 5–8/day; VGSP 1 – 3 /month.
It is observed from 1.5 years of age (febrile complex seizures), from 3 years of age – focal and VGSP.
Therapy: Phenobarbital, Benzonal + diphenine; valproate + finlepsin; valproate + topiramate + lamotrigine; lamotrigine + topiramate + levetiracetam.
Over the course of 3 years, gradual abolition of barbiturates and diphenine. Phenobarbital 50 mg/day was maintained. The following are observed: VGSP 1 – 2 / year; focal - with the same frequency, but the duration decreased by 2 times.
Then there was an increase in attacks throughout the year. In a neurological hospital, therapy: topiramate 300 mg/day, levetiracetam 2500 mg/day, lamotrigine 250 mg/day, phenobarbital 50 mg/day. The frequency of focal attacks is 2 – 6/day; VGSP 1 in 1 – 2 months.
Change in therapy: Titrate perampanel 2 mg/week to 6 mg/day. Gradual withdrawal of levetiracetam (for financial reasons). There is a decrease in focal seizures by 75%.
She was discharged from the hospital on therapy: topiramate 300 mg/day, lamotrigine 250 mg/day, perampanel 6 mg/day, phenobarbital 50 mg/day. Severe aggression was observed with perampanel at a dose of 8 mg/day.
Therapy after 4 months: perampanel 6 mg/day, lamotrigine 250 mg/day, phenobarbital 50 mg/day.
: hippocampal sclerosis on the left + FCD in the left temporal lobe.
Perampanel (Ficompa)
2-(2-oxo-1-phenyl-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3)
The first representative of selective non-competitive antagonists of inotropic, sensitive to a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), glutamate receptors of postsynaptic neurons.
Mechanisms of action of antiepileptic drugs
Rogawski MA, Löscher W. Nat Rev Neurosci 2004; 5:553–564; Rogawski MA. Epilepsy Currents 2011; 11:56–63.
Competitive antagonists can be displaced by high doses of glutamate
1. Glutamate cannot bind to the receptor and activate it. But at high concentrations of glutamate, glutamate displaces the antagonist, binds to the receptor and activates it, opening the channel and allowing an inward Na+ current.
In the presence of a competitive antagonist
In the presence of perampanel, glutamate binds but cannot activate the receptor. The noncompetitive antagonist is not displaced by glutamate. The action of the antagonist on the receptor is maintained, and the channel remains closed.
Rang HP, et al. From: Pharmacology.1995.
Perampanel (Faycompa) is a non-competitive AMPA receptor antagonist
In the presence of perampanel1
1Hanada T, et al. Epilepsia 2011;52:1331–1340; 2Kenakin T. Molecular Interventions 2004;4:222–229.
Pharmacological properties of Faikompa (perampanel)1
Possibility of single dosing
- Bioavailability when taken orally is almost 100%
- Peak PC after 2.5 hours
- PC leveling 14 days.
- Half-life 105 hours
No clinically significant effect on drug metabolism - can be combined with any other AEDs
When combined with inducers, dose adjustment is necessary
- Linear pharmacokinetics – no need for PC control
- Plasma protein binding 95% - any displacement by other drugs that bind to plasma proteins is quickly balanced.
- Unique mechanism of action - the ability to combine with any other AEDs
- Neither an inducer nor an inhibitor of P450
- CYP3A4 inductors increase the clearance of Fycompa
- Equilibrium PC Faycompa is achieved faster
Drug interactions Fycompa (perampanel)
Indications for use
As an adjuvant drug for the treatment of partial seizures in patients with epilepsy aged 12 years and older in the presence or absence of secondary generalized seizures.
Side effect (adverse events)
FREQUENT(greater than or equal to 1/100; less than 1/10):
- Decreased or increased appetite
- Aggression, anger, anxiety, confusion
- Dizziness, drowsiness, ataxia, dysarthria, imbalance, irritability
- Diplopia, blurred vision
- Central vertigo
- Nausea
- Backache
- General disorders: fatigue, gait disturbances
- Weight gain
- Falls
Safety: Commonly reported adverse events, noted in at least 5% of patients and identified using SMQs related to hostile behavior/aggression
Perampanel titration scheme (Ficomps)
- Initial dose 2 mg/day (evening)
- Titration of 2 mg/week when taking enzyme-inducing AEDs
- Titration of 2 mg/2 weeks when taking non-enzyme-inducing AEDs
Half-life 105 hours
Clinically significant improvement in seizure control was observed at a dose of 4 mg/day and increased as the dose was increased to 8 mg/day.
Dose more than 8 mg/day – no significant increase in effectiveness was observed
Contraindications
- Hypersensitivity
- Pregnancy and lactation
- Severe renal or liver failure, patients on hemodialysis
- Children under 12 years of age (no data on efficacy or safety)
- Galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
So, using clinical examples, we were convinced of the effectiveness of the newest drug for the treatment of epilepsy Perampanel (Ficompy) . Reviews about the drug help you choose the right treatment tactics; select an administration regimen and therapeutic dose; avoid side effects and take into account contraindications; start taking modern medications earlier; achieve control over epileptic seizures, despite the ineffectiveness of previously used various drugs in high doses and their combinations.
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