Multicenter trial with ubidecarenone: treatment of 44 patients with mitochondrial myopathies

Fourty four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for six months in an open multicentric trial. No side effects due to the drug administration were observed. Sixteen patients showing at least 25% decrease of post exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were further treated for 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences between the 2 groups were observed. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dosage of CoQ10 used in the study (2 mg/kg/day) the therapy requires long administration time before a response is demonstrable.     

Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease

BACKGROUND: Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons. OBJECTIVE: To determine whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial. SETTING: Academic and nonacademic movement disorder clinics. PATIENTS: One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson's Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits. RESULTS: One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups. CONCLUSIONS: Nanoparticular CoQ(10) at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ(10) does not display symptomatic effects in midstage Parkinson disease.     

Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS

An open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.     

A randomized trial of coenzyme Q10 in mitochondrial disorders

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.     

Vagus nerve stimulation is associated with mood improvements in epilepsy patients

Vagus nerve stimulation (VNS) has gained increasing acceptance for treatment of drug-resistant seizures. The aim of this study was to evaluate effects of VNS on depressed mood in epilepsy patients during the first 6 months after implantation of the stimulation device. This study was conducted as an addition to the international multisite randomized and double-blind controlled trial on anti-seizure effects of VNS (EO3). Only adult patients with >4/month medication-resistant complex-partial seizures were included (N=11). During the acute phase of the study (3 months after implantation), patients were randomly assigned to low (stimulation detection) versus high stimulation (maximal tolerability, maximum 1.75 mA). Mood and mood changes were recorded based on standardized psychiatric rating scales and self-report questionnaires. Patients were assessed 4 weeks before (baseline) as well as 3 and 6 months after implantation. Significant positive mood effects were observed in most scales and subscales at the 3-month follow-up (P<0.05). Mood improvements were sustained at the 6-month follow-up and were independent of effects on seizure activity (9/11 mood responders versus 2/11 seizure responders). Mood effects appeared more pronounced in the high stimulation group after the acute study phase, but findings were not significant (P<0.10). VNS is associated with mood improvements in patients with epilepsy, but to confirm VNS dose effects, studies with more statistical power are needed.     

Which depressed patients respond to nefazodone and when?

BACKGROUND: Retrospective data analyses were conducted of a single-blind trial of 993 outpatients with nonpsychotic major depression (DSM-III-R) treated for 12 weeks with nefazodone to provide a more specific picture of the nature and timing of response or remission to acute-phase treatment. METHOD: All patients participated in a single-blind, 16-week lead-in to obtain responders eligible for a subsequent double-blind, randomized continuation phase trial. Outcomes were defined by the 17-item Hamilton Rating Scale for Depression (HAM-D). A > or = 50% reduction from baseline defined response, and a total HAM-D exit score of < or =8 defined remission. RESULTS: Of all patients who entered the trial, 41.8% (last observation carried forward) responded at or before week 4 (early responders), and an additional 25.2% responded thereafter; 18.3% achieved remission at or before week 4; 33.6% achieved remission after week 4. Thus, 77.3% of those responding ultimately remitted. On average, remission followed response by 2 weeks. The average end-of-treatment dose was 376 mg/day at exit (last observation carried forward). Responders or remitters (as opposed to nonresponders or nonremitters) had lower baseline depressive symptomatology and were more likely to be married or cohabiting. CONCLUSION: The full symptomatic benefit of antidepressant medication may not be apparent until completion of an 8- to 10-week trial. A high number of responders ultimately attained remission. Baseline demographic and clinical features were not highly predictive of who would or would not benefit from nefazodone. For routine care, a minimal acute-phase trial, using a 50% reduction in baseline symptom severity to define response, should be 8 weeks. Whether ultimate nonresponders can be identified earlier than 8 weeks deserves further study.     

Coenzyme Q10 serum levels in Huntington's disease

Mitochondrial dysfunction contributes to the neurodegenerative process in Huntington's disease (HD). Coenzyme Q10 (CoQ10) enhances mitochondrial complex I activity and may therefore provide a therapeutic benefit in HD. We compared serum CoQ10 levels of previously untreated-and treated HD patients with those of healthy controls. CoQ10 did not significantly (ANCOVA F(dF 2, dF 55) = 2.57; p=0.086) differ between all three groups. However, the post hoc analysis showed no significant (p = 0.4) difference between treated HD patients ([CoQ10]: 88.12 [mean]+/-24.44 [SD], [range] 48.75-146.32 [pg/million platelets]) and controls (93.71+/-20.72, 65.31-157.94), however previously untreated HD patients (70.10+/-21.12, 38.67-106.14) had marked (p = 0.051) lower CoQ10 results than treated HD patients and controls (p = 0.017). Our results support that CoQ10 supplementation in HD patients may reduce impaired mitochondrial function in HD.     

Patterns of response to neuroleptic treatment: factors influencing the amelioration of individual symptoms in psychotic patients

Fifty-three patients with acute psychotic disorders (diagnosed according to DSM-III) were treated with thioridazine alone and observed during periods of up to 2 months. The amelioration of paranoid ideas and hallucinations (target symptoms) and of concentration difficulties, disorientation, reduced appetite, and reduced sleep (additional symptoms) was studied by repeated psychopathology ratings (CPRS). The patients were classified as "fast, slow or partial responders" according to the therapeutic effect registered on each target symptom. Paranoid ideas disappeared completely after less than 3 weeks of treatment in 28% of the patients (fast responders) and after more than 3 weeks in 32% (slow responders). Hallucinations disappeared significantly faster than paranoid ideas; 47% of the patients were completely free from hallucinations after less than 2 weeks of treatment (fast responders) and 38% after more than 2 weeks (slow responders). The following factors were significantly correlated to positive treatment effects of thioridazine: 1) diagnosis involving a brief history of psychotic symptoms before admission; 2) a low CPRS score for paranoid ideas on admission; 3) presence of disorientation on admission; 4) normal appetite on admission, and 5) rapidly reached optimal serum concentration of the drug.     

Koenzym Q10 beim Morbus Parkinson

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons within the substantia nigra pars compacta. Experimental and clinical data point to a defect of the mitochondrial respiratory chain as a major pathogenetic factor in PD. Although the restoration of mitochondrial respiration and reduction of oxidative stress by coenzyme Q(10) (CoQ10) could induce neuroprotective effects against the dopaminergic cell death in PD, these effects of CoQ10 could also improve the dopaminergic dysfunction. Thus CoQ10 might theoretically exert both neuroprotective and symptomatic effects in PD. Current data from controlled clinical trials are not sufficient to answer conclusively whether CoQ10 is neuroprotective in PD. Moreover, several open and controlled pilot studies on symptomatic effects of CoQ10 revealed inconsistent results. A recent randomized, double-blind, placebo-controlled trial showed no symptomatic effects in PD. CoQ10 is well tolerated and safe as both monotherapy and add-on medication in PD patients. The present review discusses the current knowledge on neuroprotective and symptomatic actions of CoQ10 in PD.     

Oral treatment with amitriptyline induces coenzyme Q deficiency and oxidative stress in psychiatric patients

Amitriptyline is a commonly prescribed tricyclic antidepressant, which has been shown to impair mitochondrial function and increase oxidative stress in a variety of in vitro assays. Coenzyme Q(10) (CoQ(10)), an essential component of the mitochondrial respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In order to evaluate the putative mitochondrial toxicity of amitriptyline, we have analyzed CoQ(10) and ATP levels, oxidative damage and mitochondrial mass in peripheral blood cells from control healthy volunteers and psychiatric patients with depressive episodes treated or non-treated with amitriptyline. In patients not following amitriptyline treatment, CoQ(10) and ATP levels and mitochondrial mass were reduced when compared to normal individuals while lipid peroxidation was clearly increased. All these alterations were aggravated in patients following oral amitriptyline therapy. These results suggest that mitochondrial dysfunction could be involved in the pathophysiology of depression and may be worsened by amitriptyline treatment. CoQ(10) supplementation is postulated to counteract the adverse effects of amitriptyline treatment in psychiatric patients.     

Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease

Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 microM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted.     

Effectiveness of coenzyme Q10 in prophylactic treatment of migraine headache: an open-label,add-on,controlled trial

Despite the huge health and economic burden of migraine headache, few medications have been approved for its prophylactic treatment, most of which can potentially induce serious adverse effects. Coenzyme Q10 (CoQ10) is a supplement and has shown preliminary benefits in migraine prophylaxis. We aimed to assess this effect in an adult population. This is an open-label, parallel, add-on, match-controlled trial. Eighty patients diagnosed with migraine headache based on International Headache Society criteria were allocated to receiving only their current preventive drugs or their current preventive drugs plus 100 mg CoQ10 daily, matching for their baseline characteristics, and were assessed for frequency and severity of attacks, and ≥50 % reduction in attack frequency per month. Thirty-six and 37 patients were analyzed in CoQ10 and control groups, respectively. Number of attacks per month dropped significantly in the CoQ10 group (mean decrease: 1.6 vs. 0.5 among CoQ10 and control groups, respectively, p < 0.001). A significant reduction was also evident in the severity of headaches (mean decrease: 2.3 vs. 0.6 among CoQ10 and control groups, respectively, p < 0.001). For ≥50 % reduction in the frequency of attacks per month, the number needed to treat was calculated as 1.6. No side effects for CoQ10 were observed. This study suggests that CoQ10 might reduce the frequency of headaches, and may also make them shorter in duration, and less severe, with a favorable safety profile.     

Hyperthyroidism associated with papilloedema and pyramidal tract involvement

Summary In a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes [MELAS] who had normal mitochondrial enzyme activity, high doses of coenzyme Q₁₀ (CoQ) were administered. Clinical improvement with decreased serum lactate and pyruvate levels was observed. Though the mechanism of action of CoQ is not known, a trial is worthwhile in patients with MELAS.     

Coenzyme Q10 protects neurons against neurotoxicity in hippocampal slice culture

This study investigated the neuroprotective effects of coenzyme Q10 (CoQ10) against oxidative stress induced by kainic acid (KA) in organotypic hippocampal slice culture of rats. Cultured slices were injured by exposure to 5 μM of KA for 18 h and then treated with different concentrations of CoQ10. Neuronal cell death measured as propidium iodide uptake was reduced at 24 h after treatment with 1 μM of CoQ10. We also observed an increased number of surviving CA3 neurons in 0.1 and 1 μM concentrations of CoQ10-treated groups using cresyl violet staining. CoQ10 (0.01, 0.1, and 1 μM) treatment significantly decreased the 2',7'-dichlorofluorescein fluorescence and the expression of NQO1 in the CoQ10-treated groups was significantly lower than that in the KA-only group. These results suggest that CoQ10 may protect hippocampal neurons against oxidative stress.     

Corticosteroids as treatment of epileptic syndromes with continuous spike-waves during slow-wave sleep

To assess the efficacy and tolerability of steroids in epileptic syndromes with continuous spike-waves during slow-wave sleep (CSWS), charts of 44 children (25 boys) who received corticosteroids for cognitive and/or behavioral deterioration associated with CSWS were retrospectively reviewed. Awake and sleep electroencephalography (EEG) records, clinical and neuropsychological assessments were available before, during, and after corticosteroid therapy. Evaluation focused on effects on EEG, behavior, and cognition. All but two patients received hydrocortisone (initial dose of 5 mg/kg/day). The treatment was slowly tapered with a total duration of 21 months. There were 18 symptomatic and 26 cryptogenic cases. Mean age was 7 years and mean intelligence quotient/developmental quotient (IQ/DQ) was 65. Mean CSWS duration before corticosteroid treatment was 1.7 years. Twenty patients had tried more than two antiepileptic drugs (AEDs) before steroids. Positive response to steroids was found during the first 3 months of treatment in 34 of 44 patients (77.2%), with normalization of the EEG in 21 patients. Relapse occurred in 14 of them. Hence, 20 patients (45.4%) were long-term responders after a single but prolonged trial of steroids, including all four cases of Landau-Kleffner syndrome. Positive response to steroids was highly significantly associated with higher IQ/DQ. Shorter CSWS duration, but not age, etiology, or previous AED trials, was associated with positive response to steroids. Early discontinuation of the treatment for side effects was encountered in seven patients. We conclude that corticosteroids are safe and efficient for treatment of epilepsy with CSWS. Poor responders are patients with very low IQ and long duration of CSWS.     

Efficacy of zonisamide in West syndrome]

The efficacy of zonisamide (ZNS) was studied in 16 patients (11 males, 5 females) with West syndrome (WS), symptomatic in 13 and cryptogenic in 3. They did not respond to pyridoxal phosphate (12 cases) or valproate (16 cases). The mean age of onset of WS was 4.4 (2-9) months. ZNS was administered from 3 to 9 months of age (mean 6.1). Four cases (2 cryptogenic and 2 symptomatic) became seizure free. Two had more than 50% seizure reduction. Ten infants remained unchanged or showed less than 50% seizure reduction. In the 4 responders, the effective dose was 4-8 mg/kg (mean 5.8), and the serum ZNS concentration was 10-21 micrograms/ml (mean 13.8). One had relapse of WS after 4 months. Three with normalized EEG remained seizure-free during the follow-up period (12-26 months). One case developed a transient drowsiness, but no serious side effects were observed. These data suggest ZNS may be regarded as a therapy of choice before synthesized ACTH therapy in the management of WS.     

Effect of coenzyme Q(10) on biochemical and morphological changes in experimental ischemia in the rat brain

The aim of the work was to evaluate an influence of CoQ(10) on lactate acidosis, adenosine-5'-triphosphate (ATP) concentrations, oxidized to reduced glutathione ratio and on superoxide dismutase activity in endothelin model of cerebral ischemia in the rat. Light microscopic studies in the central nervous system and morphometric analysis of pyramidal cells in the hippocampus were also performed. Endothelins (ET-1 or ET-3; 20 pmoles) were injected into the right lateral cerebral ventricle (intracerebroventricularly). CoQ(10) was given intraperitoneally (i.p.) just before the operation (i.p. 10 mgkg b. wt.). More severe changes of investigated biochemical parameters were observed in the animals treated with ET-1 in comparison with ET-3. Recovery was noted earlier in the group subjected to ET-3 and CoQ(10) administration, than in the animals subjected to ET-1 and CoQ(10) treatment. Histopathological observations showed sparse foci of a neuronal loss in the cerebral cortex and in the hippocampus only in the ET-1 model of ischemia. Additionally more numerous dark neurons were present in above brain structures following ET-1 administration comparing with ET-3 one. Morphometrical studies demonstrated that CoQ(10) diminished neuronal injury in the hippocampal CA1, CA2 and CA3 zones. Above data indicate on neuroprotective effect of CoQ(10) as a potent antioxidant and oxygen derived free radicals scavenger in the cerebral ischemia.     

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy

Introduction: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin‐deficient muscle. Methods: We performed an open‐label, “add‐on” pilot study of CoQ10 in thirteen 5–10‐year‐old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. Results: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject‐ and administration‐dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). Conclusions: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. Muscle Nerve, 2011     

Amantadine is beneficial in restless legs syndrome.

Twenty-one patients (mean age 70 yrs) with restless legs syndrome (RLS) were treated with amantadine in an open-label trial. Amantadine was started at 100 mg per day and was increased every 3-5 days by 100 mg (up to a maximum of 300 mg per day) until significant relief of symptoms or intolerable side effects were experienced. Patients were rated pre- and posttreatment using an RLS rating scale (0-10). Each patient also rated the degree of response in a continuous scale from 0% (no improvement) to 100% (complete improvement). Eleven of 21 (52%) had subjective benefit to amantadine, with degree of response ranging from 25%-100% (mean 69%) among responders. Six had 95%-100% improvement. The RLS score for all 21 patients dropped from a mean (+/- standard deviation) of 9.8 +/- 0.6 (range, 8-10) pretreatment to 6.6 +/- 3.8 (range, 0-10) posttreatment (p = 0.001). The duration of response was 0-13 months (mean, 3.6 +/- 4.5), with nine responders still remaining on the drug as of last follow up. The mean effective dose was 227 mg per day. The most common side effects were drowsiness (3), fatigue (2), and insomnia (2); only two stopped amantadine because of side effects. We conclude that amantadine is an effective and well-tolerated drug for RLS.