3 University of Illinois (UIC), Retina Service, Eye and...
1
PURPOSE: Spontaneous remissions from AMD suggest the human retina has large regenerative capacity, even in advanced age. In late 2009, we reported resolution of lipofuscin and 5 measures of visual function in an 80- y/o male with atrophic AMD placed on a stabilized 1 capsule / day low-dose resveratrol (RV+) based supplement called Longevinex®. 1 This OTC product has 7 years of consumer use and 10 international papers. www.longevinex.com In India, we presented additional atrophic AMD case reports of retinal remodeling, resolving AF lipofuscin and visual restoration in weeks / months of RV+ use. 2 We extend these observations to 3 compassionate – care cases of wet AMD. Taken together, this poster establishes the epigenetic framework for further evaluation of RV+ either on its own or as a powerful OTC nutritional adjunct to existing retinal injections. Our limited n, but careful (structure + function) observations suggest that RV+ is capable of restoring the architecture, health and vitality of the entire (retina + choroid), even in octogenarians. Additional case reports are in peer review. Resveratrol (RV) was discovered in the 1940s as an anti-hyperlipidemic medicinal component of grapes and red wine (think “French Red Wine Paradox”), also extracted from the dried roots of the weed Polygonum cuspidatum. In the modern era, RV has been characterized as a promiscuous small molecular weight (SMWt) molecule demonstrating broad-spectrum cell receptor modulation, protection against mt DNA mutations, SIRTUIN activation /deactivation and epigenetic microRNA activity (The “Guiding Hand” of the genome”). 3, 4 Figure 1a,b: Known gene targets of the “promiscuous” RV molecule and Medical Applications (Pezzuto JM and health applications,The phenomenon of resveratrol: redefining the virtues of promiscuity. Ann NY Acad Sci 2011; 1215: 123-30). RV also activates miRNA 539 (hypoxia inducible factor) and down regulates miRNA 20b(angiogenesis) in the heart, thru epigenetic gene networking (more so RV+). The first international conference on the biology of RV, two major literature reviews, and a published human clinical trial in Japan, all occurred recently. (www.resveratrol2010.com ) , 5, 6, 7 There are nearly 3,500 papers concerning some aspect of RV’s ability to inhibit carcinogenesis at all 3 stages of initiation, promotion, and progression. 6 It is also known that RV and RV+ prevent reperfusion injury in animal models of stressed cardiac tissue, probably through preconditioning. 8, 9 In fact, RV protects most vital organs including the kidney, heart, and brain from ischemic reperfusion injury. 9 - 15 RESVERTROL PROPERTIES •Non-flavanoid polyphenol phytoalexin toxin (increased when plants are stressed) •1mg trans resveratrol in 5-ounce glass of best red wine •Small molecule: MWt = 228 Daltons (able to enter cells) •Oral absorption – approx 70% thru small intestine •Half Life 14 minutes if not metabolized in the liver BIOAVALABILITY •Half life extended to 9 hrs via hepatic sulfonation or glucuronidation •Released by glucuronidase enzyme at site of infection / inflammation or malignancy. I RV ‘s MULTIPLE SALUTARY BIOLOGIC ACTIONS •ANTI INFLAMMATORY ↓ COX-2, C-reactive protein, TNF. •ENDOGENOUS ANTI-OXIDANT via NRF2 transcription factor (↑ SOD, CAT, GSH). •PRO- VASCULAR: Anti-cholesterol, anti-hypertensive, anti-platelet, anti-plaque. •PRO-NEURAL: Antidepressant (MAO inhibitor), anti-brain plaque (↓beta amyloid). •PRO-METABOLISM: Rescues pancreatic beta cells; ↓ blood sugar. •ANTICARCINOGENIC: Against all 3 stages of CA. •GERMICIDAL: Anti-bacterial, anti-fungal and anti – viral. RV inhibits neovascularization in rodent retina. 16 Instead of blocking the doorway to the VEGF gene with a monoconal antibody, RV downregulates by 189 x the microRNA 20b controlling the VEGF gene. 17 RVs’ additional vascular attributes have special clinical significance and promise for AMD, due to the debilitating eye diseases’ association with cardiovascular disease and accelerated choroidal thinning. 15,18 RV+ adds synergistic stabilized SMWt molecules that cross the blood-retinal barrier. These include polyphenolic red wine molecules (i.e. quercetin, ferulic acid), IP6 and Vitamin D: II RICE BRAN IP6 (INOSITOL HEXAPHOSPHATE) PROPERTIES •Divalent labile metal chelator against intracellular age accumulating CU++ and FE++ •Theoretical dissolves CA++ in Blood Vessels and Bruch’s membrane. •Required for double-strand DNA break repair. III VITAMIN D •Potent anti-inflammatory •Vascular support (decalcifying agent) •Anti-neovascular properties •Gene regulator i.e. conversion of IP6 to IP3 Science points to loss of control over divalent metals in aging, particularly in nervous systems like the eye and brain. The existence within nature of synergistic mineral chelating, vascular enhancing, cytoprotective SMWt molecules, provides an impetus beyond the restorative vitamin / mineral factors identified in the LAST, ZVF, AREDS and AREDS II studies. 19, 20, 21 Example: RV+ up- regulates HIF1 miRNA 539 (anti-hypoxia inducible factor 1) by 315 x or double that of RV while down–regulating anti-angiogenic miRNA 20b by 1367 x, some 7x greater than RV. 17 Observation of Human Retinal Remodeling in Octogenarians with Resveratrol+ Stuart P. Richer 1, 2, 3 , William R. Stiles 1 , Lawrence Ulanski, II 1 Eye Clinic 112E, Capt James Lovell Fed Health Care Center, North Chicago, IL; RFUMS / Chicago Medical School, Department Preventive and Family Medicine, North Chicago, IL; 3 University of Illinois (UIC), Retina Service, Eye and Ear Infirmary, Chicago, IL; www.eyedoctorricher.com METHODS The OTC supplement Logevinex® was suggested to patients with dry and wet AMD, who progressed on AREDS II type supplements or refused intra-vitreal injections. Patients were clinically followed with high resolution 10 raster SD OCT (OptoVue, Fremont, CA) ) & vision function tests: Notations were made in the medical chart regarding the patients' willingness to take a nutriceutical pill every day and the fact the patient was out of options, by retinal specialist consultation. Nutriceuticals are considered an extension of food under FDA law and are confined for labeling purposes to promoting health rather than treating or preventing disease. Patients secured the RV+ on their own, except in the case of inpatients who secured the product under the auspices of both the Chief of Pharmacy and Chief of Staff at of the James Lovell Federal Health Care Center. Retinal Structure Retinal Spectral Separation Images were obtained with an ARIS ® - automated retinal imaging system 110 (Visual Pathways, Inc., Prescott, AZ) camera . Compared with traditional fundus photographs, we use spectral separation images for AMD patients, because of their greater sensitivity in identifying intra-retinal pathology (i.e. retinal drusen that increase in size and volume in AMD), the critical choridal blood supply and the macular pigment optical density distribution often diminished in AMD patients. 22 Traditional colored fundus photographs, were also derived through simple wavelength recombination. Retinal Pigment Epithelium (RPE) auto fluorescent images were obtained with the Canon CX1 ® clinical fundus camera (Canon Medical, USA) employing 555 +/-25 nm excitation / 640 nm barrier filters. Excessive accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases including AMD. 23,24 In vivo Retinal Spectral Domain Optical Coherence Tomographic (SD OCT) images were obtained with the OptoVue RTVue ® instrument (Freemont, CA). Visual Function was measured with several clinical instruments. 20, 21, 26, 27 Clinical best-refracted Snellen acuity was taken in a semi-darkened room using a digital projection system (M & S Technologies, Skokie, IL). The contrast sensitivity function (CSF), a measure of how an eye sees large objects (low spatial frequencies @ 1.5 and 3 cycles / degree) and small objects such as Snellen letters (higher spatial frequencies i.e. 18 cycles / degree) – x axis, at differing contrasts – y axis. 41 The area under the curve of the resulting CSF at 5 spatial frequencies was measured with The Vision Function Analyzer ® (Stereo Optical, Chicago, IL ) with best refraction. Photo-stress glare recovery in seconds to a bright flash, a measure AMD induced retinal – RPE dysfunction, was measured with a clinical Macular Disease Detection MDD-2 ® device. (Health Research Science, LLC, Lighthouse Pt, FL) 28 CASE 1 : A 75 y/o with L foveal occult mb with better VA in 5 days and a driver’s license after 7 days. factors that determine risk in complex diseases remain unknown, leading to an interest in nongenetic factors that contribute to disease. Epigenetics is an emerging field, studying changes in the regulation of gene expression that are not a result of changes to the primary DNA sequence itself” (Nickells RW, PhD; Shannath L. Merbs, MD, , The Potential Role of Epigentics in Ocular Diseases, Arch Ophthalmol. 2012;130(4):508-9). RV+ is used in cardiology to prevent reperfusion injury. It was suggested to retinal patients because its components HIF-1 & VEGF genes (microRNA 21, 20b, 539); ↑ Nrf2 endogenous Blood clotting (platelet stickiness); ↑ Vasodilation (nitric oxide); ↑ Metal chelation (iron, Cell adhesion (platelets, microbes, tumor) and ↓ Calcification (i.e. Bruch’s membrane). Octogenarian AMD patients who take 1 oral capsule of RV+ per day often quickly demonstrate improved vision, whether or not they have atrophic or proliferative It is the control of metals which may exert the greatest influence over the epigenome. The use of low-dose SMWt molecules appears to produce a profound hormesis effect, while high- It should not be used in premenopausal females or children, who require minerals to prevent anemia and as pro-growth factors respectively. VEGF-A antibody therapy is not a panacea, as only 1/3rd third of patients recover driving vision and 1/6 th progress to registered blindness. Thus, there is interest in developing alternative or adjunct therapeutic strategies. Moreover, stem cells experimentally injected into animal hearts following a heart attack fail to survive, but instillation of RV facilitates stem cell survival and replication. This has obvious application to retinal stem cell research.. At sites of injury the eyes and other organs naturally generate stem cells which presumably would survive better if RV or RV+ is used. Stem cells may not need to be injected. Richer SP, Stiles W. Molecular Medicine in Ophthalmic Care. Optom 2009; 80: 695- 71. Richer SP, Invited Presentation, 10th Annual International Conference on Free Radical Research, India, Chennai, India on 9 January 2011. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 2005; 16: 449- Baur J. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev 2010; 131: 261-9. Vang O et al. What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol. PLoS ONE 2011; 6: Pezzuto JM. The phenomenon of resveratrol: redefining the virtues of promiscuity. Ann NY Acad Sci 2011; 1215: 123-30. Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment, Ray PS et al. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Rad Biol Med 1999; Das DK, Maulik G. Review, Resveratrol in Cardiac Protection – A therapeutic promise of alternative medicine. Molec Interv 2006; 6: 36-47. Hung L, Chen J, Huang SS, Lee R, and Su M. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res Ignatowicz E, Baer-Dubowska W. Resveratrol, a natural chemo preventive agent against degenerative diseases. Pol J Pharmacol 2001; 53: 557– Bertelli AA et al. Resveratrol, a component of wine and grapes, in the prevention of kidney disease. Ann NY Acad Sci 2002; 957: 230–8. Bhat KP, Kosmeder II JW, Pezzuto JM. Biological effects of resveratrol. Antiox Redox Sign 2001; 3:1041–64. Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but 40: 1066-75. TY. Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) mice. Invest Ophthalmol Vis Sci 2011; 52: 2809-16. J.L. Barger 1, T. Kayo 1,T.D. Pugh 1, T.A. Prolla 2*, R. Weindruch, Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart, Exp Gerontology Sept 4; 3(9), 859-66. J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early Vis Sci 2011; 52: 1606-12. Richer SP et al. Age-Related Macular Degeneration Study Group, Multicenter ophthalmic and nutritional age-related macular degeneration study J Am Optom Assoc 1996; 67: 30-49. A placebo-controlled, double blind, randomized trial of lutein and antioxidant supplementation for the treatment of age related macular degeneration: the Lutein Antioxidant Supplementation Trial. Optom 2004; 75: 216-30. Richer SP, Stiles W, Graham-Hoffman K, Levin M, Ruskin D, Wrobel J, Park DW, Thomas C. Randomized, double-blind, placebo-controlled study of zeaxanthin and visual function in patients with atrophic age-related macular degeneration: The Zeaxanthin and Visual Function Study 2011; 82(11):687-680. Jayakrishna Ambati, Age-Related Macular Degeneration and the Other Double Helix The Cogan Lecture, Investigative Ophthalmology Visual SFRR Meeting, Chennai, India 9 January 2011. Bernstein PS, Delori FC, Richer SP, van Kuijk FJ, Wenzel AJ. The value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other retinal disorders. Vision Res 2010; 50: 716-28. FG. Fundus autofluorescence and progression of age-related macular degeneration. 25. Bindewald A, Bird AC, Dandekar SS, Dolar-Szczasny J et al. Classification of Fundus Autofluorescence Patterns in Early Age-Related Macular Disease. Invest Ophthalmol Vis Sci 2005; 46: 3309-14. 26. Richer SP et al. Age-Related Macular Degeneration Study Group, Multicenter ophthalmic and nutritional age-related macular degeneration study -part 2: antioxidant intervention & conclusions. J Am Optom Assoc 1996; 67: 30-49. 27. Midena E, Degli Angeli C, Blarzino MC, Valenti M et al. Macular function impairment in eyes with early AMD. Invest Ophthalmol Vis Sci 1997; 38:469-77. 28. Newsome DA, Nagreiro M. Reproducible measurement of macular light flash recovery time using a novel device can indicate the presence and worsening of macular diseases. Curr Eye Res 2009; 34: 162-70. Author Disclosure Information: Stuart P. Richer, Travel (R); William R. Stiles, None; Lawrence Ulanski, II, None; Carla Thomas, Resveratrol Partners (C) www.Longevinex.com 9/12/11 10/4/11 Case 1: Better vision in 5 days and a driver’s license after 7 capsules. 75 y/o Vietnam Veteran w prolonged post-traumatic stress disorder, diabetes and dry AMD x 10 yrs who developed wet AMD in his L eye 6 months ago but adamantly refused repeated requests to do invasive diagnostic (fluorescein angiography) and intravitreal Lucentis® injections or any other type of injection(s). Patient was deemed to have a probable L foveal occult membrane by the retinal specialist (LU). Veteran reported “An improvement in 5 days in my L eye, somewhat in the R eye, and took the eye exam at the motor vehicle department and passed after 7 days on RV+“. The 10 SDOCT paired cross-sectional retinal scans – 5 Horizontal and 5 Vertical (left) show diminution of sub retinal fluid and restoration of foveal architecture. The spectral 875 nm images (right) shows diminished neovascularization and widening of Haller’s vasculature. Visual acuity improved approximately 2 lines with re-establishment of rudimentary contrast sensitivity L eye and a 28% increase in contrast sensitivity in his less involved R eye. 18 days Baseline Baseline 18 days Widening choroidal vasculature Diminishing neovascularization CASE 2: 86 year old male with obesity, hypertension, Barrett’s esophagitis, prostate cancer, presbycusis, vitamin D deficiency and Herpes Zoster effecting the patient’s left cornea. The patient also had wet AMD right eye with anterior retinal edema deemed untreatable by his private retinal specialist. Baseline visual acuity was 20/100 R eye with a dense temporal parafoveal central scotoma and impaired CSF beyond 3 cycles/degree. The left eye was worse with HM vision owing in part to longstanding Herpes Zoster keratitis. Fig 2a,b After 3 weeks taking oral RV+ daily, he reported being able to read normal size reading print. The 6 and 12 week examinations show 100% resolution of his central scotoma, 7 lines improvement in visual acuity, a 250% improvement in his AUC (area under the curve) integrated contrast sensitivity function. Fig 2c depicts no change in his low macular pigment density Fig 2d SDOCT depicts progressive flattening of the retina and near resolution of central anterior foveal retinal edema by 12 weeks. Fig 2e depicts increased 850nm +/- 25 nm near IR choroidal luminescence associated with widening of chroroidal vasculature denoting better choroidal perfusion. Fig 2f Corneal topography has improved in each eye over the 6 week period suggesting better corneal epithelial health. Fig 2g The audiologist noted a 5 db non- clinically significant hearing increase in each ear at multiple hearing frequencies. Pending 3 rd hearing evaluation. 06/28/11 8/11/11 Glare Recovery: MDD2- Red 06/28/11 Right Eye: 35 Sec. Left Eye: Not Possible 8/11/11 Right Eye: 18 Sec. Left Eye: Not Possible Glare Recovery: KOWA Fig.2b Measures: Peak = 0.33 Volume = 1813 2 DEG Mean MP = 0.22 Measures: Peak = 0.29 Volume = 1294 2 DEG Mean MP = 0.16 Fig.2c 06/28/11 8/11/11 Right Eye Only Fig. 2d Fig.2e 8/11/11 06/28/11 IR-Choroid – 6/28/11 IR-Choroid –8/11/11 Fig.2f Fig.2g 06/28/11 8/11/11 Fig.2a 06/28/11 8/11/11 20/100 20/30 20/100 20/30 9/27/11 9/27/11 9/27/11 Right Eye: 18 Sec. Left Eye: Not Possible Glare Recovery: KOWA 9/27/11 Measures: Peak = 0.34 Volume = 1424 2 DEG Mean MP = 0.20 IR-Choroid – 9/27/11 9/27/11 20/30 20/30 9/27/11 Red = elevation Blue = depression Resolved central scotomas ↑choroidal perfusion Better hearing Better corneal topography Resolved anterior and posterior retinal edema CASE 2 : 86 y/o with medically unresponsive L retinal edema, reads at 21 days and has 7 lines better VA. CASE 3: Better vision and blood pressure without drugs or needles 88 year old female with , bilateral wet AMD (20/60 R; 20/150 L) , chronic L dacryocystitis / keratitis and hospitalized for 2 years for unstable systemic hypotension and syncope. She also has a 40 year history of migraines. She repeatedly refused anti- VEGF therapy offered by her MD and retinal specialist and was started on RV+ compassionately. At 4 days she began to see faces with her R eye. Fig 5a 2 week visit depicts 3 measures of improved vision each eye: 1) 2 lines better visual acuity; 2) 100% increase in contrast sensitivity R eye and now nominal contrast detection left eye and 3) bilateral scotoma resolution. Macular pigment optical density remained equivocal. Fig 5b Serial horizontal registered SD OCT scans depicts clearing of central subfoveal fluid R retina beginning at 2 weeks, with continuous improvement in the photoreceptor- RPE disruption index at the 2 week and 1 month examinations. There were lesser effects in her L eye. Fig 5c depicts systemic BP (sitting and standing) 5 months before and 5 months after starting RV+. Note long-term stabilization of BP for 5 months, (since starting RV+) as reflected in tighter systolic and diastolic standard deviations. Notably, this patient has not had a single episode of syncope or migraine since starting RV+. Base Fig 5a Baseline 2 weeks Right Eye - Baseline Right Eye – 2 weeks Fig 5b Fig 5c 20/40 20/100 Right Eye – 1 month Right Eye – 3 month 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 10/20/10 5:25 … 10/26/10 21:00 … 11/02/10 7:00 … 11/09/10 12:05 … 11/16/10 14:29 … 11/21/10 21:05 … 11/27/10 8:13 … 12/2/10 5:30 … 12/7/10 12:00 … 12/12/10 21:05 … 12/17/10 12:00 … 12/23/10 12:00 … 12/28/10 12:00 … 01/02/11 20:35 … 01/07/11 21:15 … 01/13/11 5:40 … 01/19/11 21:15 … 01/25/11 5:25 … 01/31/11 5:45 … 02/05/11 12:00 … 02/11/11 12:15 … 02/17/11 13:49 … 02/23/11 5:45 … 02/28/11 21:05 … 03/06/11 5:50 … 03/11/11 20:55 … 03/17/11 12:00 … Blood Pressure 5 months PRIOR to Starting Resveratrol Systolic Avg 126 SD 13 Diastolic Avg 63 SD 7 Systolic Diastolic SITTING 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 3/20/2011 5:20 Sitting 3/24/2011 5:30 Sitting 3/27/2011 12:00 Sitting 3/31/2011 7:29 Sitting 4/4/2011 11:35 Sitting 4/8/2011 6:43 Sitting 4/11/2011 6:27 Sitting 4/14/2011 21:00 Sitting 4/20/2011 5:25 Sitting 4/23/2011 12:00 Sitting 4/26/2011 12:00 Sitting 4/29/2011 21:05 Sitting 5/03/2011 21:00 Sitting 5/07/2011 13:22 … 5/11/2011 11:30 Sitting 5/15/2011 21:00 Sitting 5/20/2011 7:18 Sitting 5/23/2011 21:00 Sitting 5/27/2011 21:00 Sitting 5/31/2011 11:30 Sitting 6/03/2011 21:00 Sitting 6/07/2011 11:56 Sitting 6/10/2011 11:30 Sitting 6/14/2011 5:25 Sitting 6/17/2011 11:30 Sitting 6/21/2011 12:00 Sitting 6/25/2011 5:40 Sitting 6/28/2011 12:00 Sitting 7/01/2011 21:20 Sitting 7/05/2011 11:30 Sitting 7/08/2011 21:05 Sitting 7/12/2011 19:30 Sitting 7/15/2011 20:50 Sitting 7/19/2011 5:45 Sitting Blood Pressure 5 Months AFTER Starting Resveratrol Systolic Avg 123 SD 11 Diastolic Avg 60 SD 6 Diastolic Systolic SITTING 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 10/20/10 5:25 … 10/26/10 21:00 … 11/02/10 7:00 … 11/09/10 12:05 … 11/16/10 14:29 … 11/21/10 21:05 … 11/27/10 8:13 … 12/2/10 5:30 … 12/7/10 12:00 … 12/12/10 21:05 … 12/17/10 12:00 … 12/23/10 12:00 … 12/28/10 12:00 … 01/02/11 20:35 … 01/07/11 21:15 … 01/13/11 5:40 … 01/19/11 21:15 … 01/25/11 5:25 … 01/31/11 5:45 … 02/05/11 12:00 … 02/11/11 12:15 … 02/17/11 13:49 … 02/23/11 5:45 … 02/28/11 21:05 … 03/06/11 5:50 … 03/11/11 20:55 … 03/17/11 12:00 … Blood Pressure 5 months PRIOR to Starting Resveratrol Systolic Avg 112 SD 15 Diastolic Avg 60 SD 7 Systolic Diastolic STANDING 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 3/20/2011 5:25 … 3/24/2011 … 3/28/2011 7:53 … 4/1/2011 7:02 … 4/6/2011 5:55 … 4/9/2011 20:55 … 4/13/2011 5:35 … 4/19/2011 … 4/23/2011 … 4/27/2011 5:50 … 4/30/2011 … 5/05/2011 5:30 … 5/09/2011 5:35 … 5/14/2011 5:35 … 5/18/2011 … 5/23/2011 8:06 … 5/27/2011 … 5/31/2011 … 6/04/2011 6:46 … 6/08/2011 5:55 … 6/11/2011 … 6/15/2011 … 6/19/2011 … 6/24/2011 5:35 … 6/27/2011 … 7/01/2011 … 7/05/2011 … 7/09/2011 5:50 … 7/13/2011 … 7/16/2011 … Blood Pressure 5 months AFTER Starting Resveratrol Systolic Avg 114 SD 12 Diastolic Avg 59 SD 5 Diastolic Systolic STANDING CASE 3 : 88 y/o w AMD refusing Lucentis® and sees faces and reads magazines at 14 days.
Transcript of 3 University of Illinois (UIC), Retina Service, Eye and...
PURPOSE Spontaneous remissions from AMD suggest the human retina has large regenerative capacity even in
advanced age In late 2009 we reported resolution of lipofuscin and 5 measures of visual function in an 80-
yo male with atrophic AMD placed on a stabilized 1 capsule day low-dose resveratrol (RV+) based
supplement called Longevinexreg 1 This OTC product has 7 years of consumer use and 10 international
papers wwwlongevinexcom In India we presented additional atrophic AMD case reports of retinal
remodeling resolving AF lipofuscin and visual restoration in weeks months of RV+ use 2 We extend these
observations to 3 compassionate ndash care cases of wet AMD Taken together this poster establishes the
epigenetic framework for further evaluation of RV+ either on its own or as a powerful OTC nutritional adjunct
to existing retinal injections Our limited n but careful (structure + function) observations suggest that RV+ is
capable of restoring the architecture health and vitality of the entire (retina + choroid) even in octogenarians
Additional case reports are in peer review
Resveratrol (RV) was discovered in the 1940s as an anti-hyperlipidemic medicinal component of grapes and
red wine (think ldquoFrench Red Wine Paradoxrdquo) also extracted from the dried roots of the weed Polygonum
cuspidatum In the modern era RV has been characterized as a promiscuous small molecular weight (SMWt)
molecule demonstrating broad-spectrum cell receptor modulation protection against mt DNA mutations
SIRTUIN activation deactivation and epigenetic microRNA activity (The ldquoGuiding Handrdquo of the genomerdquo) 3 4
Figure 1ab Known gene targets of the ldquopromiscuousrdquo RV molecule and Medical Applications (Pezzuto JM
and health applicationsThe phenomenon of resveratrol redefining the virtues of promiscuity Ann NY Acad
Sci 2011 1215 123-30) RV also activates miRNA 539 (hypoxia inducible factor) and down regulates miRNA
20b(angiogenesis) in the heart thru epigenetic gene networking (more so RV+)
The first international conference on the biology of RV two major literature reviews and a published human
clinical trial in Japan all occurred recently (wwwresveratrol2010com) 5 6 7 There are nearly 3500 papers
concerning some aspect of RVrsquos ability to inhibit carcinogenesis at all 3 stages of initiation promotion and
progression 6 It is also known that RV and RV+ prevent reperfusion injury in animal models of stressed
cardiac tissue probably through preconditioning 8 9 In fact RV protects most vital organs including the
kidney heart and brain from ischemic reperfusion injury 9 - 15
RESVERTROL PROPERTIES
bullNon-flavanoid polyphenol phytoalexin toxin (increased when plants are stressed)
bull1mg trans resveratrol in 5-ounce glass of best red wine
bullSmall molecule MWt = 228 Daltons (able to enter cells)
bullOral absorption ndash approx 70 thru small intestine
bullHalf Life 14 minutes if not metabolized in the liver
BIOAVALABILITY
bullHalf life extended to 9 hrs via hepatic sulfonation or glucuronidation
bullReleased by glucuronidase enzyme at site of infection inflammation or malignancy
I RV lsquos MULTIPLE SALUTARY BIOLOGIC ACTIONS
bullANTI INFLAMMATORY darr COX-2 C-reactive protein TNF
bullENDOGENOUS ANTI-OXIDANT via NRF2 transcription factor (uarr SOD CAT GSH)
bullPRO- VASCULAR Anti-cholesterol anti-hypertensive anti-platelet anti-plaque
bullPRO-NEURAL Antidepressant (MAO inhibitor) anti-brain plaque (darrbeta amyloid)
bullPRO-METABOLISM Rescues pancreatic beta cells darr blood sugar
bullANTICARCINOGENIC Against all 3 stages of CA
bullGERMICIDAL Anti-bacterial anti-fungal and anti ndash viral
RV inhibits neovascularization in rodent retina 16 Instead of blocking the doorway to the VEGF gene with a
monoconal antibody RV downregulates by 189 x the microRNA 20b controlling the VEGF gene 17 RVsrsquo
additional vascular attributes have special clinical significance and promise for AMD due to the debilitating
eye diseasesrsquo association with cardiovascular disease and accelerated choroidal thinning 1518
RV+ adds synergistic stabilized SMWt molecules that cross the blood-retinal barrier These include
polyphenolic red wine molecules (ie quercetin ferulic acid) IP6 and Vitamin D
II RICE BRAN IP6 (INOSITOL HEXAPHOSPHATE) PROPERTIES
bullDivalent labile metal chelator against intracellular age accumulating CU++ and FE++
bullTheoretical dissolves CA++ in Blood Vessels and Bruchrsquos membrane
bullRequired for double-strand DNA break repair
III VITAMIN D
bullPotent anti-inflammatory
bullVascular support (decalcifying agent)
bullAnti-neovascular properties
bullGene regulator ie conversion of IP6 to IP3
Science points to loss of control over divalent metals in aging particularly in nervous systems like the eye and
brain The existence within nature of synergistic mineral chelating vascular enhancing cytoprotective SMWt
molecules provides an impetus beyond the restorative vitamin mineral factors identified in the LAST ZVF
AREDS and AREDS II studies 19 20 21 Example RV+ up- regulates HIF1 miRNA 539 (anti-hypoxia inducible
factor 1) by 315 x or double that of RV while downndashregulating anti-angiogenic miRNA 20b by 1367 x some 7x
greater than RV 17
Observation of Human Retinal Remodeling in Octogenarians with Resveratrol+ Stuart P Richer 1 2 3 William R Stiles 1 Lawrence Ulanski II 3 Carla Thomas 1 1Eye Clinic 112E Capt James Lovell Fed Health Care Center North Chicago IL 2RFUMS Chicago Medical School Department Preventive and Family Medicine North Chicago IL 3 University of Illinois (UIC) Retina Service Eye and Ear Infirmary Chicago IL EMAIL StuartRicher1VAGOV RESEARCH DONATIONS wwweyedoctorrichercom
METHODS The OTC supplement Logevinexreg was suggested to patients with dry and wet AMD who progressed on
AREDS II type supplements or refused intra-vitreal injections Patients were clinically followed with high
resolution 10 raster SD OCT (OptoVue Fremont CA) ) amp vision function tests Notations were made in the
medical chart regarding the patients willingness to take a nutriceutical pill every day and the fact the
patient was out of options by retinal specialist consultation Nutriceuticals are considered an
extension of food under FDA law and are confined for labeling purposes to promoting health rather
than treating or preventing disease Patients secured the RV+ on their own except in the case of
inpatients who secured the product under the auspices of both the Chief of Pharmacy and Chief of Staff at of
the James Lovell Federal Health Care Center
Retinal Structure Retinal Spectral Separation Images were obtained with an ARIS reg - automated retinal
imaging system 110 (Visual Pathways Inc Prescott AZ) camera Compared with traditional fundus
photographs we use spectral separation images for AMD patients because of their greater sensitivity in
identifying intra-retinal pathology (ie retinal drusen that increase in size and volume in AMD) the critical
choridal blood supply and the macular pigment optical density distribution often diminished in AMD patients 22
Traditional colored fundus photographs were also derived through simple wavelength recombination
Retinal Pigment Epithelium (RPE) auto fluorescent images were obtained with the Canon CX1 reg clinical
fundus camera (Canon Medical USA) employing 555 +-25 nm excitation 640 nm barrier filters Excessive
accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common
downstream pathogenetic pathway in various hereditary and complex retinal diseases including AMD 2324 In
vivo Retinal Spectral Domain Optical Coherence Tomographic (SD OCT) images were obtained with the
OptoVue RTVue reg instrument (Freemont CA)
Visual Function was measured with several clinical instruments 20 21 26 27 Clinical best-refracted Snellen
acuity was taken in a semi-darkened room using a digital projection system (M amp S Technologies Skokie IL)
The contrast sensitivity function (CSF) a measure of how an eye sees large objects (low spatial frequencies
15 and 3 cycles degree) and small objects such as Snellen letters (higher spatial frequencies ie 18
cycles degree) ndash x axis at differing contrasts ndash y axis41 The area under the curve of the resulting CSF at 5
spatial frequencies was measured with The Vision Function Analyzer reg (Stereo Optical Chicago IL) with
best refraction Photo-stress glare recovery in seconds to a bright flash a measure AMD induced retinal ndash
RPE dysfunction was measured with a clinical Macular Disease Detection MDD-2 reg device (Health
Research Science LLC Lighthouse Pt FL) 28
CASE 1 A 75 yo with L foveal occult
mb with better VA in 5 days and a
driverrsquos license after 7 days
CONCLUSIONS ldquoMost factors that determine risk in complex diseases remain unknown leading to an interest in nongenetic factors
that contribute to disease Epigenetics is an emerging field studying changes in the regulation of gene expression
that are not a result of changes to the primary DNA sequence itselfrdquo (Nickells RW PhD Shannath L Merbs MD
PhD The Potential Role of Epigentics in Ocular Diseases Arch Ophthalmol 2012130(4)508-9)
RV+ is used in cardiology to prevent reperfusion injury It was suggested to retinal patients because its components
are known to darr Inflammation (COX-2 CRP) darr HIF-1 amp VEGF genes (microRNA 21 20b 539) uarr Nrf2 endogenous
antioxidants (glutathione) darr Blood clotting (platelet stickiness) uarr Vasodilation (nitric oxide) uarr Metal chelation (iron
copper) darr Oxidation peroxidation darr Cell adhesion (platelets microbes tumor) and darr Calcification (ie Bruchrsquos
membrane) Octogenarian AMD patients who take 1 oral capsule of RV+ per day often quickly demonstrate
anatomic retinal regeneration as well as bilateral improved vision whether or not they have atrophic or proliferative
disease
RV+ has powerful chelating properties It is the control of metals which may exert the greatest influence over the
epigenome The use of low-dose SMWt molecules appears to produce a profound hormesis effect while high-
doses produce a pro-oxidant toxic effect It should not be used in premenopausal females or children who require
minerals to prevent anemia and as pro-growth factors respectively
AntindashVEGF-A antibody therapy is not a panacea as only 13rd third of patients recover driving vision and 16th
progress to registered blindness Thus there is interest in developing alternative or adjunct therapeutic strategies 22 Moreover stem cells experimentally injected into animal hearts following a heart attack fail to survive but
instillation of RV facilitates stem cell survival and replication This has obvious application to retinal stem cell
research At sites of injury the eyes and other organs naturally generate stem cells which presumably would
survive better if RV or RV+ is used Stem cells may not need to be injected
REFERENCES 1 Richer SP Stiles W Molecular Medicine in Ophthalmic Care Optom 2009 80 695- 71
2 Richer SP Invited Presentation 10th Annual International Conference on Free Radical Research India Chennai India on 9 January 2011
3 Signorelli P Ghidoni R Resveratrol as an anticancer nutrient molecular basis open questions and promises J Nutr Biochem 2005 16 449-
66
4 Baur J Resveratrol sirtuins and the promise of a DR mimetic Mech Ageing Dev 2010 131 261-9
5 Vang O et al What Is New for an Old Molecule Systematic Review and Recommendations on the Use of Resveratrol PLoS ONE 2011 6
e1988
6 Pezzuto JM The phenomenon of resveratrol redefining the virtues of promiscuity Ann NY Acad Sci 2011 1215 123-30
7 Fujitaka et al Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment
Nutr Res 2011 Nov31(11)842-7
8 Ray PS et al The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury Free Rad Biol Med 1999
27160ndash9
9 Das DK Maulik G Review Resveratrol in Cardiac Protection ndash A therapeutic promise of alternative medicine Molec Interv 2006 6 36-47
10 Hung L Chen J Huang SS Lee R and Su M Cardioprotective effect of resveratrol a natural antioxidant derived from grapes Cardiovasc Res
2000 47 549ndash55
11 Ignatowicz E Baer-Dubowska W Resveratrol a natural chemo preventive agent against degenerative diseases Pol J Pharmacol 2001 53 557ndash
69
12 Bertelli AA et al Resveratrol a component of wine and grapes in the prevention of kidney disease Ann NY Acad Sci 2002 957 230ndash8
13 Bhat KP Kosmeder II JW Pezzuto JM Biological effects of resveratrol Antiox Redox Sign 2001 31041ndash64
14 Das S Fraga CG Das DK Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling but
does not involve NFkappaB Free Radic Res 2006 40 1066-75
15 Sun C Klein R Wong TY Age-related macular degeneration and risk of coronary heart disease and stroke the Cardiovascular Health Study
Ophthalmol 2009 116 1913-9
16 Hua J et al Resveratrol inhibits pathologic retinal neovascularization in Vldlr(--) mice Invest Ophthalmol Vis Sci 2011 52 2809-16
17 JL Barger 1 T Kayo 1TD Pugh 1 TA Prolla 2 R Weindruch Short-term consumption of a resveratrol-containing nutraceutical mixture
mimics gene expression of long-term caloric restriction in mouse heart Exp Gerontology Sept 4 3(9) 859-66
18 Mullins RF Johnson MN Faidley EA Skeie JM Huang J Choriocapillaris vascular dropout related to density of drusen in human eyes with early
age-related macular degeneration Invest Ophthalmol Vis Sci 2011 52 1606-12
19 Richer SP et al Age-Related Macular Degeneration Study Group Multicenter ophthalmic and nutritional age-related macular degeneration study
-part 2 antioxidant intervention amp conclusions J Am Optom Assoc 1996 67 30-49
20 Richer SP et al A placebo-controlled double blind randomized trial of lutein and antioxidant supplementation for the treatment of age related
macular degeneration the Lutein Antioxidant Supplementation Trial Optom 2004 75 216-30
21 Richer SP Stiles W Graham-Hoffman K Levin M Ruskin D Wrobel J Park DW Thomas C Randomized double-blind placebo-controlled
study of zeaxanthin and visual function in patients with atrophic age-related macular degeneration The Zeaxanthin and Visual Function Study
(ZVF) FDA IND 78 973 Optometry 2011 82(11)687-680
22 Jayakrishna Ambati Age-Related Macular Degeneration and the Other Double Helix The Cogan Lecture Investigative Ophthalmology Visual
Science April 5 2011 vol 52 no 5 2166-2169 SFRR Meeting Chennai India 9 January 2011
23 Bernstein PS Delori FC Richer SP van Kuijk FJ Wenzel AJ The value of measurement of macular carotenoid pigment optical densities and
distributions in age-related macular degeneration and other retinal disorders Vision Res 2010 50 716-28
24 Schmitz-Valckenberg S Fleckenstein M Scholl HP Holz FG Fundus autofluorescence and progression of age-related macular degeneration
Surv Ophthalmol 2009 Jan-Feb 54 96-117
25 Bindewald A Bird AC Dandekar SS Dolar-Szczasny J et al Classification of Fundus Autofluorescence Patterns in Early Age-Related Macular
Disease Invest Ophthalmol Vis Sci 2005 46 3309-14
26 Richer SP et al Age-Related Macular Degeneration Study Group Multicenter ophthalmic and nutritional age-related macular degeneration study
-part 2 antioxidant intervention amp conclusions J Am Optom Assoc 1996 67 30-49
27 Midena E Degli Angeli C Blarzino MC Valenti M et al Macular function impairment in eyes with early AMD Invest Ophthalmol Vis Sci 1997
38469-77
28 Newsome DA Nagreiro M Reproducible measurement of macular light flash recovery time using a novel device can indicate the presence and
worsening of macular diseases Curr Eye Res 2009 34 162-70
Author Disclosure Information Stuart P Richer Travel (R) William R Stiles None Lawrence Ulanski II
None Carla Thomas Resveratrol Partners (C) wwwLongevinexcom
91211 10411
Case 1 Better vision in 5 days and a driverrsquos license after 7
capsules 75 yo Vietnam Veteran w prolonged post-traumatic stress
disorder diabetes and dry AMD x 10 yrs who developed wet AMD in his
L eye 6 months ago but adamantly refused repeated requests to do
invasive diagnostic (fluorescein angiography) and intravitreal Lucentisreg
injections or any other type of injection(s) Patient was deemed to have
a probable L foveal occult membrane by the retinal specialist (LU)
Veteran reported ldquoAn improvement in 5 days in my L eye somewhat in
the R eye and took the eye exam at the motor vehicle department and
passed after 7 days on RV+ldquo The 10 SDOCT paired cross-sectional
retinal scans ndash 5 Horizontal and 5 Vertical (left) show diminution of sub
retinal fluid and restoration of foveal architecture The spectral 875 nm
images (right) shows diminished neovascularization and widening of
Hallerrsquos vasculature Visual acuity improved approximately 2 lines with
re-establishment of rudimentary contrast sensitivity L eye and a 28
increase in contrast sensitivity in his less involved R eye
18 daysBaseline Baseline 18 days
Widening choroidal
vasculature
Diminishing neovascularization
CASE 2 86 year old male with obesity hypertension Barrettrsquos
esophagitis prostate cancer presbycusis vitamin D deficiency
and Herpes Zoster effecting the patientrsquos left cornea The patient
also had wet AMD right eye with anterior retinal edema deemed
untreatable by his private retinal specialist Baseline visual acuity
was 20100 R eye with a dense temporal parafoveal central
scotoma and impaired CSF beyond 3 cyclesdegree The left eye
was worse with HM vision owing in part to longstanding Herpes
Zoster keratitis Fig 2ab After 3 weeks taking oral RV+ daily he
reported being able to read normal size reading print The 6 and 12
week examinations show 100 resolution of his central scotoma 7
lines improvement in visual acuity a 250 improvement in his AUC
(area under the curve) integrated contrast sensitivity function Fig
2c depicts no change in his low macular pigment density Fig 2d
SDOCT depicts progressive flattening of the retina and near
resolution of central anterior foveal retinal edema by 12 weeks Fig
2e depicts increased 850nm +- 25 nm near IR choroidal
luminescence associated with widening of chroroidal vasculature
denoting better choroidal perfusion Fig 2f Corneal topography has
improved in each eye over the 6 week period suggesting better
corneal epithelial health Fig 2g The audiologist noted a 5 db non-
clinically significant hearing increase in each ear at multiple hearing
frequencies Pending 3rd hearing evaluation
06281181111
Glare Recovery MDD2- Red
062811Right Eye 35 Sec
Left Eye Not Possible
81111Right Eye 18 Sec
Left Eye Not Possible
Glare Recovery KOWA
Fig2b
MeasuresPeak = 033Volume = 18132 DEG Mean MP = 022
MeasuresPeak = 029Volume = 12942 DEG Mean MP = 016
Fig2c062811 81111
Right Eye Only
Fig 2d
Fig2e
81111062811
IR-Choroid ndash 62811 IR-Choroid ndash81111
Fig2f
Fig2g
062811 81111
Fig2a062811 81111
201002030
20100 2030
92711
92711
92711Right Eye 18 Sec
Left Eye Not Possible
Glare Recovery KOWA
92711
MeasuresPeak = 034Volume = 14242 DEG Mean MP = 020
IR-Choroid ndash 92711
92711
2030
2030
92711
Red = elevation
Blue = depression
Resolved central scotomas
uarrchoroidal perfusion
Better hearing
Better corneal topography
Resolved anterior and
posterior retinal edema
CASE 2 86 yo with medically
unresponsive L retinal
edema reads at 21 days and
has 7 lines better VA
CASE 3 Better vision and blood pressure withoutdrugs or needles 88 year old female with bilateral wetAMD (2060 R 20150 L) chronic L dacryocystitis keratitis and hospitalized for 2 years for unstablesystemic hypotension and syncope She also has a 40year history of migraines She repeatedly refused anti-VEGF therapy offered by her MD and retinal specialistand was started on RV+ compassionately At 4 days shebegan to see faces with her R eye Fig 5a 2 week visitdepicts 3 measures of improved vision each eye 1) 2lines better visual acuity 2) 100 increase in contrastsensitivity R eye and now nominal contrast detection lefteye and 3) bilateral scotoma resolution Macular pigmentoptical density remained equivocal Fig 5b Serialhorizontal registered SD OCT scans depicts clearing ofcentral subfoveal fluid R retina beginning at 2 weekswith continuous improvement in the photoreceptor- RPEdisruption index at the 2 week and 1 monthexaminations There were lesser effects in her L eye Fig5c depicts systemic BP (sitting and standing) 5 monthsbefore and 5 months after starting RV+ Note long-termstabilization of BP for 5 months (since starting RV+) asreflected in tighter systolic and diastolic standarddeviations Notably this patient has not had a singleepisode of syncope or migraine since starting RV+
Base
Fig 5a
Baseline 2 weeks
Right Eye - Baseline Right Eye ndash 2 weeksFig 5b
Fig 5c
2040
20100
Right Eye ndash 1 month Right Eye ndash 3 month
405060708090100110120130140150160170180190200
405060708090
100110120130140150160170180190200210220
10
20
10
5
25
hellip
10
26
10
2
10
0 hellip
11
02
10
7
00
hellip
11
09
10
1
20
5 hellip
11
16
10
1
42
9 hellip
11
21
10
21
05
hellip
11
27
10
81
3 hellip
12
21
0 5
30
hellip
12
71
0 1
20
0 hellip
12
12
10
21
05
hellip
12
17
10
12
00
hellip
12
23
10
12
00
hellip
12
28
10
12
00
hellip
01
02
11
20
35
hellip
01
07
11
21
15
hellip
01
13
11
54
0 hellip
01
19
11
21
15
hellip
01
25
11
52
5 hellip
01
31
11
54
5 hellip
02
05
11
12
00
hellip
02
11
11
12
15
hellip
02
17
11
13
49
hellip
02
23
11
54
5 hellip
02
28
11
21
05
hellip
03
06
11
55
0 hellip
03
11
11
20
55
hellip
03
17
11
12
00
hellip
Blood Pressure 5 months PRIOR to Starting ResveratrolSystolic Avg 126 SD 13Diastolic Avg 63 SD 7Systolic
DiastolicSITTING
405060708090100110120130140150160170180190200
405060708090
100110120130140150160170180190200
32
02
01
1 5
20
S
ittin
g
32
42
01
1 5
30
S
ittin
g
32
72
01
1 1
20
0 S
ittin
g
33
12
01
1 7
29
S
ittin
g
44
20
11
11
35
S
ittin
g
48
20
11
64
3 S
ittin
g
41
12
01
1 6
27
S
ittin
g
41
42
01
1 2
10
0 S
ittin
g
42
02
01
1 5
25
Sittin
g
42
32
01
1 1
20
0 S
ittin
g
42
62
01
1
12
00
Sittin
g
42
92
01
1
21
05
Sittin
g
50
32
01
1
21
00
Sittin
g
50
72
01
1
13
22
hellip
51
12
01
1
11
30
Sittin
g
51
52
01
1
21
00
Sittin
g
52
02
01
1
71
8 S
ittin
g
52
32
01
1
21
00
Sittin
g
52
72
01
1
21
00
Sittin
g
53
12
01
1
11
30
Sittin
g
60
32
01
1
21
00
Sittin
g
60
72
01
1
11
56
Sittin
g
61
02
01
1
11
30
Sittin
g
61
42
01
1
52
5 S
ittin
g
61
72
01
1
11
30
Sittin
g
62
12
01
1
12
00
Sittin
g
62
52
01
1
54
0 S
ittin
g
62
82
01
1
12
00
Sittin
g
70
12
01
1
21
20
Sittin
g
70
52
01
1
11
30
Sittin
g
70
82
01
1
21
05
Sittin
g
71
22
01
1
19
30
Sittin
g
71
52
01
1
20
50
Sittin
g
71
92
01
1
54
5 S
ittin
g
Blood Pressure 5 Months AFTER Starting Resveratrol Systolic Avg 123 SD 11Diastolic Avg 60 SD 6
Diastolic
Systolic SITTING
405060708090100110120130140150160170180190200
405060708090
100110120130140150160170180190200
10
20
10
5
25
hellip
10
26
10
2
10
0 hellip
11
02
10
7
00
hellip
11
09
10
1
20
5 hellip
11
16
10
1
42
9 hellip
11
21
10
21
05
hellip
11
27
10
81
3 hellip
12
21
0 5
30
hellip
12
71
0 1
20
0 hellip
12
12
10
21
05
hellip
12
17
10
12
00
hellip
12
23
10
12
00
hellip
12
28
10
12
00
hellip
01
02
11
20
35
hellip
01
07
11
21
15
hellip
01
13
11
54
0 hellip
01
19
11
21
15
hellip
01
25
11
52
5 hellip
01
31
11
54
5 hellip
02
05
11
12
00
hellip
02
11
11
12
15
hellip
02
17
11
13
49
hellip
02
23
11
54
5 hellip
02
28
11
21
05
hellip
03
06
11
55
0 hellip
03
11
11
20
55
hellip
03
17
11
12
00
hellip
Blood Pressure 5 months PRIOR to Starting Resveratrol Systolic Avg 112 SD 15Diastolic Avg 60 SD 7Systolic
DiastolicSTANDING
405060708090100110120130140150160170180190200
405060708090
100110120130140150160170180190200
32
02
01
1 5
25
hellip3
24
20
11
hellip3
28
20
11
75
3 hellip
41
20
11
7
02
hellip4
62
01
1 5
55
hellip4
92
01
1 2
05
5 hellip
41
32
01
1 5
35
hellip4
19
20
11
hellip4
23
20
11
hellip4
27
20
11
55
0 hellip
43
02
01
1 hellip
50
52
01
1 5
30
hellip5
09
20
11
53
5 hellip
51
42
01
1 5
35
hellip5
18
20
11
hellip5
23
20
11
80
6 hellip
52
72
01
1 hellip
53
12
01
1 hellip
60
42
01
1 6
46
hellip
60
82
01
1
55
5 hellip
61
12
01
1 hellip
61
52
01
1 hellip
61
92
01
1 hellip
62
42
01
1
53
5 hellip
62
72
01
1 hellip
70
12
01
1 hellip
70
52
01
1 hellip
70
92
01
1
55
0 hellip
71
32
01
1 hellip
71
62
01
1 hellip
Blood Pressure 5 months AFTER Starting Resveratrol Systolic Avg 114 SD 12Diastolic Avg 59 SD 5
Diastolic
SystolicSTANDING
CASE 3 88 yo w AMD
refusing Lucentisreg and
sees faces and reads
magazines at 14 days
