So far, the treatment of epilepsy patients has relied heavily on antiepileptic drugs (AEDs). In recent years, with the advancement of drug development, new antiepileptic drugs have emerged, and many new drugs have been marketed in China. However, many problems in the clinical use of these new antiepileptic drugs still need to be further studied in depth. In this paper, we briefly review the characteristics and clinical application progress of new antiepileptic drugs approved by FDA in the past decade.
I. Characteristics of new antiepileptic drugs.
1. lamotrigine (LTG): As a broad-spectrum antiepileptic drug, the mechanism of action of LTG is to block voltage-dependent sodium channels and reduce the release of excitatory amino acids. Its protein binding rate is 55%, half-life is 15-30h, and 90% is cleared by the liver. Common side effects include ataxia, dizziness, diplopia, drowsiness, headache, convulsions, and insomnia. Serious toxic effects include rash, Stevens Johnson syndrome, and toxic epidermal necrolysis, as well as hepatic and renal failure, disseminated intravascular coagulation (DIC), and hypersensitivity reactions such as arthritis. Karande et al. reported a case of anticonvulsant hypersensitivity syndrome (AHS) induced by LTG use and confirmed in vitro by tests. Cunnington found that the teratogenicity of LTG was similar to that of other AEDs, at about 2.9%. However, the sample size is small and needs to be confirmed by further studies. Enzyme-induced AEDs such as phenytoin and CBZ increase clearance when combined with LTG, while the enzyme inhibitor VPA decreases clearance of LTG by about 60%. No other new AEDs have been found to have a significant effect on clearance of LTG, but there is an increased chance of side effects when combined. Contraceptives can reduce the blood concentration of lamotrigine, and no interaction with cytochrome P450 and warfarin has been observed.
2. Oxcarbazepine (OXC): Its mechanism of action is to block voltage-dependent sodium channels, with a protein binding rate of 40%, half-life of 4-9h, and hepatic clearance of 70%. Common side effects are drowsiness, dizziness, headache, ataxia, nausea, vomiting, diplopia, blurred vision, vertigo, low blood sodium, and rash. Studies have found that the likelihood of hyponatremia increases with age in patients. Previous studies have shown that pregnant women taking oxcarbazepine monotherapy for epilepsy have not shown an increased incidence of malformations in their offspring. oXC may increase PHT or PB blood levels. No interaction has been seen between OXC and erythromycin. OXC may reduce contraceptive, ethinyl estradiol, and felodipine serum concentrations, reduce 25-OHD serum concentrations, and to some extent affect other bone metabolism markers.
3, topiramate (TPM): a broad-spectrum antiepileptic drug, its mechanism of action includes blocking voltage-dependent sodium channels, enhancing γ-aminobutyric acid (GABA) receptors, and blocking AMPA-type glutamate receptors. The protein binding rate is 9-17%, half-life is 15-23h, 40-70% is cleared by kidney, and some is metabolized by liver. Side effects such as kidney stones, glaucoma, metabolic acidosis, weight loss, speech impairment, drowsiness, fatigue, nausea, loss of appetite, weight loss, abnormal sensation, slow and confused reaction, vertigo, hypohidrosis, headache, etc. are common. It is noteworthy that about 48% of patients with TPM-induced metabolic acidosis do not show clinical symptoms. The effects of TPM on cognitive function have been inconsistently concluded, and further studies are needed. tpm decreases the serum concentrations of lithium, digoxin, and ethinyl estradiol, decreases the efficacy of contraceptives, and increases the serum concentration of fluparidinol. Inhibition of CYP 2C19 leads to a decrease in plasma concentrations of PHT. Some reports indicate that the use of TPM in pregnant women can lead to fetal malformations.
4, gabapentin (GBP): its mechanism of action is unclear, probably by increasing the content of γ-aminobutyric acid (GABA) in the brain to play a role. It has a protein binding rate of 0, a half-life of 4-6 h, 100% renal clearance, and dose-dependent absorption. The main side effects are weight gain, peripheral edema, behavioral changes common in children, and viral infections. It is worth noting that patients with renal failure are prone to neurotoxicity-based side effects of GBP, which can lead to myoclonus and coma in severe cases. A small sample study found that the concentration of GBP in cord blood was 1.3-2.1 times higher than maternal blood concentration, and the milk/maternal blood gabapentin concentration ratio was 1 from 2 weeks to 3 months after delivery, suggesting active placental transport of GBP, but no serious side effects were observed in infants as a result of maternal GBP administration. No significant interactions have been seen with warfarin and contraceptives, and no results of its interaction studies with other antiepileptic drugs have been reported.
5. Levetiracetam (LEV): The mechanism of action is not yet clear. It is not protein bound, has a half-life of 6-8h, 66% is cleared by the kidneys, 34% is hydrolyzed by the acetamide group, is not metabolized by the liver, and does not induce hepatic enzyme synthesis. No serious side effects have been observed. The main side effects are irritability and behavioral changes. No interactions with other antiepileptic drugs have been observed. Studies have found that the addition of LEV for the treatment of focal epilepsy resulted in improvements in cognitive function, particularly in attention and oral fluency. It is suggested that LEV may affect the metabolism of attentional and verbal areas, thus improving neurological function.
6. zonisamide (ZNS): ZNS can inhibit seizures by blocking voltage-dependent sodium channels and T-type calcium channels. Animal studies found that ZNS increased GABA basal secretion in a concentration-dependent manner without affecting glutamate secretion. However, potassium ion-activated glutamate and GABA secretion were reduced by ZNS. This suggests that ZNS achieves neuroprotective effects by increasing GABAergic secretion, increasing interictal seizure threshold, and reducing neuroexcitability. It has a protein clearance of 40-60%, a half-life of 24-60 h, and a hepatic clearance of 70%. Common side effects are rash, kidney stones, fatigue, dizziness, drowsiness, loss of appetite, abnormal thinking, irritability, photosensitivity, weight loss, and oligohidrosis is also common in pediatric patients. Small sample studies suggest that the combination of VPA/ZNS and LTG/ZNS is well tolerated. There is a lack of reliable research findings on the interactions between ZNS and other AEDs.
7.Thiagabine (TGB): The mechanism of action is unclear. Protein binding rate 96%, half-life 4-7h, hepatic clearance 98%. Common side effects are abdominal pain, vomiting, fatigue, headache, dizziness, stiffness or spike wave stupor. common toxic reactions caused by TGB overdose are neurological symptoms: persistent epilepsy, impaired consciousness, agitation, dizziness, dystonia, abnormal posture and hallucinations, other symptoms include respiratory depression, tachycardia, hypertension, hypotension. Case reports suggest that 7.8% of TGB-treated patients develop non convulsive status epilepticus (NCSE). In patients with refractory focal epilepsy, treatment with TGB has the potential to induce NCSE. Studies have shown that TGB does not affect the cognitive status of patients. No interaction with erythromycin was seen.
Previous studies have shown that LTG monotherapy for partial epilepsy versus primary generalized epilepsy was not significantly different in treatment efficiency (50% seizure reduction) compared to CBZ or PHT, but the rate of discontinuation due to severe side effects was higher with CBZ than with LTG. Compared with PHT, the odds of discontinuation due to serious side effects were about the same, and the odds of discontinuation due to rash were 12% for LTG and only 5% for PHT. However, the starting dose of 100 mg/d in the LTG group in this study was much higher than the recommended starting dose of 25 mg/d. Similar findings were obtained in the comparison of OXC with PHT, VPA, and CBZ, as well as in the comparison of GBP with CBZ. In conclusion, the new AEDs have similar therapeutic effects compared to classical antiepileptic drugs, but with increased tolerability. It can also be seen that individualized dosing with smaller starting doses and slow dosing until seizures are controlled or side effects occur is the better dosing method.
Second, the efficacy of new AEDs on various types of epilepsy was studied.
From the perspective of clinical work, clinicians are more interested in what drugs can be used to control seizures more effectively for a certain type of epilepsy. The following is a brief analysis of the efficacy of these new AEDs for the common types of epilepsy.
Partial epilepsy (PE) refers to acquired focal epilepsy, including simple partial, complex partial, and partial seizures secondary to generalized tonic-clonic convulsions (GTCC), and can have onset in childhood or adulthood.
In studies of the efficacy of refractory PE in adults, most trials have evaluated the new AED as add-on therapy, mostly with a 50% reduction in seizures as the criterion for effectiveness. Previous studies have found that the efficacy of GBP with 600 mg-1800 mg/d was 8.4-26.4%, with higher doses (1800 mg) increasing the efficacy but also increasing the side effects.Matsuo F et al. compared 300 mg/d and 500 mg/d LTG with control, the efficacy was 20% and 34%, respectively, compared with 18% in the control group, a significant difference due to Faught E et al. found that the efficiency of TPM at 400 mg/d was about 49%, which was significantly higher than that of the 200 mg/d group, while the efficiency did not increase significantly when the dose was increased, but the incidence of side effects was significantly higher. Barcs G et al. compared OXC doses of 600 mg/d, 1,200 mg/d, and 2,400 mg/d and found efficiency rates of 26.8%, 41.2%, and 50%, respectively, which were significantly different from controls, and the rates of treatment discontinuation due to side effects were 12%, 36%, and 67%, respectively. Faught E et al. compared the therapeutic effects of 100 mg/d, 200 mg/d and 400 mg/d ZNS and found that the effective rates were 25% in the 100 mg/d and 200 mg/d groups and 43% in the 400 mg/d group, all of which were significantly different from the control group. /d of LEV were 22-33%, 31-34%, and 39.8%, respectively, and the incidence of side effects was 7-13%. These studies suggest that in adults with refractory PE, the addition of GBP (600-1800 mg), LTG (300-500 mg, 150 mg in combination with VPA), OXC (600-2400 mg), TGB (16-56 mg), TPM (300-1000 mg), ZNS (100-400 mg), and LEV (1000 -3000mg) were effective. As the treatment dose increases, the efficiency increases, but the chance of side effects also increases.
In the case of monotherapy studies in adults with refractory PE, the control group of many experiments was very low doses of the same drug or the same type of drug in order to avoid ethical issues, as the experiments required patients to take only one drug. In order to obtain better experimental results, the drug dose in the experimental group is often larger than the clinical dosage, and the clinical observation time is mostly limited. Therefore, the experimental design of such experiments is mostly flawed, and the results do not indicate whether monotherapy is effective, but rather whether there is less worsening of symptoms compared to the control. The indicator of effectiveness is mostly the proportion of patients completing the clinical observation period or a reduction in seizures by more than 50%. sachdeo et al. compared 100mg and 1000mg TPM with an effectiveness rate of 13% and 46%, respectively. 13% of patients in the 1000mg group had complete disappearance of seizures compared to none in the 100mg group. the odds of completing treatment with 1000mg also increased significantly. Beydoun et al. compared the efficacy of 300 mg and 2400 mg/d OXC. 93.3% of patients in the low-dose group dropped out of treatment during the 126-day treatment period, while only 41.2% of patients in the high-dose group dropped out. Fifty-six percent of patients in the LTG group completed treatment compared to 20% of patients in the VPA group. From the current study, OXC 2400mg/d was more effective than 300mg/d, TPM 1000mg/d was more effective than 100mg/d, and LTG 500mg/d was more effective than 1000mg/d VPA.
Generalized epilepsy (GE) is divided into idiopathic and symptomatic. Idiopathic epilepsy is considered to have a genetic basis, with normal brain structure, and the types of epilepsy include myoclonic epilepsy, generalized tonic-clonic seizures, and akathisia. Idiopathic epilepsy is easily treated but presents with drug specificity. In contrast, symptomatic GE is a destructive epilepsy, often with developmental delays and abnormal developmental structures, and drug efficacy is mostly poor.
Biton et al. studied the effect of 6 mg/kg/d TPM on the treatment of generalized tonic-clonic (which can be combined with other types of epilepsy), and 56% of patients in the TPM group had more than 50% reduction in seizures, compared with only 20% in the control group. Chadwick et al. treated refractory generalized tonic-clonic epilepsy with 1200 mg GBP, and there was no significant difference between the two groups compared with control. Reviewing previous studies, it may be related to the low dose. Frank et al. treated 45 pediatric patients with akathisia seizures with 2-15 mg/kg/d of LTG, 29 seizures stopped, and the difference in remission rate was significant after 4 weeks compared to the control. From the above studies, TPM 6 mg/kg/d was effective in the treatment of patients with generalized tonic clonic with other types of epilepsy, GBP 1200 mg was not effective in refractory generalized tonic clonic epilepsy, and LTG 2-15 mg/kg/d was effective in children with akinetic seizures. Other drugs remain to be further investigated.
In children with refractory epilepsy, it is now believed that it shares the same pathophysiological basis as adult partial epilepsy, so AEDs that are effective in adults may also be effective in children. The study found that the addition of 23-35 mg/kg/d GBP to 247 children (3-12 years old) with partial epilepsy resulted in a 35% reduction in complex partial seizures and a 28% reduction in secondary generalized tonic-clonic seizures in the treatment group, significantly higher than in the control group. 199 children (2-16 years old) were treated with LTG at 1-3 mg/kg (combined with VPA), 1-5 mg/kg (combined VPA with enzyme-induced AEDs such as PHT, CBZ, PB), and 5-15 mg/kg (enzyme-induced AEDs alone) were effective in 45% of the treated group, with a 44% reduction in seizure frequency. The addition of 30-46 mg/kg/d OXC in 267 children (3-17 years old) resulted in 41% efficiency and 35% reduction in seizure frequency. In summary, AEDs that are effective in adults with refractory partial epilepsy should be equally effective in children over the age of two. This suggests that the addition of GBP 23-35 mg/kg/d, OXC 30-46 mg/kg/d, TPM 125-400 mg/d, LTG 1-5 mg/kg/d (combined with enzyme-inducible AED) or 1-3 mg/kg/d (combined with VPA) is effective for the treatment of refractory partial epilepsy in children.
In epilepsy syndromes, OXC monotherapy for benign childhood epilepsy with centrotemporal spikes (BECT) was found to stop seizures in 53% of 70 children (5.2-11.6 years), with 21% having occasional seizures, 21% having significantly Of the 70 children (5.2-11.6 years), 53% had stopped seizures, 21% had occasional seizures, 21% had significantly fewer seizures (50%), 5% had no effect, and 35% of them had significant improvement in ECG. This suggests that OXC has a role in controlling seizures and normalizing the EEG in children with typical BECT. In contrast, for Lennox-Gastaut syndrome (LGS), Motte et al. treated LGS with 50-400 mg LTG addition, and 33% of the 79 patients in the LTG group (3-25 years old) showed a 50% reduction in seizures, a significant difference from the control. 6 mg/kg/d TPM addition for LGS resulted in a 14.8% reduction in sudden collapse seizures and major seizures ( The study by McDonald et al. suggests that GBP may exacerbate myoclonic seizures in patients with LGS.
The effects of new AED drugs on cognitive function and quality of life in patients with epilepsy, and on special patient populations such as children, the elderly, and pregnant women, especially children less than two years of age, still need to be further investigated. For primary generalized epilepsy, such as atonic seizures and childhood myoclonic seizures, almost all current studies are uncontrolled case studies, and controlled trials are urgently needed. Moreover, many experimental studies have short observation periods, and long-term clinical observations are needed to clarify the safety, stability, and pharmacokinetic indicators such as effective blood concentrations of these drugs.