Independent Studies of Dextromethorphan and of Donepezil Hydrochloride for Rett Syndrome
Summary
Rett syndrome (RTT) is a disorder in which the nervous system does not develop properly. RTT generally affects girls, but there are some boys who have been diagnosed with RTT. Symptoms of RTT include small brain size, poor language skills, repetitive hand movements, and seizures. This study will evaluate the effectiveness of two drugs in treating the symptoms of RTT.
Description
RTT is a neurodevelopmental disorder characterized by apparently normal early development followed by loss of purposeful hand use, distinctive hand stereotypies, slowed brain growth, loss of language, respiratory irregularities, GI disturbances, gait abnormalities, seizures, and mental retardation. These symptoms appear between ages 6 and 18 months (stage 2 of the disease) following apparently normal development (stage 1). Subsequently, there is gradual stabilization of severe mental retardation and motor compromise (stage 3). The majority (70% to 80%) of patients demonstrate mutations in the methyl-CpG-binding-protein-2 (MeCP2) gene, a transcription repressor located on chromosome Xq28. The disorder predominantly affects females, but a few males with mutations in MeCP2 have been identified, even though many of them do not have the classic symptoms recognized in females.
Recent studies demonstrate increased brain N-methyl-D-aspartate (NMDA) receptors in stages 2 and 3 of the disease. This age-specific increase in glutamate levels and their receptors contribute to brain damage. This first study will examine the effectiveness of dextromethorphan, an NMDA receptor antagonist, to ameliorate symptoms. Participants will be randomized to receive one of three doses of dextromethorphan. All participants will be admitted to the hospital for three days at the beginning of the study. During the hospitalization, participants will undergo physical exam, Dexascan, MRI, EEG, behavioral assessment, laboratory testing, and neuropsychological evaluations. Six months after baseline assessment, participants will be rehospitalized for 3 days for similar assessments.
Reduction in choline acetyltransferase activity in RTT patients may also contribute to disturbed cortical development and psychomotor retardation in RTT. Therefore, the second part of the study will evaluate the effect of donepezil hydrochloride, an inhibitor of acetylcholine-esterase, on acetylcholine levels. This portion of the study will not begin until pharmacokinetic data for donepezil in children is available.
Study Design
Allocation: Randomized, Control: Dose Comparison, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Conditions
Rett Syndrome
Intervention
dextromethorphan, donepezil hydrochloride
Location
Kennedy Krieger Institute
Baltimore
Maryland
United States
Status
Recruiting
Source
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00069550
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Methyl-cpg-binding Protein 2
A DNA-binding protein that interacts with methylated CPG ISLANDS. It plays a role in repressing GENETIC TRANSCRIPTION and is frequently mutated in RETT SYNDROME.
Rett Syndrome
An inherited neurological developmental disorder that is associated with X-LINKED INHERITANCE and may be lethal in utero to hemizygous males. The affected female is normal until the age of 6-25 months when progressive loss of voluntary control of hand movements and communication skills; ATAXIA; SEIZURES; autistic behavior; intermittent HYPERVENTILATION; and HYPERAMMONEMIA appear. (From Menkes, Textbook of Child Neurology, 5th ed, p199)
Dextrorphan
Dextro form of levorphanol. It acts as a noncompetitive NMDA receptor antagonist, among other effects, and has been proposed as a neuroprotective agent. It is also a metabolite of DEXTROMETHORPHAN.
Naphthylvinylpyridine
4(1-Naphthylvinyl)pyridine hydrochloride. Cholinesterase inhibitor. Synonym: YuB 25.
Tetramethylphenylenediamine
Used in the form of the hydrochloride as a reagent in ANALYTICAL CHEMISTRY TECHNIQUES.
Clinical Trials
Study of the Pathogenesis of Rett Syndrome
OBJECTIVES: I. Extend current knowledge of the phenotype and natural history of Rett syndrome (RS). II. Continue the search for a cytogenetic and/or DNA marker. III. Study the effects o...
Trial of Dextromethorphan in Rett Syndrome
Increased brain glutamate and its NMDA receptors found in the brain of younger Rett syndrome (RTT) patients cause toxic damage to neurons (the brain's nerve cells), and contributing to EEG...
The purpose of this study is to determine the safety of donepezil hydrochloride (Aricept) in children with Down syndrome who have finished the preceding 10-week, double-blind study of done...
Functional Abilities in Rett Syndrome
The purpose of this study is to evaluate and determinate the functional abilities in Rett syndrome conforming to the established Pediatric Evaluation of Disability Inventory (PEDI).
The purpose of this study is to determine whether donepezil HCl is effective and safe in improving cognitive dysfunction exhibited by children and adolescents with Down syndrome. Effective...
PubMed Articles
Use of buspirone and fluoxetine for breathing problems in rett syndrome.
Rett syndrome is a severe neurodevelopmental disease with a prevalence of 0.88 per 10,000 girls aged 5-18 years, and is often caused by mutations in methyl-cytosine-phosphate-guanine (CpG)-binding pro...
Early development and regression in Rett syndrome.
This study utilised developmental profiling to examine symptom presentation in 14 girls with genetically confirmed Rett Syndrome and whose family was participating in the Australian Rett Syndrome or I...
Epilepsy in Rett syndrome: Clinical and genetic features.
Epilepsy often occurs in Rett syndrome and is considered a major problem. The aim of this study was to define the clinical features of epilepsy and the correlation between seizures and both genotype a...
Dextromethorphan inhibition of voltage-gated proton currents in BV2 microglial cells.
Dextromethorphan, an antitussive drug, has a neuroprotective property as evidenced by its inhibition of microglial production of pro-inflammatory cytokines and reactive oxygen species. The microglial...
Discontinuing donepezil or starting memantine for Alzheimer's disease.
To the Editor: In the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO) study, Howard and coauthors (March 8 issue)(1) found that the magnitude of benefit, as assessed with th...
