Transcript LDN Trial
Dr Tom Gilhooly MS Prevalence Scotland – highest rate in the world UK ~ 85,000 sufferers Rate of 143.8 per 100,000 population Northern Europe Country Number of people with MS Prevalence (people with MS per 100,000) Scotland 10,500 210.0 UK 85,000 143.8 Sweden 12,000 134.8 Ireland 4,500 125.0 Denmark 6,000 112.0 Canada 35,000 111.0 Iceland 285 105.1 Germany 110,000 99.0 Finland 5,000 98.0 Czech Republic 10,000 97.1 Netherlands 15,000 94.9 Luxembourg 400 94.1 USA 250,000 91.7 Italy 50,000 88.2 Belgium 8,900 87.5 MS Is Scotland Highest prevalence in the World Genetic element Low sunlight exposure “The Scottish Disease” LDN in MS First prescribed Aug 2004 – NHS practice Secondary progressive MS – wheelchair bound Gross tremor right hand Marked improvement on 3mg LDN LDN Background Nutritional Medicine New Nutritional Medicine Clinic 2004 Omega 3 Vitamin D Norvik Study 16 patients newly diagnosed MS AA/EPA ratio average 6 Supplement with omega 3 AA/EPA ratio reduced to 1.5 25% improvement in symptoms ( EDSS) Vitamin D in MS Increased incidence further from equator Baseline am/pm – 2000 iu Vitamin D Low vitamin D assoc with increased autoimmunity Increased Th1 cells Vitamin D Above 100 nmol/l assoc 63% reduction MS Supplementing with Vit D – 40% reduction Emigration to Australia – 73% reduction Northern Australia – 73% less MS LDN Trial Prescribing experience 4 years Research experience Addiction medicine 20 yrs Stats and research contacts LDN Trial MS symptoms gradual change EDSS difficult to produce change Two patients 1mg LDN Marked improvement in bladder symptoms LDN Trial Urinary frequency – chart MSQOL questionnaire 120 subjects Double blind RCT LDN Trial Consultant Neurologist Dr Jonathan O’Riordan MS Research Centre - Dundee Clinical Research Facility Glasgow LDN Trial LDN Research Trust 2004 MS Society – rejection ! 2007 Chief Scientists Office - 2008 Awaiting confirmation of funding LDN Trial Mechanism of action and safety of LDN LFTs, U&Es and FBC Beta endorphins Nitrotyrosine Dr Agrawal Medical Hypothesis 2005 “ LDN exerts its action by reducing nitric oxide production and therefore the level of peroxynitrites” Mechanism of Action LDN LDN partial blockade of mu receptor Rebound increase in endorphins Inhibition of inducible nitric oxide synthase Reduced peroxynitrites Mechanism of Action LDN Peroxynitrites (ONOO) Nitrates amino acids ( enzymes) Combination of nitric oxide (NO) and superoxide (OO) ONOO highly toxic – damages lipid cell membranes, proteins, DNA, mitochondria Immune Function White blood cells produce two gases Nitric Oxide Superoxide Combine to produce peroxynitrite Nitric Oxide in MS Nobel Prize NO in Heart Disease Louis Ignarro Giovannoni – nitric oxide metabolites in CSF MS patients Cross et al – nitrotyrosine in MS lesions 1988 1998 1992 2001 Medical Hypothesis – NO in pathology of MS – Louis Ignarro Animal studies showed ONOO damaged nerve cells and produced MS type lesions Nitric Oxide in MS Calabrese – iNOS in MS patients CSF Nitrotyrosine in CSF Redjak et al 2002 2004 2003 Danilov – nitric oxide products in progressive and RRMS Increased amounts during relapse Nitric Oxide in MS ONOO in acute and chronic MS ONOO production brain cells ONOO damaging but not NO 2006 2008 2007 Lui – nitrotyrosine in lesions Rejdak et al Neurology 2004 Examined NO metabolites in CSF Correlates to MRI scan lesions Greater levels in those with less disability Correlation NO levels and severity of disability/MRI appearance at 3 yrs 2008 – nitrosative stress assoc with sustained disability in MS LDN Trial Vital to measure Nitrotyrosine levels Key to understanding mechanism of action of LDN Endorphin increase well established Reduced NO levels due to increased endorphins? Measuring ONOO Nitrotyrosine – nitrated amino acid Stable biomarker of ONOO activity Levels only raised in presence of ONOO Measurable in CSF Measuring ONOO Nitrotyrosine Blood test Measure of ONOO activity New test developed in Essential Diagnostic Laboratory Glasgow First test available in world! Tyscore Assay in Progressive MS Tyscore Measuring disease activity Increased Tyscore in absence of clinical signs 25% of progressive MS patients have raised levels 25% Treatment with steroids/co paxone/LDN may reduce levels and disability Tyscore – Measuring Nitrotyrosine New test for MS patients Highlights increased immune activity Progressive forms of MS Key to unlock treatment New Paradym In MS Treatment 75% of all MS patients have progressive disease Majority are not in active treatment Tyscore can help identify the periods of increased immune activity. Active treatment at these times has potential to reduce/prevent disability. Unanswered Questions? Does LDN work soley through endorphin increase ? Does LDN/other Rx reduce the Tyscore? How do we respond to a raised Tyscore? Cost implications of treating more MS ? Crohn’s Disease 60 year old male patient Severe crohn’s – nine bloody motions daily Recent blood transfusion 19 colonoscopys Started LDN 2007 Crohn’s Disease Review August 2008 Normal motions for one year Complete remission of disease Single dose LDN Tyscore negative Psoriasis Autoimmune Disorder Guttate Psoriasis several years Plamoplantar pustulosis 2008 Commenced LDN 1mg Sept 2008 Marked Clinical Improvement Next Steps LDN MS Study 1rst European LDN Conference Glasgow 25th April 2009 LDN Prescribers Network Training and Support Summary LDN wonderful treatment Scientific LDN Data Defining Mechanism of action Development of Tyscore Assay New Paradym in MS treatment!