22/ALKOXYGLYCEROLS PDR FOR NUTRITIONAL SUPPLEMENTS

ACTIONS AND PHARMACOLOGY

ACTIONS

Alkoxyglycerols have putative antiproliferative and immuno-modulatory activities.

MECHANISM OF ACTION

The mechanism of the putative antiproliferative and immu-nomodulatory actions of alkoxyglycerols is not known.Speculative mechanisms include protein kinase C inhibition,macrophage activation and natural killer cell activation.

PHARMACOKINETICS

Ether glycerols, when absorbed, may be incorporated intoplasmalogens and alkylacyl glycerophospholipids. Little isavailable on the specific pharmacokinetics of the shark oilalkoxyglycerols in humans.

INDICATIONS AND USAGE

Support for claims that the alkoxyglycerols are indicated forthe prevention and treatment of any cancer or for thetreatment of ~ounds and inflammatory conditions in humansis limited and unsystematic. There is little support for claimsthat they are immune-enhancing in humans.

RESEARCH SUMMARY

This shark-liver oil derivative has been touted as an effectiveanti-cancer treatment. Unfortunately, there is little evidenceto support this claim, 'at least for humans. There is scantevidence it inhibits tumor growth or reduces cancer mortalityin humans. It should in no way be relied upon in thetreatment of any form of cancer. Similarly, there is littleevidence to support claims that this substance is useful fortreating wounds and inflammatory conditions. Neither has itbeen demonstrated in appropriate human clinical studies thatit has immune-enhancingeffects.There are some in vitro andanimal studies reporting antiproliferative and immunomodu-latory effects for these substances, and perhaps alkoxygly-cerols may eventually have a role to play in adjuvantmanagement of certain types of cancer. However, this wouldneed to be established by well-designed, double-blind,placebo-controlled trials, which have not yet been done.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRA INDICA TIONS

Known hypersensitivity to an alkoxyglycerol-containing

product.

PRECAUTIONS

Those with cancer who are interested in alkoxyglycerolsshould discuss their use with their physicians. Under nocircumstance should they be relied upon as principleelements in the management of their disease. Pregnantwomen and nursing mothers should avoid alkoxyglycerolsupplements.

ADVERSE REACTIONS

Mild gastrointestinal symptoms, including diarrhea, havebeen reported.

DOSAGE AND ADMINISTRATION

There are no typical doses. Those who use shark liver oilproducts are cautioned that some preparations may containhigh amounts of vitamins A and D.

LITERATURE

Brohult A, Brohult J, Brohult S, Joelsson I. Reduced mortalityin cancer patients after administration of alkoxyglycerols. ActaObstet Gynecol Scand. 1986; 65:779-785.

Das AK, Holmes RD, Wilson GN, Hajra AK. Dietary etherlipid incorporation into tissue plasmologens of humans androdents. Lipids. 1992; 27:401-405.

Hallgren B, Niklasson A, Stallberg G, Thorin H. On theoccurrence of 1-0-(2-methoxyalkyl)glycerols and 1-0-phytanylglycerol in marine animals. Acta Chern Scand B. 1974;28: 1035-1040.

Hasle H, Rose C. [Shark liver oil (alkoxyglycerol) and cancertreatment). [Article in Danish]. Uge~~ Laeger. 1991; 153:343-346.

Oh SY, Jadhav LS. Effects of dietary alkoxyglycerols inlactating rats on immune responses in pups. Pediatr Res. 1994;36:300-305.

Alpha-Amylase Inhibitor(Phaseolamin)DESCRIPTION

The enzyme pancreatic alpha-amylase plays a major role inthe digestion of the starch. Starch is comprised of twopolysaccharides-amylose and amylopectin. Amylose iscomprised of long unbranched chains of D-glucose unitsbound in alpha (1)4) linkages. Amylopectin is a highlybranched structure, also made up of D-glucose units. Thebackbone glycosidic linkages are alpha (1)4), as' in amylose,but the branch points have alpha (1)6) glycosidic linkages.Pancreatic alpha-amylase hydrolyzes alpha (1)4) linkagesrandomly to produce maltotriose, oligosaccharides, maltoseand some D-glucose. Alpha-amylase cannot hydrolyze alpha(1)6) linkages, which occur at the branch points ofamylopectin, consequently forming a highly branched corecalled limit dextrin. A debranching enzyme-alpha (1)6)glycosidase-hydrolyzes the alpha (1)6) linkages at thebranch points producing D-glucose. The brush border of thecells lining the lumen of the small intestine contains enzymesthat covert oligosaccharides and disaccharides to D-glucose.Alpha-glucosidases convert maltose and maltotriose to D-glucose. D-glucose is then the major end product of thedigestion of starch.

SUPPLEMENT MONOGRAPHS ALPHA-AMYLASE INHIBITOR (PHASEOLAMIN) /23

The regulation of plasma glucose levels and of glucosemetabolism is one of the most important homeostaticmechanismsin the body. In a normal situation, some of theD-glucose formed from starch digestion is stored as glyco-gen in the liver and some is metabolized to producebiological energy. This occurs when an appropriate amountof non-resistant insulin is secreted in response to the glucoseformed via digestion. Under conditions of insulin resistance,postprandial serum glucose is abnormally elevated and lessglucose goes into the production of glycogen and into thepathways that produce biological, energy, among othermetabolic events. A way of rectifying this abnormal situationwould be to decrease the amount of D-glucose producedfrom carbohydrate digestion, slowing down its absorptionand consequently diminishing postprandial excursions ofinsulin and D-glucose. One way of doing that might be toinhibit the enzyme pancreatic alpha-amylase..

Alpha-amylase inhibitors are found in many plants and areabundant in cereals and legumes. A major impetus forresearch and discovery of these inhibitors is their potential asbioinsecticides. Three different isoforms of an alpha-amylaseinhibitor are found in the common bean Phaseolus vulgaris.These isoforms are designated alphaAI-l, alphaAI-2 andalphaAI-3.

AlphaAI-l was purified and analyzed in the mid 1970s andfound to be a glycoprotein having a molecular weight of 45kDa (kilo Daltons) to 50 kDa. This glycoprotein was namedphaseolamin in recognition of its origin. Later, it wasdetermined that this glycoprote,in had a molecular weight of56.7 kDa, that it was composed of two kinds of glycopeptidestructure,s, alpha and beta, and that it had a tetramericstructure, alphazbetaz.

I

AlphaAI-l inhibits animal alpha-amylase and forms the basisof a dietary supplement that was introduced into the dietarysupplement marketplace in the ,early 1980s. It was called a"starch blocker," with claims that it would lower plasmaglucose levels and also help in weight reduction. However,even though it was demonstrated in some animal studies tohave a serum glucose-lowering effect, and even thoughalpha-amylase inhibition seemed like a good bet for an agentthat would result in a decreased release of glucose andinsulin, phaseolamin did not appear to work in humans andalmost disappeared from the marketplace. However, phaseo-lamin had a rebirth in the early 2000s that coincided with anincreased interest in low-carbohydrate diets for we'ightmanagement.

ACTIONS AND PHARMACOLOGY

ACTIONSAlpha-amylase inhibitor (phaseolamin) has possible hypo-glycemic activity and possible anorexigenic activity.

MECHANISM OF ACTION

Phaseolamin has demonstrated alpha-amylase activIty, invitro. and in animal studies. Further, inhibition of pancreaticalpha-amylase might be expected to demonstrate less of anincrease in plasma glucose and plasma insulin levelsfollowing a meal, and possibly even a modest weightreduction effect. Parallels might be drawn between apancreatic alpha-amylase inhibitor and two drugs that inhibita related enzyme (alpha-glucosidase) in the digestion ofstarch-acarbose (a maltotetrose derivative) and miglitol (N-hydroxyethyl-l-deoxynojirimycin, a monosaccharide-likesubstance). Both of these drugs r~duce fasting and postpran-dial serum glucose levels and have a modest effect on weightreduction. The possible mechanism of action of thesesubstances is unclear, but may be due to energy loss fromi~creased colonic fermentation of oligosaccharides andmaltose and/or may be due to adiponectin elevation causedby these drugs, among other possibilities. Gastrointestinalside effects, including flatulence, abdominal cramping,borborygms, bloating, diarrhea and nausea, are common inthose who use acarbose or miglitol and have to do withundigested carbohydrates entering the large intestine andundergoing fermentation to short-chain fatty acids and thegases methane and hydrogen. Interestingly, these adverseeffects have rarely been reported in those using phaseolamin,suggesting the possibility that very little or no inhibition ofalpha-amylaseis taking place in vivo. These gastrointestinalsymptoms would very likely occur if undigested starch wereto enter the large intestine to be fermented by its bacterialmicroflora. In this way, the undigested starch would beacting like resistant starch (see Resistant Starch).

Assuming that the inhibition of alpha-amylase does have aweight reduction effect, the mechanism of action of thiseffect is unclear. It is known that a reduction in postprandialinsulin secretion, by preventing rebouild hypoglycemia, canhave a favorable effect on appetite control. There are otherpossibilities and it is conceivable that this might occur viayet unknown mechanisms.

The phaseolamin marketed in the 1980s as a "starch blocker"to control hyperglycemia and obesity showed little or noeffect on plasma glucose levels or on weight. It was thoughtthat was because the preparations at the time were verycrude, had many impurities and little of the alpha-amylaseinhibitor. The "new" alpha-amylase inhibitor is said to haveno impurities and to have much higher alpha-amylaseactivity.

Much research and evidence-based clinical trials are neededin order to determine if the new, reformulated phaseolaminhas a role in postprandial glucose control and weightmanagement.

24/ ALPHA-AMYLASE INHIBITOR (PHASEOLAMIN) PDR FOR NUTRITIONAL SUPPLEMENTS

PHARMACOKINETICS

Little is known about the pharmacokinetics of phaseolamin.Most importantly, research is needed on the stability ofphaseolamin in the stomach and small intestine.

INDICATIONS AND USAGE

There is some evidence that alpha-amylase inhibitor, a so-called "starch blocker" derived from the common whitekidney bean (PhaseDIus vulgaris), may have hypoglycemicand anorexigenic actions and might thus be of benefit in theprevention and treatment of diabetes and obesity. A sugges-tion that this substance might be protective against colorectalcancer is, at this point, based entirely upon a theoreticalmode of action that remains to be demonstrated.

RESEARCH SUMMARY

So-called starch blockers have been marketed for some timeas antiobesity and antidiabetic agents. The claim has beenthat these starch blockers interfere with the breakdown ofcomplex carbohydrate, reducing or prolonging its digestibili-ty and thus reducing carbohydrate absorption, as well asreducing postprandial glucose and insulin levels. There are invitro as well as in vivo animal ,and human data to support thishypothesis, but studies have yielded mixed results over theyears. The inconsistency of these results has been attributedby one rec«nt reviewer of the relevant literature to inefficientextraction methods that resulted in products with impuritiesand low alpha-amylase inhibiting activity. Newer, improvedextraction techniques have resulted in purer, more potentproducts.

Various rat studies using kidney beans or alpha-amylaseinhibitor have demonstrated reduced food intake and subse-quent modest weight loss. There is some evidence thatprolonged administration of the inhibitor is necessary inorder to get any meaningful results. Clinical studies havebeen few, have again reported mixed results and, whenpositive, have mostly, reported what the authors, of a reviewarticle called "subtle weight loss." It appears that moreresearch is needed in order to establish that alpha-amylaseinhibitor has consistent, significant appetite-suppressing!weight-reducing effects.

Rats have exhibited reduced postprandial glucose levelswhen given amylase inhibitor with or before starch-contain-ing meals. Reductions have also been observed in somehuman subjects similarly treated. Decreased serum insulinlevels have been found in both normal and diabetic rats fedamylase inhibitor. There is sufficient preliminary data towarrant further study of the possible beneficial effects ofalpha-amylase inhibitor in diabetes.

The suggestion that alpha-amylase inhibitor might havesome protective effects against colon cancer is purelyhypothetical but may be worthy of further investigation.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRA INDICA T10NS

Products containing alpha-amylase (phaseolamin) should not

be used by anyone who is allergic to any component of a

phaseolamin-containing product.

PRECAUTIONS

Those with type 2 diabetes who wish to try phaseolaminshould do so only with a physician's approval andsupervIsion.

Pregnant women and nursing mothers should avoid the useof phaseolamin.

ADVERSE REACTIONS

If phaseolamin does inhibit pancreatic alpha-amylase, thefollowing gastrointestinal adverse events may be expected:flatulence, abdominal cramping; borborygms, bloating, diar-rhea and nausea.

INTERACTIONS

DRUGSNone known.

FOODS

No known interactions.

DIETARY SUPPLEMENTS

No known interactions.

OVERDOSAGE

No reports.

DOSAGE AND ADMINISTRATION

Phaseolamin is available in 500mg ana 600mg capsules.Those who use phaseolamin take two pills either once a dayin the morning before meals, or two pills before or with eachmeal.

LITERATURE

Carlson GL, Li BU, Bass P, et al. A bean alpha-amylaseinhibitor formulation (starch blocker) is ineffective in man.Sciellce. 1983;219(4583):393-395.

Celleno L, Tolaini MV, D'Amore A, et al. A Dietarysupplement containing standardized Phaseolus vulgaris extractinfluences body composition of overweight men and women. liltJ Med Sci. 2007;4(1):45-52.

Chokshi D. Toxicity studies of Blockal, a dietary supplement,containing Phase 2 Starch Neutralizer (Phase 2), a standardizedextract of the common white kidney bean (Phaseolus vulgaris).lilt J Toxicol. 2006;25(5):361-371.

Draeger KE, Vertesy L, Grigoleit HG. Starch blockers. Lallcet.1983;I(8320):354-355.

Garrow JS, Scott PF, Heels S, et al. A study of 'starchblockers' in man using 13C-enriched starch as a tracer. HumNutr Clill Nutr. 1983;37(4):301-305.

SUPPLEMENT MONOGRAPHS ALPHA-LIPOIC ACID /25

Guzman-Partida AM, Jatomea-Fino 0, Robles-Burgueiio MR, etal. Characterization of alpha-amylase inhibitor from Palo Fierroseeds. Plant Physiol Biochem. 2007;45(9):711-715.

Lee SC, Gepts PL, Whitaker JR. Protein structures of commonbean (Phaseolus vulgaris) alpha-amylase inhibitors. J AgricFood Chem. 2002;50(22):6618-6627.

Marshall JJ, Lauda CM. Purification and properties ofphaseolamin, an inhibitor of alpha-amylase, from the kidneybean, Phaseolus vulgaris. J Bioi Chem. 1975;250(20):8030-8037.

,Nakaguchi T, Arakawa T, Philo JS, et al. Structuralcharacterization of an alpha-amylase inhibitor from a wildcommon bean (Phaseolus vulgaris): insight into the commonstructural features of leguminous alpha-amylase inhibitors. JBiochem. 1997; 121(2):350-354.

Obiro WC, Zhang T, Jiang B. The nutraceutical role of thePhaseolus vulgaris alpha-amylase inhibitor. Br J Nutr.2008; 100(I): 1-12.

Tormo MA, Gil-Exojo I, Romero de Tejada A, et al.Hypoglycaemic and anorexigenic activities of an alpha-amylaseinhibitor from white kidney beans (Phaseolus vulgaris) inWistar rats. Br J Nutr. 2004;92(5):785-790.

Udani J, Hardy M, Madsen DC. Blocking carbohydrateabsorption and weight loss: a clinical trial using Phase 2 brandproprietary fractionated white bean extract. Altern Med Rev.2004;9(1 ):63-69.

Valencia-Jimenez A, Arboleda Valencia JW, Grossi-De-Sa MF.Activity of alpha-amylase inhibitors from Phaseolus coccineuson digestive alpha-amylases of the coffee berry borer. J AgricFood Chem. 2008;56(7):2315-2320.

Zhang XQ, Yang MY, Ma Y, et al. Isolation and activity of analpha-amylase inhibitor from white kidney beans. Yao Xue XueBaa. 2007;42(12): 1282-7.

Alpha-Lipoic AcidDESCRIPTION

Alpha-lipoic acid, also known as thioctic acid, is a disulfidecompound that is a cofactor in vital energy-producingreactions in the body. It is also a potent biologicalantioxidant. Alpha-lipoic acid was once thought to be avitamin for animals and humans. It is made endogenously inhumans-the details of its synthesis are still not fullyunderstood-and so it is not an essential nutrient. There are,however, certain situations, for example, diabetic polyneuro-pathy, where alpha-lipoic acid might have conditionalessentiality. And recent research indicates that the antioxi-dant roles of alpha-lipoic acid may confer several healthbenefits. Alpha-lipoic acid is found widely in plant andanimal sources.

Most of the metabolic reactions in which alpha-lipoic acidparticipates occur in mitochondria. These include the oxida-

tion of pyruvic acid (as pyruvate) by the pyruvate dehydro-genase enzyme complex and the oxidation of alpha-ketoglutarate by the alpha-ketoglutarate dehydrogenaseenzyme complex. It is also a cofactor for the oxidation ofbranched-chain amino acids (leucine, isoleucine and valine)via the branched-chain alpha-keto acid dehydrogenase en-zyme complex.

Alpha-lipoic acid is approved in Germany as a drug for thetreatment of polyneuropathies, such as diabetic and alcoholicpolyneuropathies, and liver disease.

Alpha-lipoic acid contains a chiral center and consists of twoenantiomers, the natural R- or D- enantiomer and the S- orL- enantiomer. Commercial preparations of alpha-lipoic acidconsist of the racemic mixture, i.e. a 50/50 mixture of the R-and E-enantiomers. It is represented by the followingchemical structure:

J 0

H CH2CH2CH2CH2-g-0H

c)Alpha-Lipoic acid

Alpha-lipoic acid has a variety of names. In addition to beingknown as alpha-lipoic acid and thioctic acid, it is also knownas lipoic acid, 1,2-dithiolane-3-pentanoic acid; 1,2-ditholane-3-valeric acid; 6,S-thiotic acid; 5-[3-C I,2-dithiolanyl)]-pen-tanoic acid; delta-[3-(l,2-dithiacyclopentyl)] pentanoic acid;ac~tate replacing factor and pyruvate oxidation factor.Alpha-lipoic acid is water-insoluble.

Although the details of its synthesis have yet to be workedout, alpha-lipoic acid is synthesized in mitochondria; octa-noic acid and L-cysteine (for its sulfur) are precursors in itssynthesis.

ACTIONS AND PHARMACOLOGY

ACTIONS

Alpha-lipoic acid has biological antioxidant activity, antioxi-dant recycling activity and activity in enhancing biologicalenergy production.

MECHANISM OF ACTIONAlpha-lipoic acid and its reduced metabolite, dihydrolipoic

acid (DHLA), form a redox couple and may scavenge a widerange of reactive oxygen species. Both alpha-lipoic acid and

DHLA can scavenge hydroxyl radicals, the nitric oxideradical, peroxynitrite, hydrogen peroxide and hypochlorite.

Alpha-lipoic acid, but not DHLA, may scavenge singlet