coenzyme-q10 and remacemide

Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.

Topics: Acetamides; Antioxidants; Caudate Nucleus; Coenzymes; Humans; Huntington Disease; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Neuropsychological Tests; Pilot Projects; Radiography; Treatment Outcome; Ubiquinone

To determine whether chronic treatment with coenzyme Q10 or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD).. The authors conducted a multicenter, parallel group, double-blind, 2 x 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q10 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events.. Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q10 showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q10.. Neither remacemide nor coenzyme Q10, at the dosages studied, produced significant slowing in functional decline in early HD.

Topics: Acetamides; Adult; Coenzymes; Double-Blind Method; Female; Humans; Huntington Disease; Male; Middle Aged; Prognosis; Time Factors; Ubiquinone

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials.. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal.. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models.. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies.. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Topics: Acetamides; Female; Humans; Huntington Disease; Kaplan-Meier Estimate; Male; Middle Aged; Minocycline; Neuroprotective Agents; Neuropsychological Tests; Patient Dropouts; Proportional Hazards Models; Randomized Controlled Trials as Topic; Ubiquinone

The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice. However, life expectancy was not prolonged. Significant improvements in motor function, without prolonging survival, were also observed in N171-82Q mice treated with Coenzyme Q10 (CoQ10, an energy metabolism enhancer). Several compounds were not effective in either improving motor skills or prolonging life, including Remacemide (a glutamate antagonist), Celecoxib (a COX-2 inhibitor), and Chlorpromazine (a prion inhibitor); Celecoxib dramatically shortened life expectancy. We also tested whether raising cellular antioxidant capacity by co-expressing high levels of wild-type human Cu/Zn superoxide dismutase 1 (SOD1) was beneficial. However, no improvement in motor performance or life expectancy was observed. Although we would argue that positive outcomes in mice carry far greater weight than negative outcomes, we suggest that caution may be warranted in testing Celecoxib in HD patients. The positive outcomes achieved by CoQ10 therapy and environmental stimuli point toward two potentially therapeutic approaches that should be readily accessible to HD patients and at-risk family members.

Topics: Acetamides; Animals; Celecoxib; Chlorpromazine; Coenzymes; Cyclooxygenase Inhibitors; Disease Models, Animal; Disease Progression; Dopamine Antagonists; Environment, Controlled; Female; Humans; Huntington Disease; Mice; Mice, Transgenic; Motor Activity; Motor Skills; Neuroprotective Agents; Phenotype; Pyrazoles; Sulfonamides; Superoxide Dismutase; Superoxide Dismutase-1; Survival Rate; Treatment Outcome; Ubiquinone

There is substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide. We found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using coenzyme Q10 and remacemide together, was more efficacious than either compound alone, resulting in an approximately 32 and 17% increase in survival in the R6/2 and N171-82Q mice, respectively. Magnetic resonance imaging showed that combined treatment significantly attenuated ventricular enlargement in vivo. These studies further implicate defective energy metabolism and excitotoxicity in the R6/2 and N171-82Q transgenic mouse models of HD and are of interest in comparison with the outcome of a recent clinical trial examining coenzyme Q10 and remacemide in HD patients.

Topics: Acetamides; Administration, Oral; Animals; Behavior, Animal; Body Weight; Brain; Cerebral Ventricles; Coenzymes; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Huntingtin Protein; Huntington Disease; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Motor Activity; Nerve Tissue Proteins; Nuclear Proteins; Organ Size; Survival Rate; Treatment Outcome; Ubiquinone

Huntington's disease (HD) is a progressive inherited neurodegenerative disorder, for which there is no effective therapy. The CARE-HD study, recently published, evaluated the ability of a combination of coenzyme Q10 (CoQ10) and remacemide hydrochloride (R) to ameliorate symptoms, which might arise from glutamate-mediated excitotoxicity and abnormalities in mitochondrial energy production. In this study, we examined the efficacy of CoQ10/R therapy on ameliorating the motor dysfunction and premature death of HD-N171-82Q transgenic mice. Motor performance, measured on the Rotarod, was specifically but transiently improved beginning 3 weeks after initiating the CoQ10/R therapy. Survival, however was not prolonged. Our findings suggest that further study of CoQ10/R in mouse models is warranted to investigate whether this therapeutic approach can ameliorate the symptoms of HD in early stages of the disease.

Topics: Acetamides; Animals; Antioxidants; Coenzymes; Drug Therapy, Combination; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Motor Activity; Nerve Tissue Proteins; Nuclear Proteins; Peptide Fragments; Survival Analysis; Time Factors; Ubiquinone