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R &D Report 
In this paper we detail the development of Mannatech’s antioxidant, Ambrotose
 A
O
™
, which culminated in a small human clinical trial. Consumption of two capsules of  Ambrotose
 A
O
™
per day was found to increase a blood serum marker of oxidativeprotection by 37.4%, which is over twice the increase caused by consumption of anadditional ve servings of fruits and vegetables each day (Figure 1).
1,2
Background
The body has an elaborate network of innate molecules and ingested compounds designedto maintain a balanced oxidative state, which is important for optimal function and health(Figure 2).
3
Oxidative stress, a condition characterized by an imbalance between pro-oxidants andantioxidants within the body, has been linked to the aging process. A growing body of evidence suggests thata diet high in fruits and vegetables helps preventoxidative stress. In fact,antioxidants—chemicalsable to quench orneutralize free radicals—are thought to beresponsible for many of the benets that fruits and vegetables confer. Becausefew eat sufcient amountsof fruits and vegetables,supplementation withantioxidants would seemto be the key to providingthe benets offered by diets high in fruits and
Innovations in theDevelopment of a Superior Antioxidant: Ambrotose
 A
O
™
Bill McAnalley, PhD; Tom Gardiner, PhD; Alyssa Summey; Shayne McAnalley;Eileen Vennum, RAC
 Additional 5Servings ofFruits and Vegetables1 Capsule Ambrotose
 A
O
™
2 Capsules Ambrotose
 A
O
™
Figure 1.Comparsion of Percent Change in Human Serum ORAC
ß-PE
 Values Following Consumption of 5 Additional Fruits and Vegetables* or Ambrotose
 A
O
™
Finished Product**
* Cao G, Booth SL, Sadowski JA, et al.
 AM JClin Nutr.
1998; 68(S):1081-1087.**Boyd S, Ford C, Koepke CM, et al.
GlycoScience & Nutrition
2003.4(6):1-6.4035302520151050
   P  e  r  c  e  n   t   C   h  a  n  g  e   f  r  o  m    B  a  s  e   l   i  n  e
EXTERNAL EDITORIAL BOARDTom Gardiner, PhD
Global Health Safety Environmentand Regulatory Affairs CoordinatorShell Chemical Company (Retired)Houston, Texas
Robert K. Murray, MD, PhD
Professor (Emeritus)Department of Biochemistry University of TorontoToronto, Ontario, Canada
 Alice Johnson-Zeiger, PhD
Professor of Biochemistry (Retired)University of Texas Health CenterTyler, Texas
James C. Garriott, PhD, D-ABFT
Professor (Clinical Adjunct Faculty)University of Texas HealthScience CenterConsulting ToxicologistSan Antonio, Texas
MANNATECH INCORPORATEDINTERNAL CONTRIBUTING ANDCONSULTING EDITORS
Stephen Boyd, MD, PhD, FRSMBill McAnalley, PhD
TECHNICAL STAFF
Gary CarterBarbara Kinsey Mary Wood
GRAPHIC ARTISTS
Bruce Peschel John Pavel
SCIENCE EDITOR
C. Michael Koepke, RAC
MANAGING EDITOR
 Jane Ramberg, MS
EDITOR IN CHIEF
Eileen Vennum, RAC
 The Ofcial Scientic Publicationof the Research & DevelopmentDepartment of Mannatech Inc.
Coppell, Texas, USA. © 2004. All rights reserved.
www.mannatech.com
Glossary Terms on Page 6References on Page 7
 Volume 1, January 1, 2004
 
Page 2—Mannatech R&D Report, Vol. 1. January 1, 2004
 vegetables.
4,5
However, caution should be observed whenchoosing an antioxidant supplement.
Figure 2.Problems with Antioxidant Supplementation
Supplementation with high doses of single antioxidantsupplements or combinations of a few antioxidants hasproven ineffective in some cases and harmful in others.The doses used in these failed trials differed greatly fromamounts found in fruits and vegetables and often includedonly either lipid- or water-soluble antioxidants.
4
There are other key differences between foods withabundant antioxidant nutrients and antioxidant supplements. Antioxidants in the body do not function independently. Whole foods provide numerous compounds that canenhance antioxidant function, while supplements oftenprovide pure forms of isolated nutrients that lack theaccompanying nutrients necessary for proper function. Also,nutrients in foods can be released more slowly than thosein supplement form. The large doses of highly bioavailableantioxidants may result in a brief spike in blood plasmaantioxidant levels (which may exceed healthy levels)followed by a return to decient levels (Figure 3).
Figure 3.
In contrast, foods may offer more subtle and sustainedprotection. The high doses of isolated nutrients that areoften involved in supplementation can have undesirableconsequences. Because free (unbound) vitamin A damagescells, symptoms of toxicity arise when the amount of vitamin A ingested overwhelms the number of proteins available tobind and transport it throughout the body. Toxic levels of  vitamin A are unlikely to develop in individuals who derivetheir vitamin A from a balanced diet. Supplementation,on the other hand, makes an overdose of vitamin A quitepossible. Similarly, supplemental forms of beta-carotenecan be dangerous, but eating too much beta-carotenefrom food sources, though it may cause the skin to appear yellow, is harmless.
6
Researchers found that whole tomatopowder but not lycopene, a carotenoid found in tomatoes,inhibited prostate carcinogenesis in rats, demonstrating thefunctionality of a whole-food supplement and the lack of efcacy of a high dose of an isolated nutrient.
7
Since foods have been effective in combating oxidativestress, and supplements generally have not, reconcilingthe differences between the two and minimizing theirshared vulnerability in processing and handling becameour focus during the formulation of Ambrotose
 A
O
™
. Ourconsiderations are summarized in Table 1.
Importance of Balance
Numerous studies have demonstrated that cooperationamong antioxidant nutrients is essential for properfunction.
8,9
Without such cooperation, free radicals canbecome concentrated in certain areas within the body,creating a capacitor effect, meaning that antioxidants fuellocalized chain reactions, harming rather than protecting
Comparison of Foods Rich in Antioxidants and Antioxidant Supplements
Foods Rich in AntioxidantsHave been shown to protectfrom oxidative stress.There may be no singleactive compound. In fact,studies point to the effec-tiveness of combinationsrather than single nutrients.Foods can provide theseeffective combinations inlow but balanced, highlyeffective amounts.Can offer a slower, sustaineddelivery of nutrients.Symptoms of toxicity areunlikely to develop inindividuals who derivenutrients from a balanceddiet.Can suffer tremendousnutrient losses duringcultivation, cooking,processing and storage. Antioxidant SupplementsHave often failed to showany protective effect againstoxidative stress and havebeen demonstrated to bedangerous in some cases.Can provide high doses ofisolated nutrients (a “magicbullet” approach), with noneof the accompanyingcompounds that enablefunction.Generally lack a controlledrelease.High doses of readilyavailable nutrients insupplement form canoverwhelm the body andupset the natural balance.Can suffer tremendousnutrient losses duringprocessing, handling andstorage (e.g., exposure toheat or oxygen).Effect in HumansDosage of Active CompoundDelivery of NutrientsPotential for Toxicity Vulnerability in Processing
minimum effectiveconcentration (MEC)for adverse responseminimum effectiveconcentration (MEC)for desired response
Therapeutic Window for Antioxidants
therapeuticwindowonset ofeffectdurationof action
   L  e  v  e   l  o   f   V   i   t  a  m   i  n   i  n   B   l  o  o   d   P   l  a  s  m  a
Time
Table 1.
Scheme for Balanced Cellular Oxidative Status
 Yu. BP. In: Cutler RG. Packer L. Bertram J. and Mori A. Editors.
Oxidative Stress and Aging
.Berkgauser Verlag, Switzerland. 1995:331-342.
Oxidative Reactions
Reactive oxygen species generationOxidation of proteins, lipids, nucleic acids, and sugarsTransition metal catalysis AntioxidantsRegulation of metalsScavenger enzymesDamage repairElimination of oxidatively damaged by-products
Defense Systems
 
Mannatech R&D Report Vol. 1, January 1, 2004—Page 3
cells.
10,11
Hence, the idea of balance extends from a balancebetween pro-oxidants and antioxidants within the body to abalance among antioxidants themselves (Figure 4).
Figure 4.
 When formulating antioxidant supplements, achievingbalance has been impeded because scientists have lackedthe tools to analyze interactions among antioxidantcompounds with varying solubilities. Current methods forassessing the antioxidant potential of samples, the bestof which are uorescence-based ORAC (oxygen radicalabsorbance capacity) methods,
5
do not allow lipid- and water-soluble samples to be tested at the same time. TheORAC
method is appropriate for assaying the antioxidantcapacity of water-soluble samples.
12
The ORAC
-lipo
method was designed to assay lipid-soluble samples
13
but oftendoes not take into account water-soluble elements. Thesecurrently used methods also involve an initial extraction thatreduces or excludes less soluble (but perhaps functionally important) parts of a sample. At best, lipid- and water-soluble portions of samples are separated and analyzedindividually, but this separation prevents analysis of meaningful interactions. Since antioxidants in the body often work in concert and include both lipid- and water-solublecompounds, an assay that allows both types of antioxidantsto interact (potentially cooperating or interfering with eachother) would provide a more accurate model of antioxidantactivity in humans.The ORAC
o
method, which uses an oxygen-specic probe, was created to address problems with current industry standards. Because of its unique solvent system andsample preparation technique, the ORAC
o
method, whichsimultaneously measures the activities of lipid- and water-soluble compounds, allows the detection of interactions thatcannot be measured through the use of uorescence-basedantioxidant assays.
Formulation of Mannatech’s Ambrotose
 A
O
™
Balance, with the aim of optimal performance in humans, was the controlling idea behind the formulation of the MTech AO Blend
™
. Synergy (meaning the activity of a mixture asa whole is greater than that of the sum of its parts) wasdiscovered between quercetin and mixed tocopherols usingthe ORAC
o
method, demonstrating the type of cooperationnecessary for effective radical quenching in humans. Roughly two times the expected net antioxidant activity was found atthe optimal ratio of the two compounds.Mixed tocopherols are lipid-soluble, and quercetin is only slightly soluble in water. Focus was then shifted to theinclusion of water-soluble antioxidants. Based on theirknown benets, green tea extract and grape extract wereselected, as well as freeze-dried Australian bush plum, which has the highest amount of vitamin C per gram of any known natural source,
14
and Phyt
•
 Aloe
®
complex, which provides dehydrated fruits and vegetables. Numeroussamples of quercetin, mixed tocopherols, grape extractand green tea extract were individually assayed for activity using the ORAC
method. The sample with the highestactivity for each component was included in blends, andthe ratio of components was optimized using the ORAC
o
 method, the assay best suited to analyze interactions among various compounds.
Oxygen Radical Absorption Capacityof the MTech AO Blend
™
The resulting in-process MTech AO Blend
™
, the activecomponent of Ambrotose
 A
O
™
, was run using the ORAC
o
,ORAC
and ORAC
-lipo
assays. Results were reported in μmolTrolox Equivalents (TE)/g or /mL. The ORAC
assay detectsonly the activity of water-soluble components. It measuredonly the activity of green tea extract, grape extract, bushplum, Phyt
•
 Aloe
®
, and part of quercetin’s activity, butexcluded the contribution of mixed tocopherols entirely.The ORAC
-lipo
detects only the activity of lipid-solublecomponents. It measured mixed tocopherols and part of quercetin’s activity, but excluded the contributions of the water-soluble components listed above. In comparison, theORAC
o
picks up the activity of both water- and lipid-solublecomponents and was able to detect the synergistic activity of all components of the MTech AO Blend
™
. The MTech AOBlend
™
measured a whopping 17,454 ORAC
o
units!
Mother Nature Knows Best
Previous failures with high-dose antioxidant supplemen-tation have shown that more of pure substances is notnecessarily better. For example, large doses of puried,individual vitamins can lead to very high, followed by very low, levels of those vitamins in the blood and tissues thatneed them (Figure 3). As a result, antioxidant nutrients areoften not available when they are needed for necessary biological functions, or they can be present in toxicamounts. A steady, sustained bioavailability of a sufcient
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