Two decades of research towards a potential first anti-epileptic drug

Benassi, Simone K.; Alves, Julieta Goncalves Silva Macedo; Guidoreni, Cristiane Gorgatti; Massant, Cristina Gonçalves; Queiroz, Cláudio Marcos Teixeira de; Garrido-Sanabria, Emilio R.; Loduca, Rafael Duarte de Souza; Susemihl, Maria Alice; Paiva, Wellingson Silva; Andrade, Almir Ferreira de; Teixeira, Manoel Jacobsen; Andrade, Joaquina Queiroz; Garzón, Eliana; Foresti, Maira Licia; Mello, Luiz Eugenio Araujo de Moraes

doi:10.1016/j.seizure.2021.02.031

Cited by 10 publications

(23 citation statements)

References 33 publications

(36 reference statements)

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“…Assuming a difference in reduction of PTE of 15% between the placebo and biperiden groups at 24 months, type 1 error (alpha) of 0,05 and type 2 error (beta) of 0.10 and 20% dropout rate, 156 patients per group would be required to provide 90% power with 5% level of significance. According to epidemiological data provided by a pilot study [10], we estimated that the inclusion pace could be 3-5 patients/center/month leading to study completion within 42 months.…”

Section: Discussionmentioning

confidence: 99%

“…The cholinergic system on the other hand, raises a limited interest from the clinical perspective (with some notable exceptions such as soman and sarin) in the epilepsy arena [24]. However, recently different strategies to modulate neuronal cholinergic activity have been shown to be effective at modifying the epileptogenic process in preclinical studies [10,12]. Among various approaches, acute treatment with biperiden, showed to hamper the development of PTE in animal models of brain injury [11].…”

Section: Discussionmentioning

confidence: 99%

“…As a subsequent step, the use of biperiden in the acute phase after brain injury showed to be safe in a small phase II clinical study, which also served to test the feasibility of an interventional and prospective trial [10]. Here, the present Phase III study was designed to evaluate the safety and efficacy of biperiden in preventing the development of PTE in adult patients, who have suffered moderate or severe TBI, in a larger multicenter prospective study.…”

Section: Introductionmentioning

confidence: 98%

“…Preclinical studies showed that anticholinergic drugs have the potential to modify neural plastic processes hampering epileptogenesis in animal models of epilepsy [10]. Among these drugs, biperiden, a cholinergic antagonist acting in the muscarinic receptor, administered soon after brain injury, delayed the latency and decreased the incidence and intensity of spontaneous seizures after brain injury [11].…”

Section: Introductionmentioning

confidence: 99%

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Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

et al. 2022

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Background Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. Methods This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Other outcomes include exploratory investigation of factors that might have benefits for the treatment or might influence its results, such as genetic background, clinical progression, electroencephalographic abnormalities, health-related quality of life and neuropsychological status. Analyses will be conducted following the safety, intention-to-treat and efficacy concepts. Discussion We hypothesize that biperiden treatment will be effective to prevent or mitigate the development of post-traumatic epilepsy in TBI patients. Other health measures from this population also may benefit from treatment with biperiden. Trial registration ClinicalTrials.gov, NCT04945213. Registered on June 30, 2021.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

et al. 2022

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“…So far, apart from AEDs, only biperiden (an anti-parkinsonian anticholinergic drug) has been evaluated in patients after brain injury in a small phase II safety assessment, prior to a double blind, randomized, placebo-controlled trial. The initial assessment confirmed its safety in patients with brain injuries and preliminary data seem to indicate that the drug seems to reduce the incidence of post-traumatic epilepsy [ 94 ]. Interestingly, biperiden has shown clear-cut antiepileptogenic properties in post-SE (induced by pilocarpine in rats) model of recurrent spontaneous convulsions [ 95 ].…”

Section: Discussionmentioning

confidence: 99%

Selected Molecular Targets for Antiepileptogenesis

Pawlik

Miziak

Walczak

et al. 2021

IJMS

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The term epileptogenesis defines the usually durable process of converting normal brain into an epileptic one. The resistance of a significant proportion of patients with epilepsy to the available pharmacotherapy prompted the concept of a causative treatment option consisting in stopping or modifying the progress of epileptogenesis. Most antiepileptic drugs possess only a weak or no antiepileptogenic potential at all, but a few of them appear promising in this regard; these include, for example, eslicarbazepine (a sodium and T-type channel blocker), lamotrigine (a sodium channel blocker and glutamate antagonist) or levetiracetam (a ligand of synaptic vehicle protein SV2A). Among the approved non-antiepileptic drugs, antiepileptogenic potential seems to reside in losartan (a blocker of angiotensin II type 1 receptors), biperiden (an antiparkinsonian drug), nonsteroidal anti-inflammatory drugs, antioxidative drugs and minocycline (a second-generation tetracycline with anti-inflammatory and antioxidant properties). Among other possible antiepileptogenic compounds, antisense nucleotides have been considered, among these an antagomir targeting microRNA-134. The drugs and agents mentioned above have been evaluated in post-status epilepticus models of epileptogenesis, so their preventive efficacy must be verified. Limited clinical data indicate that biperiden in patients with brain injuries is well-tolerated and seems to reduce the incidence of post-traumatic epilepsy. Exceptionally, in this regard, our own original data presented here point to c-Fos as an early seizure duration, but not seizure intensity-related, marker of early epileptogenesis. Further research of reliable markers of early epileptogenesis is definitely needed to improve the process of designing adequate antiepileptogenic therapies.

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Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury

Dulla

Pitkänen

2021

Neurotherapeutics

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Two decades of research towards a potential first anti-epileptic drug

Cited by 10 publications

References 33 publications

Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

Selected Molecular Targets for Antiepileptogenesis

Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury

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