Glyconutrient Technology For Doctors

 2002 Dr. Dan

Daniel L Fouts

Over

$ 1.3 trillion

a year spent on U.S. HEALTH CARE.

That is more per person than any country in the world! That 1.3 Trillion Dollars bought us

# 37 In the world in ability to achieve vital health goals according to the World Health Organization’s World Health Report 2000

FOU R M AJOR CHA LLE NGES IN HEA LTH C ARE TOD AY  Chronic degenerative diseases -120+ million Americans  Autoimmune diseases 50+ million Americans  Infectious diseases multiple anti-biotic resistant strains

CHILDR EN A RE DEVELOP ING “A DULT ONS ET” DI SEASE S AT A FRIGHTE NING RATE  Hundreds of medical studies in the last few years are looking at viruses and bacteria as etiological factors in diabetes, heart disease and heart attacks.  Antibiotic resistant bacteria and rapidly mutating viruses indicate that our only reliable defense may be a strong immune system.  The incidence of cancer and autoimmune diseases occurring in children is increasing.

• HMO’s and PPO’s try to tell us how to treat and how much they are willing to pay. • Many patient’s have the opinion that prescription drugs can be: “too toxic, too expensive and too unreliable”.

• “50%

of patients had or were using some form of alternative medicine…” JAMA, July 2, 1997

• “…it

is no longer possible to get all of the nutrients necessary in our standard diet to maintain optimal health.” JAMA, July 2, 1997 • “243

million more visits to alternative providers than all types of traditional primary care physicians combined.” JAMA,

CONSIDER THIS 1998,(19)1548-1553 article:

from the above JAMA

An estimated $21.2 billion was spent on alternative providers with an estimated $12.2 billion out of pocket AND the public is spending more $ BILLIONS in cash on

MEDICAL EDUCATION

• Presenthealthcaresystemis EVENT-FOCUSED: HealthMaintenanceOrganizationsounds good- butinreality is only anattemptatearlier detectionof diseasewhenitis cheaper to treat. Wearegoodatprev entingdeath- not ve preservinghealth. After theevent, wedo somethingaboutit. • Complementary medicineis morePATIENT-FOCUSED: Meaning: DiseasePrevention, HealthPromotionandDiseaseManagementby usingthe“bestof bothworlds”- modern MedicineandNutraceutical Technology. • This results inimprovedpatientresponse, decreased expense and increasedfinancial rewards for thehealthcareprofessional.

Thehealthcareprofessional faces TWOCHALLENGES in incorporatingnutritioninto thedailypractice: 1. Greater degreeof Liability for recommendations - wemustbe confidentof thescientific validationof Nutraceutical products. 2. Thousands of products to choose- whichto use? Fewof us hav e ve thetimeor desirefor another “four years”of study to learnall aboutnutrition. WhatcanweSTART usingsafely and effectively intheofficeTOMORROW?

CARBO HYD RATE BAS ED TH ERAPE UTI C TEC HNO LOG Y AN D

GLYCO NUTR IENT TEC HNO LOG Y

THE CHANGING CARBOHYDRATE PARADIGM: FUEL SUPPLY BUILDING BLOCKS

VS

STRUCTURAL

One of the newest and most exciting areas of medical research is in the area of Glycobiology - carbohydrate technology.

Nutrition literature - carbohydrates are fuel supply only. fuel supply only.

Recent biochemistry - some special

“Super Carbs” are information rich molecules that control a vast array of

Glycocompounds 98 Intertech’s Business Development Forum on Bioactive Carbohydrates Glycocompounds 98 – the road to commercialization November 2-4, 1998 – Renaissance Vancouver Hotel – Vancouver BC  

Anti-Cancer, Anti-Infective,anti-Inflammatory, Anti-Biotic, Anti-Viral  

Get a comprehensive business and technical update from 22 leading organizations as they map a path for successful glyco-drug development – from discovery technologies and structure function analysis through pre-clinical screening, clinical trials and approvals. Along the way you’ll… receive the latest information on carbohydrateprotein interactions and their impact on the development of a new class of pharmaceutical compounds. Get updated on the biological Advanced Bioresearch Archer Daniels Midland Bayer AGLearn howBiosolutions functions of glycoconjugates and their receptors. to speed Blanver/Zetapharm Cantox Cargill Inc. CH2M up and capitalize on drug discovery by utlilizing advanced research and Hill Chemstar Products Ciba Chomerica production technologies. Get briefed on the commercial prospects and Cytec Industries Dai-Ichi Kogo Seiyaku Dow Chemical Drug current applications for carbohydrate-based therapeutics. Discovery Dupont FMC Corp Genentech Gist-Brocades Hercules Inc Hoffman-Laroche AG Johnson & Johnson ICI Lonza Inc. KPMG Peat Marwick McNeil Labs Maryland Biochemical Merck MIT Metsa-Serla Chemicals Monsanto Life Sciences National Starch Proctor and Gamble Phytogen Life Sciences Quest International Remy Industries Rhone-Poulenc Roche Bioscience Ross Laboratories SafeScience Inc. Searle Schwabe USFDA Stanford Univ. University of California Zeneca Warner-Jenkinson

  Glycoconj J 2000 Jul-Sep;17(7-9):553-65  

Progress in deciphering the information content of the 'glycome'-a crescendo in the closing years of the millennium. Feizi T. The Glycosciences Laboratory, Imperial College School of Medicine, Harrow, United Kingdom. The closing years of the second millennium have been uplifting for carbohydrate biology. Optimism that oligosaccharide sequences are bearers of crucial biological information has been borne out by the constellation of efforts of carbohydrate chemists, biochemists, immunochemists, and cell-

The direct involvement of specific oligosaccharide sequences in protein targeting and folding, and in mechanisms of infection, inflammation and immunity is now unquestioned. and molecular biologists.

With the emergence of families of proteins with carbohydrate-binding activities, assignments of information content for defined oligosaccharide

Dr. Mondoa’s book is helping to change the old biochemical paradigm that carbohydrates are just a fuel supply for the body. The tremendous potential of this special group of bioactive sugars promises to change

AnnuRevBiochem 1976; 45:217-37

Comparativeaspects ofglycoproteinstructure. Kornfeld R,KornfeldS. Glycoproteinshaveawidedistributioninnatureandserveavastnumber of functions. Thereareglycoproteinenzymes andhormones;glycoproteinsare foundinbloodand secretions, in cell membranes, and in connective tissue. Of all the biologically occurringmacromolecules theglycoproteins, which consistof carbohydratemoieties convalently linked to a polypeptide backbone, represent themost diverse group, rangingfromsubstances inwhichthecarbohydrate component represents less than 1% of the total weight to those in which It represents over 80% of thetotal. The proteoglycans, which areclassified separately from otherglycoproteinsandinclude thechondroitinsulfates,dermatansulfates, andheparinprimarilycarbohydrateinthe form of numerous heteropolysaccharide chains attachedto apolypeptidechainat closely spacedintervals. Thesugars thatcommonlyoccur inglycoproteins

include galactose, mannose, glucose, N-acetylglucosamine, N-acetylgalactosamine, sialicacids, fucose, and xylose. The proteoglycans also containvariousuronicandsulfatedamino sugars.

• Structural molecules - cell walls

- collagen, elastin fibrins matrix

mucins

-

immunoglobulins histocompatability antigens

-

- bone

• Lubricants and protective agent

• Immunolgic molecules

• Enzymes - proteases - nucleases

-

- mucous secretions

• Transport molecules for - vitamins

glycosidases factors

- clotting

• Cell attachment / recognition site

Science 2001 Mar 23;291(5512):2370-6

Glycosylation and the immune system. Rudd PM, Elliott T, Cresswell P, Wilson IA, Dwek RA. The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the

humoral immune system, all of the immunoglobulins

SCIENTIFIC DISCOVERIES continue to reveal new information about how our bodies maintain health, prevent disease, fight disease and how to slow the aging process. NEW KNOWLEDGE - NOW WHAT ? TWO OPTIONS to use the knowledge:

1. Try to develop a new drug that will block, alter, stimulate or inhibit so that we can “fix” the body or “cure” a problem. 2. Cooperate with what the body knows how, and is trying to do by supplying it with the raw material “tools” it is already

Recognizing the critical importance of a special group of carbohydrate molecules, the pharmaceutical industry has been spending billions of dollars in development of • “New carbohydrate technology will provide carbohydrate drugs. novel products for treating a broad range of diseases, including immune disorders, cancer, infectious diseases, and cardiovascular conditions.” Biotechnology, Vol 9, July 1991 “The day may not be far off when antiadhesive drugs, possibly in the form of pills that are both sugar-coated and sugar-loaded will be used to prevent and •

(Continued)

Currently over 15 pharmaceutical companies are in Phase I, II, or III drug testing of carbohydrate drugs for treating: • Influenza • various Reperfusion injury • HIV / Aids • Cancer • Infection / wound healing • Thrombosis • Post-surgical • Diabetes infection • Stomach ulcers • Epilepsy • Haemorrhagic • Parkinson’s disease colitis Unfortunately, the synthetic carbohydrate Organ transplants drugs will still have •toxicity and the

Essays Biochem 1995;30:59-75  

Lectins--proteins with a sweet tooth: functions in cell recognition.  

Sharon N, Lis H Dept of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.  

Lectins, non-enzymic proteins that bind mono- and oligosaccharides reversibly and with high specificity, occur widely in nature. They come in a variety of sizes and shapes, but can be grouped in families with similar structural features. The combining sites of lectins are also diverse, although they are similar in the same family.The specificities of lectins are determined by the exact shape of the binding sites and the nature of the amino acid residues to which the carbohydrate is linked. Small changes in the structure of the sites, such as the substitution of only one or two amino acids, may result in marked changes in specificity. The carbohydrate is linked to the protein mainly through hydrogen bonds, with added contributions from van der Waals contacts and hydrophobic interactions. Coordination with metal ions may occasionally play a role too. Microbial surface lectins serve as a means of adhesion to host cells of viruses (e.g. influenza virus), bacteria (e.g. E. coli) and protozoa (e.g. amoeba): a prerequisite for the initiation

Blocking the adhesion by carbohydrates that mimic those to which the lectins bind prevents infection by these organisms. The way is thus open for the development of anti-adhesive therapy against microbial diseases. Lectin-carbohydrate mediated interactions between leucocytes and endothelial cells are the first of infection.

the most attractive strategy for developing anti-adhesive thera-peutic agents is to use soluble forms of the human oligosaccharide component, which are small and non“A striking example of the successful immunogenic.” application of antiadhesive, soluble carbohydrates involved application of a mixture of sialyated complex N-linked glycopeptides (500 mg/day) to protect newborn calvesforfrom a oligosaccharides lethal dose of Drug prospects use of enterotoxic E coli 99.” pneumonia, chronic include otitis media, bronchitis, gastrointestinal diseases, cystitis, gonorrhea, chlamydia Lancet and1996; possibly 347: enhancement of the effects of standardized 1017-21

Eur J ClinMicrobiol 1987Oct;6(5):591-3

Lectin-mediatedbacterial adhesionto human tissue. BeuthJ, Ko HL, UhlenbruckG, Pulverer G Instituteof Hygiene, Universityof Cologne, FRG.

In vitro experiments with frozen sections of human lung and kidney demonstrated that adhesion of Streptococcus pneumoniae Pn 629 Type 14 and Pseudomonas aeruginosaATCC 27853 to human cells was mediated by bacterial lectins (adhesins) with N-acetyl-D-glucosamine/D-galactose or N-acetyl-neuraminic acid specificity.

Blockingof thelectinbindingsites onbacterial surfaces withcompetitive carbohydrates completely prevented the bacterial adherence, whereas non-specific carbohydrates (D-mannose, D-xylose) did not inhibit adherence.

BACTERIA

BACTERIA(cont’ VIRUSES d) Proteus HIV 

Actinomyces naeslundil mirabilis  Bordetella Pseudomonas Influenza virus  pertussis   aeruginosa  Parvovirus Chlamydia Burkholderia Rotavirus pneumoniae cepacia Salmonella Citrobacter freundi typhimurium  ------------------------- Enterobacter Serratia -----------aerogenes  marcescens  Escherechia coli  Shigella  Haemophilius FUNGI dysenteriae influenzae  H S flexneri  Candida parainfluenza Staphylococcus albicans Helicobacter pylori aureus S   Klebsiella saprophyticus  -------------------------pneumoniae Streptococcus  Specific oligosaccharides shown to be effective -----------Mycobacterium antiadhesive agents inmutans vitro.  S (Lancet,1996; OTHER tuberculosis  Specific oligosaccharides shown to be prophylactic347:1017) or pneumoniae  

ANTI-INFECTIVE AGENTS Further studies of the sugars on host cells and of bacterial lectins should lead to the design of better adhesion inhibitors. One point about the approach is certain: because different infectious agents - even different bacteria within the same strain - can have a wide variety of carbohydrate specificities, a cocktail of inhibitors will undoubtedly be necessary to prevent or treat the diseases. Scientific American: Jan, 1993; p87

AmJ Respir CritCareMed1997Jun;155(6):2102-4

Pseudomonas aeruginosa II lectin stops human ciliary beating: therapeutic implications of fucose. AdamEC, Mitchell BS, Schumacher DU, Grant G, Schumacher U Department of Human Morphology, University of Southampton, United Kingdom.

Respiratory tract infection by Pseudomomas aeruginosa may be life-threatening for intensive care patients and patients with cystic fibrosis (CF). The colonization of airways can be facilitated by bacterial lectins (carbohydrate-binding proteins) that attach bacteria to the glycoconjugates of the mucosa. We show in this paper that the fucose-specific lectin P. aeruginosa agglutinin II (PAII) produced by these bacteria can, in addition to facilitating bacterial adhesion, arrest ciliary beating in human airways in vitro. This inhibitory effect of the lectin can be abolished by preincubating PAII with its specific sugar, fucose. Furthermore, ciliary beating is completely restored by addition of fucose 2 h after administration of PAII to cell cultures. Therefore, adding a simple monosaccharide to nebulizers may improve the management of P. aeruginosa infection by abrogating the effect of PAII on ciliary beating, thus restoring

part of the nonspecific pulmonary defense mechanisms of the airways. …if fucose treatment

of P.Aeruginosa infections were to be started at an early stage, it mightbepossibleto control thefurther spreadof theinfection.

Klin Padiatr 2001 Sep-Oct;213(5):285-7  

Successful treatment of Pseudomonas aeruginosa respiratory tract infection with a sugar solution--a case report on a lectin based therapeutic principle. von Bismarck P, Schneppenheim R, Schumacher U. Department of Paediatric Haematology and Oncology, University Hospital Eppendorf, Germany.

BACKGROUND: Airway infections with Pseudomonas aeruginosa

often represent a life-threatening event in immunocompromised patients or patients with Cystic Fibrosis. The adhesion of this bacterium to surfaces such as the airway epithelium is mediated by two lectins, sugar binding proteins. In addition to their adhesive properties, these lectins have been shown to stop human ciliary beating thus compromising the mucociliary clearance as an important non-specific defence mechanism of the airways. Inhibition of these lectins by their specific sugars galactose and fucose, respectively, could therefore be of benefit in the

An infant suffering from P. aeruginosa airway infection after chemotherapy for neuroblastoma, which could not successfully be treated by antibiotics, was subjected to a series of additional galactose / fucose inhalations, which eliminated the germ as evidenced by microbiological testing. This is the first report suggesting the effectiveness of elimination therapy of P. aeruginosa. CASE REPORT:

      Biol Neonate 1998;74(2):143-162  

Glycoproteins of the human milk fat globule in the protection of the breast-fed infant against infections. Peterson JA, Patton S, Hamosh M. Cancer Research Institute of Contra Costa, Walnut Creek, Calif 94596, USA.

Nonimmunological components in human milk can protect breast-fed infants against infection by microorganisms. The structural and functional characteristics of four such components are discussed. The mucin inhibits binding of Sfimbriated Escherichia coli to bucal epithelial cells; lactadherin prevents

symptomatic

glycoaminoglycans

rotavirus-induced

infection;

inhibit binding of human immunodeficiency

Glycoconj J 1995Feb;12(1):1-6

Importanceof lectins for thepreventionof bacterial infections andcancer metastases. BeuthJ, Ko HL, Pulverer G, UhlenbruckG, Pichlmaier H Instituteof Medical MicrobiologyandHygiene, Universityof Cologne, FRG. Adhesion of bacteria and of metastasizing tumour cells have much in common, especially the participation of lectins in this process. In the future it might be possible to inhibit the

metastatic process and bacterial adhesion by blocking with lectins specific for appropriate (oligo) saccharides or glycoconjugates. Initial clinical trials arevery promising.

Cancer cells have unusual carbohydrates on their surface, which may account for many of their invasive properties. Drugs that interfere with the adhesiveness of abnormal cells may someday be used in cancer therapies. Sharon and Lis, “Carbohydrates in Cell Recognition,” Scientific American, January 1993, pgs. 8289

•

Billions of dollar$ are being spent to create synthetic carbohydrate drugs because the effectiveness of natural carbohydrates have been demonstrated repeatedly in medical research.

•

GLYCONUTRIENTS are available for patients NOW -

Anticancer Res 1997 Mar-Apr;17 (2B):1223-6

Prevention of hepatic metastases by liver lectin blocking with Dgalactose in colon cancer patients. A prospectively randomized clinical trial. Warczynski p, Gil J, Szmigielski S, Beuth J, Pulverer G MMA Postgraduate Medical School Warsaw, Poland.

76 colon adenocarcinoma patients (stages 1-3, NO, Mo) were enrolled into a prospectively randomized clinical trial, 39 patients were perioperatively treated with D-galactose-(therapy group:1.9 g/kg BW and day) or D-glucose-containing electrolyte infusions ( control group: n = 37). There were no cases of perioperative mortality. The complication rate was 17.1% (therapy group 15.3%; control group: 18.9%). Since tumor staging and grading were equally distributed for therapy and control groups, a non stratified statistical analysis yielded:

a) significantly reduced hepatic metastases and

Anticancer Res 1997 Mar-Apr;17(2b):1411-5

Prevention of hepatic metastases by liver lectin block-ing with D-galactose in stomach cancer patients. A prospectively randomized clinical trial. Kosik J, Gil J, Szmigielski S, Beuth Jm Pulverer G Postgraduate Medical School, Warsaw, Poland

80 stomach adenocarcinoma patients (T1-3, NO,MO) were enrolled into a prospectively randomized clinical study. 40 patients were perioperatively treated with D-galactose (treatment group:1.9 g/kg BW and per day) or D-glucose-containing electrolyte infusions (control group: n = 40). Perioperatively mortality was low (3.7%), complication rate was 11.2% (treatment group: 12.5%; control group:10%. Since tumor staging and grading were similarly distributed for treatment and control groups, a non-stratified statistical analysis yielded:

J ournal of Surgical Oncology 3(1): 79-88 (1971)

TheEffectof L-FucoseonRatMammaryTumor Growth. II. InVitro Studies J ames M. Roseman, A.B., Elizabeth Miller, Ph.D., Murray H. Seltzer, M.D., Daniel Wolfe, B.S., and Francis E Rosato, M.D. Different concentrations of L-fucose uniformly produced a suppression in the growth rate and a change in the morphology of cells grown in tissue culture. The inhibition of growth of these malignant cells

was found to be concentration dependent with 100% inhibition of growth at a concentration of 50 mg fucose per milliliter of medium and 60% inhibition at a concentration of 12.5 mg per milliliter medium. Using other sugars that are components of glycoproteins, it was shownthatmannoseandgalactosecouldalso depress the rate of growth of these tumor cells in culture. When 0.05 ml of packed tumor cells used in these experiments was resuspended in 1 ml of mediumand injected into a rat, a tumor grew at the site of injection. This newtumor exhibited similar growth characteristics and showed the same histological appearance as the tumor fromwhich the cell line was derived.

Acta Univ Palacki Olomuc Fac Med 1989;122:113-20

Effect of some sugars on the growth and differenti-ation of MCF-7 cells: I. Detection of glycosylative changes using lectin histochemistry. Kolar Z, Negrini R, Lisato The effects of lactose, L-fucose, and D-glucose on differentiation and glycosylation of MCF-7 cells from human mammary cancer were tested. For determination of glycosylation, six lectins with various binding specificity were used. The cells cultivated in the medium with D-glucose alone showed the best

The cells growing in the medium with L-fucose displayed, at the beginning growth acceleration which was followed by a rapid onset of necrotization. A decreased content of Dgrowth.

glucose usually resulted in an accelerated differentiation and a more pronounced secretory activity of cells. Expression of binding sites for lectins PNA and WGA was higher in cultures with elevated proliferation and reduced differentiation, DBA bound

Experientia 1989 Jun 15;45(6):584-8

Blocking of lectin-like adhesion molecules on pulmonary cells inhibits lung sarcoma L-1 colonization in BALB/c-mice. Roszkowski W, Beuth J, Ko HL, Uhlenbruck G, Pulverer G National Institute of Lung Diseases and Tuberculosis, Warsaw, Poland. Adhesion and inhibition experiments with pulmonary cells o f BALB/c-mouse origin and syngeneic sarcom a L-1 cells indicated that L-fucose specific lectin-like adhesion molecules, presumably situated on pulmonary cell surfaces are (at least partly) responsible for the specificity of this cell-cell interaction. Addition of specific sugars and glycoconjugates (L-fucose and fucoidan, respectively) to the incubation medium evidently inhibited the ad-hesion process as quantified using radiolabelled tumor cells . Unspecific carbohydrates (e.g.Dgalactose) did not affect the cellular interaction. In vivo, repeated administration of fucoidan (but not of unspecific

Oral Presentation: ComprehensiveCancer Carell: IntegratingComplementary&AlternativeTherapies, Sponsoredby Center for Mind-BodyMedicine&National Cancer Institute, attheHyattRegencyinCrystal City, Arlington, VA, June1999.

A PILOT SURVEY: STANDARD CANCER THERAPY COMBINED WITH NUTRACEUTICAL DIETARY SUPPLEMENTATION IMPROVES TREATMENT RESPONSES ANDPATIENT QUALITY OF LIFE. G. Hyland, M.D., D. Miller, M.T., Medcenter One, Dept. RadiationOncology, Bismarck, NorthDakota. In thousands of cancer cases evaluated by H. Foster, 87%percent of those with "spontaneous remissions" had made major dietary changes prior to tumor regression. The Dietary Supplement Health Education Act of 1994resulted in millions of US citizens addingaplethoraof supplements to their diets. A favorableresponseby 5patients that failed all cancer therapy was noted after it was stopped. We found that they had consumed glyconutrient, phytonutrient and phytogenin containingdietary supplements. A search revealed that Dr. Busbee et. al 1994found a glyconutrient inthesedietsupplements increasedIL-1, IL-6, INFandTNFproductioninmonocytecultures. Dr. Seeet. al 1999 reported enhanced NK lymphocyte cytolytic function in response to multiple glyconutrients. Dr. Barhomi et. al 1997 found glyconutrients increased intracellular reduced-glutathioneprotection50%inliver cells. Suchactivity provides apotential differential effectfor tumor cell destructionandnormal cell protection.

To increase our observations, patients with malignancies were solicited from a 3 state area and 127 volunteered to add nutraceuticals to their diet. 100 patients returned a quality of life survey focusing on weight loss, fatigue, nausea, vomiting, pain control, ability to complete treat-ments on schedule, physical activity and sense of well being. 40% of the group had failed standard therapy and were in a state of progressive disease (sent home to die). 60% were starting radiation or chemotherapy. 85% reported improvements in the above clinical parameters. The phytogenin supplement contains plant sterols for nutrient based endocrine support. Ovarian, breast, uterine, and prostate malignancy patients werediscouragedfromtakingthis nutrient. Someelectedto add thephytogenin to their dietandthey reportedthebestpreservationof appetite, muscle mass, and had the least side-effects during treatment. Patients with a diagnoses of ovarian carcinoma, astrocytoma grade IV, lymphomawithmildmarrowsuppression, a massivepelvic myxosarcoma, andcolonadenocarcinoma with brainmetastasis hadunprecedented responses.

: Nutraceutical dietary supplements:(Glyconutrients, Phytonutrients andPhytogenins) ♦ Do notinhibittumor cell destructionby radiationandchemotherapy ♦ Enhancetumor cell destruction ♦ Protectnormal cells fromradiationandcytotoxic damage ♦ Inducereductions intumor mass inmalignancies resistantto all treatments ♦ Improve quality of life for patients by reducing treatment toxicity and side effects from radiationandchemotherapy. CONCLUSIONS

A formal, controlled clinical study is warranted to further evaluatetheeffects of nutraceutical dietary supplementation in combinationwithstandardcancer therapy.

Clin Exp Rheumatol 1995 Mar-Apr;13(2):243-6

Fucose concentrations in sera from patients with rheumatoidarthritis. Kamel M, Serafi T Dr. Fakhry Hospital, Dhahran, Saudi Arabia.

The clinical significance of L-fucose was investigated in serumof a well characterized cohort of 135 RA patients and 60 healthy controls. In RA patients, serumL-fucose was significantly decreased to a mean of 5.57 +/- 0.97 mg%, (range 2.2-7.5 mg%), compared with 7.5 +/- 1.04 mg%(range 5.7-9.8 mg%) (p < 0.001) innormal controls. InearlyRA serumL-fucosewas significantlydepressedto ameanof 6.08mg%, a value which was significantly higher than the mean concentration of L-fucose in patients with advanced RA. SerumL-fucose was significantly correlated with the rheumatoid disease activity, duration, number of involved joints, and bone erosions. No statistically significant difference was found between seropositive and seronegativeRA patients. However, asignificantdifference(p<0.001) betweenfemale(5.57mg%) and male(6.59mg%) patients with advancedRA, andbetweenmale(6.08mg%) andfemale(5.99mg%) patients

These findings suggest that serum L-fucose is depressed in patients with rheumatoid arthritis, a promising observation since L-fucose is a safe and simple natural sugar. It may be with early RA was found.

usedas anadditional parameter andas anindicator for thediseaseactivity inthefollowupof patients with rheumatoidarthritis.

J Pediatr Gastroenterol Nutr, Vol, 26, No. 5, May 1998

N-Acetyl glucosamine– anovel “nutraceutical” therapyfor IBD. Salvatore S, Heuschkel R, Davies S, Walker-Smith J , Murch S; Royal Free Hospital, London, UK. Background: tissue damage in IBD occurs by inflammatory degradation of extracellular matrix, notably glycosaminoglycans

We nowreport thetherapeutic effects of matrix restoration with N-acetyl glucosamine (NAG), a “nutraceutical” substrate for GAG production. In (GAG – Lancet 1993; 341: 711-714).

addition to its role as a fuel for fibroblast repair, there is recent evidence that NAG may act intracellularly as an antagonist of O-phosphorylation and may thus regulate inflammatory pathways (Annu Rev Biochem1997; 66: 313-335). We have thus stained biopsies for GAGs and used the lectin wheatgermagglutinin (WGA) to detect intracellular NAG. Results: Rectal administration of NAG (1.5-2g bd) to 9 children with therapy-resistant distal colitis induced clinical remission in 4, improvement in 3 and no effect in 2. Biopsies before and after treatment showed histological improvement in all tested, with a striking increase in GAG density and intrapithelial WGA staining. Oral NAG therapy, in combination with existing therapies, was also commenced in 11 children with severe small intestinal and colonic disease, including 7 with critical strictures. 8/11 have shown improvement, while 3 have required surgical resection. 6/7 with treatment-resistant strictures showed marked resolution of symptoms, with endoscopic or radiological improvements in 4/6. GAG density and WGA staining was enhanced in all, to an extent greater than in other children treated with steroids or enteral nutrition.

Discussion: This first uncontrolled trial suggests that NAG is potentially of therapeutic efficacy in resistant IBD. Its mode of action is distinct from conventional therapies, and its lack of known adverse effects makes it particularly suitablefor pediatric use.

Aliment Pharmacol Ther 2000 Dec;14(12):1567-79

A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease. Salvatore S, Heuschkel R, Tomlin S, Davies SE, Edwards S, Walker-Smith J A, French I, Murch SH University Department of Paediatric Gastroenterology, Royal Free, London, UK. BACKGROUND: The breakdown of glycosaminoglycans is an important consequence of inflammation at mucosal surfaces, and inhibition of

metalloprotease activity may be effective in treating chronic inflammation. AIM: To report an alternative approach, using

the nutriceutical agent N-acetyl glucosamine (GlcNAc), an amino-sugar directly incorporated into glycosaminoglycans and glycoproteins, as a substrate for tissue repair mechanisms. METHODS: GlcNAc (total daily dose 3-6 g) was administered orally as adjunct therapy to 12 children with severe treatment-resistant inflammatory bowel disease (10 Crohn's disease, 2 ulcerative colitis). Seven of these children suffered from symptomatic strictures. In addition, similar doses were administered rectally as sole therapy in nine children with distal ulcerative colitis or proctitis resistant to steroids and antibiotics. Where pre- and post-treatment biopsies were available (nine cases), histochemical assessment of epithelial and matrix glycosaminoglycans and GlcNAc residues was made. FINDINGS: Eight of the children given oral GlcNAc showed clear improvement, while four required resection. Of the children with symptomatic Crohn's stricture, only 3 of 7 have required surgery over a mean follow-up of > 2.5 years, and endoscopic or radiological improvement was detected in the others. Rectal administration induced remission in two cases, clear improvement in three and no effect in two. In all cases biopsied there was evidence of histological improvement, and a significant increase in epithelial and lamina propria glycosaminoglycans and intracellular GlcNAc. CONCLUSIONS:

GlcNAc shows promise as an inexpensive and nontoxic treatment in chronic inflammatory bowel disease, with a mode of action which is distinct from conventional treatments. It may havethe potential to be helpful in stricturing disease. However, controlled trials and an assessment of enteric-release preparations are required to confirmits efficacy and establish indications for use.

The In Vitro Immunomodulatory Effects of Glyconutrients on Peripheral Blood Mononuclear Cells of Patients with Darryl M.Chronic See,M.D, PaulFatigue Cimoch,MD, Shioweh Chou, Jennifer Chang, Syndrome Integ Physio and Behav Sci,Jul-Sep 1998, Vol. 33, Jeremiah Tilles, MD 1 University of California, Irvine 2 Center for Special No.3,280-287 In h umans, eightIrvine, monosa ccharides are required for the Immunology, California

synthesis of glycoproteins. Dietary supplements that supply these crucial sugars are known as glyconutrients. A glyconutrientcompoundwas addedto Peripheral BloodMononuclear Cells (PBMC) isolated from normal controls and patients with the Chronic Fatigue Syndrome (CFS), a disease associated with immune dysregulation. The in vitro immunomodulatory effects were investigated. Cell surface expression of the glycoproteins CD5, CD8, and CD11a were significantly lower inpatients withCFS comparedto normal controls. Additionof glyconutrienthomogenate to PBMC from patients with CFS stimulated with phytohemagglutinin significantly increased the expression of each glycoprotein. Furthermore, natural killer (NK) cell function was reduced in CFS patients. The glyconutrient preparation significantly enhanced NK cell activity versus human herpes virus 6(HHV-6)-infected H9 cells in an 8 h 51Cr release assay compared to placebo for PBMC from patients with CFS (p< .01). Finally, apoptosis was significantly higher in patients with CFS. The percentage of apoptotic cells was significantly decreased in PBMC frompatients with CFS that had been incubated for 48h with glyconutrients. Thus, glyconutrients improvedabnormal immuneparameters invitro

inpatients withCFS.

The Effects of Dietary Supplements on Lupus: A Retrospective Survey KathrynDDykman; Cindy R Ford; CatherineMTone Proceedings of theFisher Institutefor Medical Research. 1;1:1997. Page26-30.

Twenty-six subjects with a positive diagnosis of lupus agreed to complete a retro-

spective questionnaire designed to assess their response to dietary supplements. The subjects (25 women and one man) had a mean age of 42years and had been taking supplements for an averageof 13months. They all

reported a significant improvement in their overall condition since beginning dietary supplementation. Of the 14 symptoms of lupus which were surveyed, statistically significant improvement were noted in the following symptoms: aching joints, fever, prolonged or extreme fatigue, arthritis, kidney involvement, and hair loss. Subjects also reported a statistically significant decrease in number, frequency and severity of flares. In addition, they experienced significant improvement in all activities that were assessed, including physical activities, work, family responsibilities, hobbies, and self-care. They enjoyed these improvements even in light of a significant reduction in their use of nonsteroidal anti-inflammatories, analgesics, and narcotics. These results indicate lupus patients may experienceanenhancedquality of lifewiththeuseof dietary supplements.

J Cardiovasc Pharmacol 1993Jul;22(1):74-81

Reductionof myocardial ischemic reperfusioninjury by sialylatedGlycosphingolipids, gangliosides. Maulik N, Das DK, Gogineni M, Cordis GA, Avrova N, Denisova N Department of Surgery, University of Connecticut School of Medicine, Farmington 06030-1110.

Gangliosides, sialic acid-containingglycosphingolipids, arelocalizedmostlyto the outer leaflet of the lipid bilayer in the plasma membrane, particularly in brain.. Gangliosides reduce edema formation, restore glucose metabolism, and increase cerebral blood flow after focal ischemia in the rat brain. We wished to determine whether gangliosides could also reduce myocardial ischemic and reperfusion injury. Isolated rat heart perfused by Langendorff technique was pretreated with gangliosides (1 microM) purified fromthe rat brain. After 15-min perfusion with gangliosides, hearts were made ischemic for 30 min by termination of coronary flow, followed by 60-min reperfusion. Ganglioside-treated heart exhibited better myocardial preservation, as evidenced by reduction in creatine kinase release and lipid peroxidation product formation enhanced coronary flow and contractile functions [left ventricular developed pressure (LVDP) and maximumfirst derivative of LVDP, LVdp/dtmax]. In addition, gangliosides reduced the hydroxyl radical formed during reperfusion of ischemic myocardium, as shown by high-performance liquid chromatography (HPLC)-electrochemical detection technique. In vitro studies demonstrated that these gangliosides were direct scavengers of superoxide anions (IC50 0.8 microM), and hydroxyl radicals (IC50 10 microM), as well hypohalite radicals (IC50 0.7 microM). Furthermore, ganglioside pretreatment was accompanied by reduced intracellular calcium overloading during ischemia and

The results of this study thus suggest that gangliosides can reduce ischemic reperfusion injury in isolated heart, probably by inhibiting intra-cellular calciumoverloading and/or by directly scavenging the free radicals generatedduringreperfusionof ischemic myocardium. reperfusion as compared with untreated controls.

Ann Thorac Surg 1996 Nov;62(5):1295-300

Blockade of selectin-mediated leukocyte adhesion improves postischemic functioninlambhearts. MiuraT, NelsonDP, SchermerhornML, Shin'okaT, ZundG, HickeyPR, NeufeldEJ, Mayer JE Jr Department of Cardiovascular Surgery, Children's Hospital, Boston, Massachusetts 02115, USA. BACKGROUND: Leukocyte-endothelial interactions appear to have a important role in ischemia/reperfusion injury and are mediated by specific leukocyte and endothelial adhesion molecules. The selectins are adhesion molecules found on leukocytes (L-selectin) and endothelium(P and E selectin) that bind to oligosaccharide ligands containing fucose and sialic acid to mediate leukocyte rolling on the endothelium. Fucoidin is a nontoxic sulfated fucose oligosaccharide derived fromseaweed that blocks the selectins. METHODS: We tested the effects of fucoidin in an isolated blood-perfused neonatal (age range, 3 to 7 days; mean age, 4.3 days) lamb heart model undergoing 2 hours of cold cardioplegic ischemia. In group F (n =8) fucoidin (30 mg/L) was added at initial reperfusion. Group C (n =9) received only cardioplegia with no reperfusion intervention. Isovolumic maximumdeveloped pressure and the maximumpositive and negative first derivatives of pressure were measured using a catheter-tip transducer in an intraventricular balloon before ischemia and at 30 minutes of reperfusion. Coronary blood flow, myocardial oxygen consumption, and white blood cell counts in the circulating blood were also measured. RESULTS: Percent recoveries of baseline maximum developed pressure and maximumpositive and negative first derivatives of pressure in group F (86% +/- 5%, 81% +/- 10%, and 74% +/- 8%, respectively; mean +/- standard deviation) were higher than in group C (77% +/- 5%, 70% +/- 9%, and 65% +/6%; p <0.05). Group F postischemic coronary blood flow was greater (190% +/- 35%) than in group C (102% +/- 10%; p <0.05). Recovery of myocardial oxygen consumption in group F (86% +/- 14%) was greater than group C (72% +/- 11%; p <0.05). Postischemic white blood cell

count in group F (88% +/- 4%) was greater than in group C (81% +/- 5%; p <0.05). CONCLUSIONS: Selectin blockadewith

fucoidin resulted in better recovery of left ventricular function, coronary blood flow, and myocardial oxygen consumption after cold ischemia, despiteahigher circulatingwhiteblood cell count. These data support the hypothesis that endothelial-leukocyte interactions play an important role in ischemia/reperfusion and suggest that selectin blockade may be a useful therapeutic strategy.

BiochemBiophys Res Commun1999Feb16;255(2):189-93

Human glycosylation disorders and sugar supplementtherapy. Freeze HH The BurnhamInstitute, La J olla, California 92037, USA.

Some genetic defects in protein glycosylation can be treated effectively with dietary supplements of monosaccharides. An easy screening test and non-toxic therapy for potentially lethal disorders should encourage physicians to search for more patients with glycosylation disorders. It should also stimulate research on the occurrence and availability of monosaccharides used for glycoconjugate synthesis and for vertebrate models to study their utilization.

Biochem Mol Med 1997 Apr;60(2):127-33  

Oral ingestion of mannose elevates blood mannose levels: a first step toward a potential therapy for Alton G, Kjaergaard S, Etchison JR, Skovby F, Freeze HH ; carbohydrate-deficient glycoprotein Burnham Institute, La Jolla, California syndrome type I. Carbohydrate-deficient glycoprotein syndrome type I  

(CDGS) is an inherited metabolic disorder with multisystemic abnormalities resulting from a failure to add entire N-linked oligosaccharide chains to many glycoproteins. Fibroblasts from these patients also abnormally glycosylate proteins, but this lesion is corrected by providing 250 microM mannose to the culture medium. This correction of protein glycosylation suggests that providing dietary mannose to elevate blood mannose concentrations might also remedy some of the underglycosylation observed in these patients. We find that ingested mannose is efficiently absorbed and increases blood mannose levels in both normal subjects and CDGS patients. Blood mannose levels increased in a dosedependent fashion with increasing oral doses of mannose (0.07-0.21 g mannose/kg body weight). Peak blood mannose concentrations occurred at 1-2 h following ingestion and the clearance half-time was approximately 4 h. Doses of 0.1 g mannose/ kg body weight given at 3-h intervals maintained blood mannose conentrations at levels 3- to 5-fold higher than the basal level in both normal

J ClinInvest1996Mar 15;97(6):1478-87

Mannosecorrects alteredN-glycosylationin carbohydrate-deficientglycoproteinsyndrome fibroblasts. PanneerselvamK, FreezeHH; LaJollaCancer ResearchFoundation, Type I carbohydrate-deficient glycoprotein syndrome (CDGS) patients fail to add entire N-linked oligosaccharide chains to some serumglycoproteins. Here we showthat four CDGS fibroblast cell lines have two related glycosylation abnormalities. First, they incorporate 3-10-fold less [3H] mannose into proteins, and, second, the size of the lipid-linked oligosaccharide precursor (LLO) is much smaller than in controls. Addition of exogen-ous mannose, but not glucose, to these CDGS cells corrects both the lowered [3H] mannose incorporation and the size of LLO. These corrections are not permanent, and the defects immediately reappear when mannose is removed. To explore further the basis of mannose correction, we analyzed the amount of 3H- labeled LLO intermediates. Except for dolichol-P-mannose, other precursors, including mannose, mannose-6-phosphate, mannose-1-phosphate, and GDP-mannose, all showed a 3-10-fold decrease in CDGS cells. Thus, there are no obvious lesions in the intracellular conversion of mannose into LLO, and, once inside the cell, [3H]mannose appeared to be metabolized normally. Initial velocities of [3H]mannose uptake were two-to threefold less in CDGS cells compared with controls, and this slower transport may partially explain the re-duced [3H]mannose incorporation in CDGS cells. Since we previously showed that the enzymes converting glucose to mannose-6-phosphate appear to be normal, our results suggest that cells may acquire or generate mannose in other ways. Although we have not identified the primary defect in CDGS, these studies showthat intracellular mannose islimited

and that some patients might benefit from including mannose in their regular diets.

J ClinInvest1998Apr1;101(7):1414-20

Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency andmannosetherapy. Niehues R, Hasilik M, Alton G, Korner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T Klinik und Poliklinik fur Kinderheilkunde, 48149 Munster, Germany.

a new type of carbohydrate-deficient glyco-protein syndrome (CDGS). The disorder Phosphomannose isomerase (PMI) deficiency is the cause of

is caused by mutations in the PMI1 gene. The clinical phenotype is characterized by proteinlosing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent. Using standard diagnostic procedures, the disorder is indistinguishable from CDGS type Ia (phosphomannomutase deficiency. Daily oral mannose administration

is a successful therapy for this new type of CDG syndrome classifiedas CDGS typeIb.

Blood 1999 Dec 15;94(12):3976-85

Correction of leukocyte adhesion deficiency type II with oral Fucose. Marquardt T, Luhn K, Srikrishna G, Freeze HH, Harms E, Vestweber D Klinik und Poliklinik fur Kinderheilkunde and the Institut fur Zellbiologie, ZMBE, Universitat Munster, Munster, Germany.

We describe a simple, noninvasive, and effective therapy for leukocyte adhesion deficiency type II (LAD II), a rare inherited disorder of fucose metabolism. This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based selectin ligands on the surface of neutrophils as well as to severe psychomotor and mental retardation. The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose to the culture medium. This prompted us to initiate dietary fucose therapy on a patient with LAD II. Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins. During 9 months of

treatment, infections and fever disappeared , elevated neutrophil counts returned to normal, and psychomotor capabilities improved.

Blood 2001 J an 1;97(1):330-2

Discontinuation of fucose therapy in LADII causes rapid loss of selectinligands andriseof leukocytecounts Luhn K, Marquardt T, Harms E, Vestweber D

Institute of Cell Biology, ZMBE, University of Munster; Max-Planck-Institute for Physiological and Clinical Research, Munster, Germany; and Klinik und Poliklinik fur Kinderheilkunde, Munster, Germany.

Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate

ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyteendothelial interactions. A simple and effective therapy has recently been described

for LADII, based on the administration of oral fucose. Parallel to this treatment the lack

of E- and P-selectin ligands on neutrophils was corrected, and high peripheral neutrophil counts were reduced to normal levels. This study reports that discontinuation of this therapy leads to the

complete loss of E-selectin ligands within 3 days and of P-selectin ligands within 7 days. Peripheral neutrophil counts increased parallel to the decrease of selectin ligands. Selectin ligands reappeared promptly after resumption of the fucose therapy, demonstrating a causal relationship between fucose treatmentandselectinligandexpressionandperipheral neutrophil counts.

FASEB J 1987 Dec;1(6):462-8  

Trafficking of lysosomal enzymes.  

Kornfeld S. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.  

The targeting of lysosomal enzymes from their site of synthesis in the rough endoplasmic reticulum (RER) to their final destination in lysosomes is directed by a series of protein and carbohydrate recognition signals on the enzymes. Lysosomal enzymes, along with secretory and plasma membrane proteins, contain amino-terminal signal sequences that direct the vectorial discharge of the nascent proteins into the lumen of the RER. The three classes of proteins also share a common peptide signal for asparagine glycosylation. The next signal is unique to lysosomal enzymes and permits their highaffinity binding to a specific phosphotransferase that catalyzes the formation of the

This carbohydrate determinant allows binding to specific receptors that translocate the lysosomal enzymes from the Golgi complex to an acidified prelysosomal compartment. There the lysosomal enzymes are discharged for final packaging into lysosomes. Two distinct mannose 6-phosphate mannose

6-phosphate

recognition

marker.

   

Surg Clin North Am 1999 Dec;79(6):1385416  

Immune dysfunction in trauma.  

Napolitano LM, Faist E, Wichmann MW, Coimbra R Department of Surgery, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany.  

This article documents that all immunomodulation strategies for patients sustaining traumatic injury are still under intense investigation. Although we can speculate that combination strategies may be more beneficial than single-agent immunomodulation approaches, comprehensive clinical studies are required to determine efficacious immune therapy for

The only strategy available to clinicians caring for trauma patients is immunonutrition, and this should be strongly considered as a rational approach to improve trauma

patients.

Proc Natl Acad Sci USA 1998 Oct 27;95(22): 13188-93

CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury. Wamil AW, Wamil BD, Hellerqvist CG.Dept of Surgery, Vanderbilt University, Nashville, TN

CM101, an antiangiogenic polysaccharide derived from group B streptococcus, was administered by i.v. injection 1 hr post-spinal-cord crush injury in an effort to prevent inflammatory angiogenesis and gliosis (scarring) in a mouse model. We postulated that gliosis would sterically prevent the reestablishment of neuronal connectivity; thus, treatment with CM101 was repeated every other day for five more infusions for the purpose of facilitating regeneration of neuronal function. Twenty-five of 26 mice

treated with CM101 survived 28 days after surgery, and 24 of 26 recovered walking ability within 2-12 days. Only 6 of 14 mice in the control groups

6th International Congress onAnti-AgingandBio-Medical Technology, Las Vegas, Nevada, Dec 1998 WardB, Kaats G, Mcdaniel C, DykmanK, BoydS, McAnnalley B, Hall J, McDaniel HR

BIO-MARKERS OF AGING ARE IMPROVEDBY A NUTRACEUTICAL-AUGMENTEDOPTIMAL HEALTHPLAN Parameter 1. Musclemass 2. Percentbody fat 3. Strength 4. Aerobic capacity 5. Bloodpressure 6. Bonedensity 7. Bloodglucosetolerance 8. Cholesterol / HDL ratio 9. Basal metabolic rate 10. Body temperatureregulation

Healthy Intervention

Nutraceutical+ PlanEffect

Increase Decrease Increase Increase Decrease Increase Increase Decrease Increase Increase

Increase Decrease Increase Increase Decrease Increase Increase Decrease ? ?

( ? ) Has notbeenevaluated. Nutraceuticals includedglyconutrients, phytonutrients, diosgenins

• No miracles involved, just an essential group of saccharide nutrients that we didn’t know were necessary or missing until 1996. • If anything, it represents an under-estimation by scientists and doctors of the body’s incredible ability to fix and maintain itself! • The list is both extensive and quite varied in • Dyslexia • Urinary • Diabetes the medical literature. infections • Otitis media • Heart disease • URI • Candida • Hepatitis • Stroke infection C • Asthma • Cerebral • Cancer Palsy • Menopause • Autism • Organ • Tay-Sach’s • ADD /

OBVIOUSLY ONLY A FEW EXAMPLES OF THE MEDICAL RESEARCH CAN BE INCLUDED ON THIS CD SO…. Check out the NEW nutrition science site at:

Additional information on Glyconutrients as well as other nutra-ceuticals can be reviewed at the new Glyco-Science website.