Electronic Pump Delivers Drugs to the Brain to Stop Seizures

Researchers have engineered an electronic drug delivery tool that pumps seizure-stopping molecules directly to the source of the problem in the brain. The device, reported in the journal Science Advances, offers an alternative to conventional, systemic drugs that can cause unwanted side effects throughout the body.

The device, a microfluidic ion pump, uses an electrical potential to move drug molecules from a reservoir on the device across a short channel and out the tip of the device. The pump can be implanted in the brain at the site of a problem, such as a focal point of a seizure, where it will deliver the drug when needed.

The pump technology is based on the concept of electrophoresis: the transport of molecules through a fluid or gel under the influence of an electrical field. When a voltage is applied, electrons withdraw from the source electrode, and positively charged ions—in this case positively charged drug molecules—are driven out of the reservoir, across the ion-conducting membrane, and out of the device for delivery

ZX008 Reduces Convulsive Seizures in Majority of Patients with Lennox-Gastaut Syndrome in Pilot Study

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198).

METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ?4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram.

RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ?50% CS reduction; three (23%) patients had a ?75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ?50% reduction, and three (33%) patients had a ?75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed.

SIGNIFICANCE: ZX008 provided clinically meaningful reduction (?50%) in convulsive seizure frequency in the majority of patients with Lennox-Gastaut syndrome in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.

FDA Approves Diacomit (stiripentol) for Seizures Associated with Dravet Syndrome

The FDA approved Diacomit (stiripentol) for seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam.

Dravet syndrome is a rare genetic condition that usually appears during the first year of life with prolonged fever-related seizures. Later, other types of seizures typically appear, and additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity, and difficulty relating to others.

The efficacy of Diacomit was established in two multicenter placebo-controlled double-blind randomized studies (Study 1 and Study 2). Patients enrolled in the studies were required to be aged between 3 years and under 18 years with Dravet syndrome that was inadequately controlled with clobazam and valproate, and experiencing at least 4 generalized clonic or tonic-clonic seizures per month.

Clinical Trial: A Study to Assess the Safety and Efficacy of Lacosamide Versus Placebo (a Pill Without Active Medication) in Patients With Idiopathic Generalised Epilepsy Who Are Already Taking Anti-epileptic Medications (VALOR)

The VALOR study is investigating whether Lacosamide (Vimpat®)—when taken with current anti-epileptic medicine—helps decrease the number of seizures patients experience. This study enrolls children and adults who are at least 4 years or older, have epilepsy with primary generalized tonic-clonic seizures, had at least 2 seizures in the past 12 weeks, and are on a stable dose of anti-epileptic medicines. Patients have a 50% chance of receiving placebo; they have the opportunity to receive Lacosamide for another two years afterwards in an open-label extension study. The study is running in a total of 23 countries, including the United States.

Eligibility Criteria:

Ages Eligible for Study: 4 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset prior to 30 years of age, consistent with idiopathic generalized epilepsy (IGE) experiencing primary generalizedtonic-clonic (PGTC) seizures (Type IIE) that are classifiable according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (ILAE, 1981)
  • Subject has 3 PGTC seizures during the 16-week Combined Baseline (12-week Historical Baseline plus 4-week Prospective Baseline)
  • If a brain magnetic resonance imaging (MRI)/computed tomography (CT) scan has been performed, there must be no evidence of any progressive abnormality or any lesion likely to be associated with partial-onset seizures
  • Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed Antiepileptic drugs (AEDs) OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to Visit 1 with or without additional concurrent stable Vagus nerve stimulation (VNS)
  • Subjects are required to have had an electroencephalogram (EEG) report consistent with IGE (eg, generalized 3Hz epileptiform discharges and a normal EEG background) confirmed by a Central Reviewer

 

Exclusion Criteria:

  • History of partial onset seizures or EEG findings indicating partial onset seizures
  • Symptomatic generalized epilepsy, e.g. Lennox-Gastaut Syndrome
  • Lifetime history of suicide attempt, or suicidal ideation in past 6 months
  • Women of child bearing potential must practice contraception according to protocol requirements
  • Regular use of clozapine, monoamine oxidase (MAO-A) inhibitors, barbiturates (for indication other than epilepsy) within 28 days prior to Visit 1
  • Use of Vigabatrin within the last 6 months

Clinical Trail: A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Intravenous Brivaracetam in Subjects >= 1 Month to < 16 Years of Age With Epilepsy

The BELLE study is investigating whether Brivaracetam (Briviact®) given intravenously (into the vein) is safe for children and what it does in the body. This study enrolls children who are between 1 month and 16 years of age who have epilepsy and are currently treated with at least one anti-epileptic medicine. All children will receive Brivaracetam in the study, which can take between 3 and 68 days, depending on the child’s condition. The study is running in a total of eight countries, including the US.

Eligibility Criteria:

Ages Eligible for Study: 1 Month to 16 years (child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Male or female from >= 1 month to < 16 years of age. For subjects who are < 1 year from birth and who were preterm infants, the corrected gestational age should be used for this entry requirement
  • Weight >= 3 kg (6.6 lbs)
  • Diagnosis of epilepsy
  • Acceptable candidate for venipuncture and intravenous (iv) infusion
  • Treatment with >=1 anti epileptic drug (AED; including BRV) without a change of dose regimen for at least 7 days prior to Screening
  • No treatment with vagus nerve stimulation (VNS), OR the subject is being treated with VNS and the settings have been constant for >=7 days prior to Screening
  • For female subjects: not of childbearing potential, OR of childbearing potential and not sexually active/negative pregnancy test, OR of childbearing potential and sexually active/negative pregnancy test/uses medically acceptable contraceptive methods

Exclusion Criteria:

  • Subject has previously received iv Brivaracetam (BRV) in this study
  • Subject is being treated with BRV at a dose >5mg/kg/day (rounded) or >200mg/day for subjects with body weights >40kg
  • Subject requires or is likely to require a change in concomitant antiepileptic drug(s) (AED[s]), dose of concomitant AED(s), or formulation of AED(s) during the 7 days prior to the intravenous (iv) pharmacokinetic (PK) Period
  • Subject is likely, in the opinion of the Investigator, to require rescue medication during the Initiating Oral BRV (IOB) Treatment or iv PK Periods
  • Subject has experienced generalized convulsive status epilepticus in the 28 days prior to Screening or during the Screening Period

New Guidelines for the Treatment of New-Onset Epilepsy: AAN, AES Update Practice Guidelines

The American Academy of Neurology (AAN) and the American Epilepsy Society (AES) have provided new recommended practice guidelines for the management of new-onset and treatment-resistant epilepsy with anti-epileptic drugs (AEDs). The new guidelines highlight the evidence supporting the use of lamotrigine, vigabatrin, levetiracetam, pregabalin, gabapentin, and zonisamide for reducing the frequency of seizures in new-onset focal epilepsy and treatment-resistant epilepsy.

An expert subcommittee was formed consisting of members of the AAN and AES to update the 2004 evidence-based guidelines on epilepsy treatment with AEDs. Based on recent evidence, the investigators recommend the use of gabapentin and topiramate in adults and children with newly diagnosed epilepsy.

Class I and II studies support the use of rufinamide, ezogabine, clobazam, perampanel, and immediate-release pregabalin as add-on therapy in adults with treatment-resistant focal epilepsy; however, the adverse events associated with these therapies warrant careful consideration prior to prescribing. Other studies (class I, II, and III) suggest eslicarbazepine at 800 mg/day and 1200 mg/day may possibly be effective in treatment-resistant adult epilepsy.

Everolimus in Infants with Tuberous Sclerosis Complex-Related West Syndrome: First Results from a Single-Center Prospective Observational Study

Tuberous sclerosis complex (TSC) is the most common cause of West syndrome (WS). Currently available treatment options are ineffective in the majority of affected infants and/or associated with potential serious side effects. Based on the assumption that mTOR overactivation results in increased neuroexcitability in TSC, mTOR inhibitors have been studied as antiseizure therapy.

As a result, everolimus recently received approval for the adjunctive treatment of patients aged ?2 years with refractory TSC-associated focal and secondary generalized seizures. However, efficacy and safety data for infants with TSC-associated WS are still lacking. Therefore, a prospective open-label observational study was initiated at our center, to evaluate everolimus add-on treatment in infants with TSC-associated WS, previously refractory to standard treatment.

For this preliminary report, data from four male infants with TSC2 and a median observation period of 13 (range = 8-42) months after treatment initiation were analyzed. Two infants showed electroclinical remission until day 14 after everolimus treatment initiation. In one additional infant, hypsarrhythmia resolved. No relapse after initial response was documented. Developmental progress improved in three infants. Tolerability was similar to that described in older children.

According to these preliminary results, everolimus appears to have the potential to treat successfully both spasms and hypsarrhythmia in infants with TSC-associated WS, contributing to better developmental progress.

Cannabidiol Improves Frequency and Severity of Seizures and Reduces Adverse Events in an Open-Label Add-On Prospective Study

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study.

Researchers initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5?mg/kg/day and titrated it up to a maximum dosage of 50?mg/kg/day. At each visit, they monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars.

Data for the enrollment and visits at 12, 24, and 48?weeks was analyzed. Researchers recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year.

There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p?<?0.0001) with stable AEP scores thereafter (all p???0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12?weeks (p?<?0.0001) and stable CSSS thereafter (all p???0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12?weeks (p?=?0.01) and remained stable thereafter (all p???0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30?mg/kg/day.

For the first time, this prospective, open-label safety study of CBD in treatment-resistant epilepsy provides evidence for significant improvements in the adverse event profile, Chalfont seizure severity scale, and seizure frequency at 12?weeks that are sustained over the 48-week duration of treatment.

Compound from Spider Venom Reduces Seizure Susceptibility, Mortality in Dravet Syndrome Mice

A compound isolated from spider venom called Hm1a helps reduce seizure susceptibility and mortality in mice with Dravet syndrome, according to researchers.

Their study, “Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death,” was published in PNAS.

Dravet syndrome is resistant to several pharmaceutical therapies that are geared toward treatment of other types of epilepsy. This creates an urgent need to develop new therapeutic strategies to treat this genetic disease.

Most patients with Dravet syndrome have a mutation in the SCN1A gene which results in a deficiency in the sodium channel NaV1.1. In the brain, NaV1.1 is expressed on the surface of nerve cells and plays a critical role in nerve-nerve cell signaling.

Spider venom is a rich source of compounds that target ion channels, much like Nav1.1.

Hm1a is a peptide — short chains of amino acids, which are the building blocks of proteins — present in spider venom that selectively improves the functioning of Nav1.1.

Drug Interactions With Carbamazepine: An Ever Expanding List?

Abstract
In a study that applied a nonlinear mixed effect model to evaluate factors affecting steady-state serum carbamazepine concentrations in elderly nursing home residents, co-administration of iron supplements was reported to reduce serum carbamazepine concentrations by approximately one third. Although these findings suggest that iron ions reduce the oral bioavailability of carbamazepine, the influence of confounders cannot be excluded. Further studies are required to confirm this interaction.