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Pim B.
van der Meer et al.
of the Department of Neurology, Leiden University Medical Center, the Netherlands, studied the efficacy and tolerability
of LEV+VPA combination.
The results were published online in Neurology in September 2022
.
- Excerpted from the article chapter
【Ref: van der Meer PB, et al.
Neurology.
2022 Sep 6; 99(10):e999-e1008.
doi: 10.
1212/WNL.
0000000000200807.
Epub 2022 Jun 8.
】
Research background
Epilepsy is a common complication in glioma patients, with preoperative morbidity of 25% to 75%.
Levetiracetam (LEV) and valproic acid (VPA) are commonly used antiepileptic drugs (ASM)
in patients with gliomas.
In about 30% of patients with glioma, ASM monotherapy does not adequately control seizures and usually requires ASM polytherapy
.
The results of preclinical studies showed that the combined application of LEV+VPA significantly enhanced the anti-epileptic effect in preclinical models, and the effect was more prominent
than that of other ASM combined applications.
Pim B.
van der Meer et al.
of the Department of Neurology, Leiden University Medical Center, the Netherlands, studied the efficacy and tolerability
of LEV+VPA combination.
The results were published online in Neurology in September 2022
.
Research methods
According to the 2016 edition of the WHO guidelines for the diagnosis and treatment of glioma, the investigators included patients
with histologically diagnosed grade 2-4 glioma who were treated at several medical centers in the Netherlands between January 1, 2004 and January 1, 2018.
In the initial study cohort, epilepsy patients with LEV or VPA monotherapy and patients with
LEV or VPA monotherapy failed to control seizures well.
Divide patients into LEV+VPA treatment groups; For other ASM combination groups, comparisons
were made.
Patient ASM load is the sum
of the ratio between the prescribed dose and the daily dose to the agreed daily dose (DDD) of each ASM drug in the ASM treatment group.
The primary observation of the study was the time
to treatment failure for any reason since ASM double-agent therapy.
Treatment failure refers to withdrawal, replacement, or addition of new ASM
.
Secondary observation indicators include: (1) the time to treatment failure due to uncontrolled seizures at the beginning of ASM double-therapy therapy, which is an indicator of efficacy; (2) the time of treatment failure due to adverse reactions at the beginning of ASM double-agent therapy is an indicator to measure tolerability; (3) the time from the onset of ASM double-therapy to the recurrence of epilepsy is the standard for measuring efficacy; (4) Toxicity level is defined as the severity (grade 1-5) of intolerable adverse reactions that lead to ASM discontinuation, which is a measure of tolerability
.
Adverse effects that improve after discontinuation of ASM within 1 to 2 months are considered attributable to the ASM combination
.
Study results
The initially included study population included 1435 patients
treated with single-agent LEV or VPA.
A total of 382 patients had treatment failure due to uncontrolled ASM, of which 27 (7%) were started on monotherapy
with another class of ASM.
355 patients (93%) received ASM dual therapy; Among them, 236 (66%) received LEV+VPA, and 119 (34%) received other ASM dual therapy, including LEV or VPA
.
Other dual treatments for ASM included 15 unique combinations, 68 with VPA and 51 with LEV
.
Of the most common ASM combined antiepileptic therapy, 16% were LEV+clobazam and 15% were VPA+phenytoin
.
At 36 months of follow-up, 42% (99/236) of patients using the LEV+VPA combination failed treatment, compared with 55% (65/119) of patients with dual therapy using LEV or VPA in combination with another ASM
.
The cumulative incidence of treatment failure for any reason with LEV+VPA versus other dual therapies at 12 months ranged from 37% to 50%; At 12 months, the cumulative incidence of treatment failure due to uncontrolled seizures with LEV+VPA versus other dual therapies was 21% to 29%, and the cumulative incidence of treatment failure due to adverse effects was 13% to 11%.
Compared with the LEV+VPA combination, other ASM dual therapies have a significantly higher
risk of treatment failure for any reason.
At 36 months of follow-up, 78% (182/232) of patients taking LEV+VPA and 85% (99/116) of patients taking other dual therapies had seizure recurrence
.
The cumulative incidence of relapse at 12 months was 74% for LEV+VPA and 87%
for other dual therapies.
Patients with other dual therapies are at significantly higher risk of seizure recurrence
.
In the LEV+VPA group, 15% (35/236) of patients experienced 47 adverse reactions leading to treatment failure
.
Similarly, in the other dual therapy groups, 13% (15/119) of patients experienced 24 adverse effects leading to treatment failure
.
Hepatobiliary dysfunction occurred in 4% of patients in the LEV+VPA group, and half of the cases were short-term adverse effects
.
In the LEV+VPA group, 17% (8/47) of patients developed mental disorders, which improved in the later stage; In the other dual therapy groups, 8% (2/24) of patients developed psychiatric disorders and did not improve in later stages of psychiatric symptoms
.
The two most common intolerable adverse effects of the LEV+VPA combination were tremor (17%) and decreased platelet count (9%); Intolerable adverse effects of other dual therapies were drowsiness (13%) and rash (13%)
.
In the LEV+VPA group versus other dual therapy groups, only a few adverse effects were of grade 3 or 4 severity or did not improve
after discontinuation of ASM.
Conclusion of the study
In summary, this retrospective observational cohort study showed that LEV+VPA was more effective in antiepileptic than other dual therapy combinations of ASM plus LEV or VPA, but with similar levels of drug toxicity
.
If seizure control is not adequately controlled with single-agent LEV or VPA, LEV+VPA dual therapy is a good choice
for controlling seizures in glioma patients.
