1、Treating Chronic Fatigue Syndrome (CFS) & Fibromyalgia (FM) by Targeting the Methylation Cycle,Derek Enlander, MD 860 Fifth Avenue New York, NY 10065 USA 1-212-794-2000 ,Basic cell process,Pathogenisis,Virus as Causative Agent,CFS often starts with a flu-like episodeCFS symptoms wax and waneAntivira
2、l pathways are activatedCFS symptoms are similar to many viral conditions including: EBV mononucleosis Ross River virus Geographic outbreaks have been reportedGene expression profiling found genetic variants that impact antiviral defenses Antiviral treatments have been effective in in small studies
3、Ampligen isoprinosine beta interferon valganiclovir,Viruses Implicated In CFS,Human herpesvirusesEBV (HHV-4)CMV (HHV-5)HHV-6HHV-7Stealth Virus (Simian) Enteroviruses PolioCoxsackie A & BEchovirus Foamy virus spuma virusParvo virusB-19 Hepatitis-C virus JHKV Rubella virus Ross River virus (RRV) Inoue
4、-Melnick virus Borna virus HERV Human Endogenous Retrovirus,HHV6 virus,Discovered in 1986 by Ablashi and Salahuddin at NCI in patients with lymphoproliferative disease( slide by kind permission of Dharam Ablashi)HHV-6 is an enveloped, double-stranded DNA virus with an icosahedral capsid and virion s
5、ize of 160-200 nm. The genome contains 70 proteins. Some of these proteins (early antigen and immediate early antigen) can be used to detect active infections.Two very distinct variants with 90% nucleotide sequence homology. The genome of variant A or B ranges from 159 170 kb.Beta herpesvirus and ge
6、nus roseola virusOver 90% of adults seropositivePredominantly CD4 lymphotropic,HHV-6 has two variants, A and B. Each variant is associated with a subset of illnesses. HHV-6A infection comes later in life and has been linked to the pathogenesis of CFS, rhomboencephalitis, and MS. It also plays a role
7、 in HIV, causing more immunosuppression in AIDS patients. HHV-6B is the causative agent of Exanthem subitum, is strongly linked to infections in transplant patients and is also associated with epilepsy and post-transplant acute limbic encephalitis.HHV-6A is more lytic, and readily infects a variety
8、of neural and other cells such as astrocytes , and is also more neurotropic, leading to cognitive disorders in CFS and MS patients.Both A & B strains cause encephalitis, amnesia, facial paralysis, chronic myelitis and transverse myelitis.HHV-6A can lead to enhanced production of EBV, HSV and HHV-8.
9、Both variants also induce expression of human endogenous retrovirus K-18 encoded super antigen.,HHV6,Both strains establish latency in monocytes, macrophages and target CD4 cells for infection. Since HHV-6, like other human herpesviruses, is ubiquitous, its role in the pathogenesis is established wh
10、en the virus is in the active state of infection. Anti-viral agents foscarnet, cidofovir and ganciclovir inhibit CMV infection do not block HHV-6 infection, especially of the A variant as efficiently. HHV-6 infection contributes to immune suppression by: Disturbing key immune activation pathways and
11、 cytokine networks. Depleting CD4 T lymphocytes via direct infection and induction of apoptosis (Lusso) Upregulating TNF alpha, TNF- gamma, IL-1beta and IL-10.(Flamand, Dockerell, Li) and IL-21. Downregulating complement activity through the CD46 receptor suppressing macrophages to produce IL-12 sti
12、mulated with gamma interferon.(Lusso 2004),HHV6 (cont.),,HHV-6 B,HHV-6 A,Detection of interstitial cells,IHC Labeling of cardiomyocyte,Localization of HHV-6 variants in myocardial tissue by IHC,Khl et al., 2008, submitted,Myocardial hhv6,Infected astrocyte,Astrocytes obtained from lateral temporal l
13、obe infected with HHV-6,Astrocyte hhv6,Antiviral / immuno used for CFS,Antiviral Study effective?ampligen Strayer 1994 yes ? isoprinosine (Immunovir) Pinching 2002 yes alpha 2a interferon See, 1996 yes ? acyclovir (Zovirax) Straus 1990 (5 weeks) no valacyclvir (Valtrex) Lerner, 2001 (6 mos) yes ? va
14、lganciclovir (Valcyte) Lerner, 2006 (6 mos) yes valganciclovir (Valcyte) Montoya, 2006 (6 mos) yes Hepapressin, Immunoprop Enlander 2007 (12 mos) yes,Methylation cycle,Reasons to Target Methylation Cycle,Paul Cheney, M.D. reported “almost universal” glutathione depletion in CFS in 1999 Rich Van Kony
15、nenburg, Ph.D. reported that CFS symptoms can be explained by glutathione depletion AACFS 7th Intl. Conf.Personal experience with glutathione supplementation and methylation targeting,Current Treatment part 1,Hepapressin Complex Weekly Injection Hepapressin Magnesium Sulphate Folic Acid B12 Calphosa
16、n Glutathione Trace elementsClinical trial 1994Kutapressin DerivativeHistory of treatment,Current Treatment part 2,BetaMax Methyl B12 Spray Methyl Cobalamine Vitamin B6Lectrolyte Sodium Potassium Calcium Magnesium Trace ZincCatapult Picamilon Cats Claw Glutathione L-cystine Trace SeleniumProvides en
17、ergy Relieves muscle pain Clears Brain Fog,Current Treatment part 3,ImmunopropGlutathione L-cystine Picamilon/Ascorbic Acid? Trace SeleniumImmunoplusFolinic Acid Folic Acid Vitamin B complex Glutathione L-cystine Phosphadylserine Trace Selenium Trace Magnesium Trace Zinc,Major Pathways - Methylation
18、 Cycle,Diet,Choline,Betaine TMG,Zn,DHF,THF,DNA, RNA,Methionine,Protein synthesis, Carnitine,SAM,Methyl Synthase (MS),SAH,Homocysteine,Cystathionine,Glutathione,Zn, B6,BHMT,B12,MAT (methionine adenosyltransferase),Main Role of Methylation Cycle,Methyl Group Source for the bodyCoordinate sulfur metabo
19、lismCoordinate production of DNA,Methionine-Homocysteine Pathway,Methionine,S-Adenosylmethionine,S-Adenosylhomocysteine,Homocysteine,Cystathionine,Cysteine,Toxic Sulphites,Sulphates,Glutathione,B12, B6, Mg,Role of Hepapressin Injection,Methionine,S-Adenosylmethionine,S-Adenosylhomocysteine,Homocyste
20、ine,Cystathionine,Cysteine,Toxic Sulphites,Sulphates,Glutathione,B12, B6, Mg,Folic Acid,Hepapressin / Kutapressin / Nexavir Bovine/Porcine Liver Extract once weekly Phase I clinical trial 1994 Invivo antiviral activity Valganciclovir Valcyte 450mg twice daily Montoya, 2006 Case Study, Retinal Uveiti
21、s + CFS Modest Effect Important to identify appropriate CFS patient titer 1:640,Antiviral treatment,Gene expression 2005,Kerr collaborators,CFS Gene microarray,Gene Microarray,CFS Associated genes,Diagnostic slide test,GcMaf,GcMaf protein Gc Macrophage Activation Factor original work Yamamoto Reduce
22、d by action of Nagalase Nagalase if increased GcMaf is decreased Research into ME/CFS serum nagalase levels Administration of GcMaf injection in research protocol Cheney researches MAF 314 probiotic yogurt ME/CFS center researches MAF 878 probiotic,Ampligen,Research treatment protocol Thought to act
23、 on the immune system 5 centers chosen in US California, New York, Utah, Carolina, Florida Hemispherx part funding Patient cost for 6 months $12,000 Not yet FDA approved,Retro Virus XMRV,New retrovirus XMRV testing in Nevada. Judy Mikovits Exciting press releases Oct 2009 Helps patients and doctors
24、stress the physiological aspect of CFS / ME Harvey Alter, NIH confirms MLV results 2010 Small number of patients tested, not adequately replicated as yet Moderation in determining this as causative agent Researcher battle ensues Science requests withdrawal of original paper May 2011WPI dismisses Dr
25、Mikovits , sues her for stealing her own notebooks , jails her for 4 days,XMRV retro virus,Whitmore Pederson Institute, Reno, Nevada XMRV retro virus study Science journal publishes article 8th Oct 2009 Battle ensues by other researchers some confirm, other deny May 2011 Science asks Judy Miklovits
26、to withdraw article,Dr Judy Mikovits,Proc. Natl. Acad. Sci. USA Vol. 88, pp. 2922-2926, April 1991 Medical Sciences Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome (Epstein-Barr virus syndrome/infectious mononucleosis/my
27、algic encephalomyelitis/polymerase chain reaction/in situ hybridization) ELAINE DEFREITAS*, BRENDAN HILLIARD, PAUL R. CHENEY, DAVID S. BELLS, EDWARD KIGGUNDU, DIANE SANKEY, ZOFIA WROBLEWSKA, MARIA PALLADINO, JOHN P. WOODWARD, AND HILARY KOPROWSKI The Wistar Institute, 3601 Spruce Street, Philadelphi
28、a, PA 19104 Contributed by Hilary Koprowski, Nov13, 1990 ABSTRACT Chronic fatigue immune dysfunction syndrome (CFIDS) is a recently recognized illness characterized by debilitating fatigue as well as immunological and neurological abnormalities Straus, S. E. (1988) J. Inf. Dis. 157, 405412. Once tho
29、ught to be caused by Epstein-Barr virus, it is now thought to have a different but unknown etiology. We evaluated 30 adult and pediatric CFIDS patients from six eastern states for the presence of human T-lymphotropic virus (HTLV) types I and II by Western immunoblotting, polymerase chain reaction, a
30、nd in situ hybridization of blood samples. The majority of patients were positive for HTLV antibodies by Western blotting and for HTLV-II gag sequences by polymerase chain reaction and in situ hybridization. Twenty nonexposure healthy controls were negative in all assays. These data support an assoc
31、iation between an HTLV-ll-like virus and CFIDS.,Hepapressin complex treatment Karnofsky & Fatigue scores,GcMaf / Nagalase. Collaboration with Dr. Kenny deMeirleir GcMaf Study in treatment of CFIDS/ME patients Ampligen treatment study Part Sponsored by Hemispherx Inc B12 changes with BetaMax (subling
32、ual methyl B12) Average increase 56% after avg. 3 months of use Retrospective analysis of Carnitine in CFS 120 patients, randomly selected serum Carnitine Low Analysis of urinary H2S with Lead Arsenate 70 patients, randomly selected 35% positive Lead arsenate analysis,Ongoing research,Proposed Resea
33、rch,Retuximab CMX 1000 Enbrel Pre and post Exertional Malaise study,Retuximab Study,Norwegian Study Oct 2011 ME/CFS Patients with lymphoma ME/CFS seemed to improve after chemo Initial study 5 patients Followup with 15 patients 15 controls,Retuximab Study,Patients have to be hospitalised overnight Re
34、tuximab is a chemotherapeutic infusion Administered monthly for 6 months Not FDA / GMC approved Past side effects including fatal outcome Relapse 6 months after infusion completion Reversed after second infusion,The UK and Ireland scene,Problems in finding the diagnosis If diagnosis is made here or
35、elsewhere problem in finding suitable care and treatment Doctors are only given psychiatric methods of treatment CBT & GET Research into physical aspect of ME/CFS is neglected Disability is undercompensated National cost in GNP is estimated at 10,000 million pound annually,The UK and Ireland scene,P
36、rovide research funds to physical diagnosis and treatment Provide training to young doctors Provide information to old doctors Set up Central and regional ME/CFS centres to diagnose and treat this physical disease Reverse old ideas of psychiatric treatment,Immediate Provisional solution,Initiation a
37、nd funding of two fellowships in the diagnosis and treatment of ME/CFS by the Government and/or Private sources We have set up the fellowship training for 12 months for two post Doc physicians The training will be provided at the ME/CFS Centre in New York Dr Eric Schadt will supervise the research p
38、art of the fellowship Dr Derek Enlander will supervise the clinical part of the fellowship,ME/CFS Center Mount Sinai Medical Center, New York,set up in Nov 2011 with a donation of one million dollars by a patient of Dr Enlander First ME/CFS centre in a major School of medicine Research in Genomics Eric Schadt Immunology Miriam Merad Virology Ila Singh Pulmonology Christian Becker Clinical diagnosis and treatment Derek Enlander and David Bell,
