Studies of Ethyl-EPA in the treatment of Huntington disease...
1: Neuroreport. 2002 Jan 21;13(1):123-6. Links
MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment.Puri BK, Bydder GM, Counsell SJ, Corridan BJ, Richardson AJ, Hajnal JV, Appel C, Mckee HM, Vaddadi KS, Horrobin DF.
Magnetic Resonance Unit, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, London UK.
A 6-month randomized, placebo-controlled pilot study of the ethyl-ester of eicosapentaenoic acid (ethyl-EPA) was carried out in seven in-patients with advanced (stage III) Huntington's disease (three on ethyl-EPA, four on placebo; no significant difference in age or sex between the groups). After 6 months all the patients treated with ethyl-EPA improved on the orofacial component of the Unified Huntington's Disease Rating Scale while all the patients on placebo deteriorated on this scale (p < 0.03). Following subvoxel registration of follow-up 3D MRI brain scans with baseline scans, subtraction images showed that while the placebo was associated with progressive cerebral atrophy, the ethyl-EPA was associated with a reverse process. We conclude that treatment with ethyl-EPA is associated with beneficial motor and MRI changes.
PMID: 11924873 [PubMed - indexed for MEDLINE]
1: Neurology. 2005 Jul 26;65(2):286-92. Links
Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial.Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, Manku M, Murck H.
Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, UK.
BACKGROUND: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). METHODS: A total of 135 patients with HD were randomized to enter a multicenter, double-blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington's Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a chi2 test on response, defined as absence of increase in the TMS-4, were performed. RESULTS: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the chi2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. CONCLUSIONS: Ethyl-eicosapentaenoate (ethyl-EPA) (purity > 95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.
PMID: 16043801 [PubMed - indexed for MEDLINE]
1: Exp Neurol. 2005 Dec;196(2):266-72. Epub 2005 Aug 29. Links
Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease.Van Raamsdonk JM, Pearson J, Rogers DA, Lu G, Barakauskas VE, Barr AM, Honer WG, Hayden MR, Leavitt BR.
Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
Huntington disease (HD) is an adult-onset neurodegenerative disorder that is characterized by selective degeneration in the striatum. There are currently no treatments that can prevent the progressive decline of motor and cognitive function in HD. In parallel with a human clinical trial, we examined the efficacy of ethyl-EPA treatment in the YAC128 mouse model of HD. Oral delivery of ethyl-EPA to symptomatic YAC128 mice beginning at 7 months of age increased membrane EPA levels 3-fold (P < 0.001) and resulted in a modest but significant improvement in motor dysfunction by 12 months of age as measured by open-field activity (P = 0.01) and performance on the rotarod (P = 0.05). At this age, ethyl-EPA-treated YAC128 mice showed no improvement in striatal volume, striatal neuron counts, striatal neuronal cross-sectional area, or striatal DARPP-32 expression compared to untreated YAC128 mice, thereby indicating no reduction of striatal neuropathology. This result is congruent with modest motor benefits observed in HD patients treated with ethyl-EPA. Overall, this work demonstrates the feasibility of experimental therapeutics in the YAC128 mouse model and suggests that experiments in these mice may be predictive for future human clinical trials.
PMID: 16129433 [PubMed - indexed for MEDLINE]
1: Brain Res Bull. 2007 Apr 30;72(2-3):159-64. Epub 2006 Nov 15. Links
Ethyl-EPA in Huntington disease: potentially relevant mechanism of action.Murck H, Manku M.
Amarin Neuroscience Ltd, Laurelhill Business Park, Stirling, UK. hmurck@amarin-neuro.com
The pathomechanisms involved in the neuronal dysfunction in Huntington disease (HD) are still unresolved and may be heterogeneous. One potential mechanism might be related to the induction of mitochondrial dysfunction in the CNS. This might lead firstly to neuronal dysfunction and finally to the activation of apoptotic pathways. Several compounds, which should alleviate mitochondrial dysfunction, have been tested in preclinical models as well as in clinical trials of different scale. Recently we reported the efficacy of Ethyl-eicosapentaenoic acid (Ethyl-EPA) in patients with HD. Ethyl-EPA is a polyunsaturated fatty acid from the n-3 group, which is in clinical development for HD and melancholic depression. In our trial with Ethyl-EPA in HD responding patients could be characterized by either a lower CAG repeat number or a chorea-predominant clinical expression of the disease. Here we would like to describe some evidence on the potential mechanism of action of Ethyl-EPA in HD. We specifically focus on pathways, which are known to be influenced in HD and are modified by Ethyl-EPA and which points to an involvement of mitochondrial function as a common target. Some attention is given to the NF-kappa B pathway and the c-Jun amino-terminal kinases (JNK) pathway, which both may lead to an activation of the antiproliferative factor p53 and consequently mitochondrial dysfunction. Further the effects of EPA or Ethyl-EPA in preclinical models of HD are described. The evidence from these studies led to the design of phase III clinical trials, which are ongoing.
PMID: 17352940 [PubMed - indexed for MEDLINE]
Edited by Visionary7903, 14 June 2008 - 05:19 AM.