158/COLLOIDAL SILVER PDR FOR NUTRITIONAL SUPPLEMENTS

Slawson RM, Lee H, Trevors JT. Bacterial interactions with CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
silver. Bioi Met. 1990; 3:151-154. CONTRAINDICA T10NS
Known hypersensitivity to a colosolic acid-containing
product.

Colosolic Acid PRECAUTIONS

DESCRIPTION
Colosolic acid, sometimes called corosolic acid, is a
triterpene compound extracted from the leaves of the plant
Lagerstroemia speciosa. The leaves of Lagerstroemia speci-
osa are used in Southeast Asia as an herbal remedy for a
number of disorders, including diabetes and obesity. In the
Philippines, the plant is known by the Tagalog name of
banaba.
Colosolic acid has been reported to activate glucose transport
in cell cultures and to lower glucose in diabetic mice. There
are a few reports that colosolic acid lowers blood glucose
levels in type 2 diabetic subjects. However, none of these
reports has appeared in peer-reviewed scientific literature.
Colosolic acid is also known as 2alpha-hydroxyursolic acid,
corosolic acid and botanical insulin. A similar triterpene
called corosolic acid has been isolated from the fruit of
Crataegus pinnatifida var. pilosa, a member of the hawthorn
family.
ACTIONS AND PHARMACOLOGY
ACTIONS
Supplemental colosolic acid is reputed to activate glucose
transport, resulting in hypoglycemic activity.
MECHANISM OF ACTION
The mechanism of action of colosolic's putative hypoglyce-
mic action is not known.
PHARMACOKINETICS
There are no reported pharmacokinetics on colosolic acid.
INDICATIONS AND USAGE
It is claimed that colosolic acid lowers blood glucose in type
2 diabetics, burns fat, lowers elevated blood pressure and
boosts energy, among other things. Currently, there is no
credible evidence to support any claim for the use of this
substance in humans.
RESEARCH SUMMARY
Colosolic acid is reported to activate glucose transport in
Ehrlich ascites tumor cells. Extracts from Lagerstroemia
speciosa. Leaves have been reported to have hypoglycemic
activity in genetically diabetic KK-AY mice. There are no
credible reports that colosolic acid can lower blood glucose
in type 2 diabetics, boost energy, burn fat or lower blood
pressure in hypertensives.
Children, pregnant women and nursing mothers should avoid
using products called colosolic acid or corosolic acid. Those
with diabetes should be extremely cautious about using
colosoliclcorosolic acid. Those with hypoglycemia should
avoid using colosolic/corosolic acid.
ADVERSE REACTIONS
None reported.
INTERACTIONS
If colosolic acid were to lower blood glucose, it could have
additive effects with drugs used in the management of
diabetes, and therefore blood glucose must be closely
monitored.
OVERDOSAGE
None reported.
DOSAGE AND ADMINISTRATION
No recommended dose. Colosolic acid is marketed in stand-
alone supplements and in combination products. Colosolic
acid in these products is usually from extracts of Lagerstroe-
mia speciosa leaves.
LITERATURE
Ahn KS, Hahm MS, Park EJ, et al. Corosolic acid isolated
from the fruit of Crataegus pinnatifida var. pilosa is a prolein
kinase inhibitor a well as a cytotoxic agent. Planta Med. 1998;
64:468-470.
Kakuda T, Sakane I, Takhara T, et al. Hypoglycemic effect of
extracts from Lagerstroernia speciosa L. leaves in genetically
diabetic KK-A Y mice. Biosci Biotechnol Biochern. 1996;
60:204-208.
Murakami C, Myoga K, Kasai R, et al. Screening of planl
constituents for effect on glucose transport activity in Ehrlich
ascites tumour cells. Chern Pharrn Bull. 1993; 41 :2129-2131.
Conjugated Linoleic Acid
(CLA)
DESCRIPTION
Conjugated linoleic acid or CLA refers to a group of
positional and geometric octadecadienoic acid isomers of
linoleic acid. CLA is not a single substance. In contrast to
linoleic acid, all the CLA isomers have conjugated bonds. In
an unsaturated organic compound, two double bonds sepa-
rated by a single bond are said to be conjugated. CLA is
represented by the following structural formulas:
SUPPLEMENT MONOGRAPHS
Conjugated linoleic acid (CLA)
A.
trans,9-cis, 1I-octadecadienoic acid
B. COOH
trans, IO-cis, l2-octadecadienoic acid
CLA is found naturally in animal tissues and food sources,
including ruminant meats, poultry, eggs and dairy products,
such as cheeses, milk and yogurt that have undergone heat
processing treatments. Vegetable fats are generally poorer
sources of CLA. However, CLA is produced from linoleic
acid in safflower oil and sunflower oil by special treatment
of these oils. CLA was originally found in milk fat where it
exists in the form of phospholipids and triglycerides. Also,
there is evidence that human milk contains CLA.
The principal dietary isomer of CLA is cis-9, trans-II CLA,
also known as rumenic acid and RA. This isomer is produced
in the rumen of ruminant animals by microbial metabolism
of linoleic and linolenic acids. Cis-9, trans-ll CLA may be
absorbed directly or undergo further metabolism. Another
CLA isomer, also found in ruminant tissue, is trans-1O, cis-
12 CLA. Most of the animal studies to date with CLA have
used mixtures of CLA isomers that are mostly cis-9, trans-II
CLA and trans-lO, cis-12 CLA in approximately equal
amounts. Most commercial preparations of CLA contain cis-
9, trans-ll CLA and trans-lO, cis-12 CLA along with
smaller amounts of other CLA isomers, including trans-9,
cis-II CLA, cis-1O, cis-12 CLA, trans-9, trans-II CLA,
trans-lO, trans-12 CLA and other isomers with conjugated
double bonds at the 8, 10 and II, 13 positions. The various
isomers may produce different biologic effects.
Cis-9, trans-II CLA is also known as c9, tlI-octadecadien-
oic acid; trans-1O, cis-12 CLA is also known as t1O, cJ2-
octadecadienoic acid. The term octadecadienoates IS
sometimes used synonymously with CLA.
ACTIONS AND PHARMACOLOGY
ACTIONS
CLA may have anti-carcinogenic, anti-atherogenic, anti-
diabetagenic and body composition-modifying activities in
humans. These activities have been reported in experimental
animals.
MECHANISM OF ACTION
The mechanism(s) of actions of CLA are not clearly
understood. To reach a better understanding, it is necessary
to determine the specific, possibly varying, effects of the
different isomers. For example, the CLA-associated body
composition changes observed in animals appear to be
CONJUGATED LINOLEIC ACID (CLA) /159
associated mainly with the trans-lO, cis-12 CLA isomer. In
mouse tissue culture, the trans-lO, cis-12 CLA isomer was
found to reduce lipoprotein lipase activity and concentrations
of intracellular triglyceride. The trans-lO, cis-12 isomer also
decreased the expression of hepatic steroyl-CoA desaturase
mRNA in one mouse study and the expression of stearoyl-
CoA desaturase activity in mouse adipocytes in tissue culture
in another study. Inhibition of stearoyl-CoA desaturase
activity may depress fat synthesis.
Both cis-9, trans-II and trans-lO, cis-12 CLA isomers show
anti-cancer activity. It is speculated that CLA may modulate
eicosanoid activity as well as the activity of such cytokines
as tumor necrosis factor-alpha. It is also speculated that
activation of peroxisome proliferator-activated receptor-
gamma (PPAR-gamma) may play some role in the putative
anti-diabetic activity of CLA. Activation of PPAR-gamma
and/or PPAR-alpha may account, in part, for the anti-
carcinogenic, lipid-lowering and anti-atherogenic effects of
CLA reported in animal studies. The enzymes to produce the
major isomers are being cloned in bacteria, and it is expected
that with the availability of larger amounts of these
materials, the effects and mechanisms of actions of these
isomers, alone or in combination, will become clearer.
PHARMACOKINETICS
Little is currently known about the pharmacokinetics of CLA
in humans. In experimental animals, the CLA isomers do get
absorbed following digestion, but not much is known about
CLA's metabolism subsequent to absorption. Some CLA
appears to get incorporated into the phospholipids of cell
membranes.
INDICATIONS AND USAGE
A hoped-for and early indicated CLA antiobesity effect is
not supported by recent research. Similarly, inconsistent
results make it impossible to conclude at present that CLA is
an effective antiatherogenic agent. Some data suggest
harmful effects from some CLA isomers. There is some
evidence of anticancer activity and some suggestion of
possible benefit in diabetes in a preliminary animal study.
There is also, however, some equally preliminary evidence
that CLA might be prodiabetic.
RESEARCH SUMMARY
Much of the early media "buzz" about CLA was related to
claims that it could "bum fat" and fight obesity. In some
early trials using animal obesity models, it was reported that
CLA-enriched diets reduced body weight independent of
food intake. Some CLA isomers were said to be more
effective than others in fighting fat. Now, many years later, it
appears that CLA does, in fact, reduce weight in some
animal models but shows very little efficacy in humans. One
recent review concluded: "Experiments in humans have not
160 I CONJUGATED LINOLEIC ACID (CLA)
been able to show a significant effect on body weight, body
composition or weight regain related to either of the CLA
isomers" commonly promoted for this purpose. The trans-I 0,
cis-12 and cis-9, trans-II isomers have been combined in
some weight-loss products. And, these reviewers cautioned,
there is some data suggesting possible harm from the trans-
10, cis-12 isomer in terms of negative effects on lipid profile,
glucose metabolism and insulin sensitivity. Another recent
review of CLA weight studies concluded that body weight
loss is "rarely observed" with CLA supplementation in
humans. These reviewers further make reference to "the
absence of confirmed or even plausible mechanisms" by
which CLA might promote weight loss in humans. They
stated that CLA should not be recommended for this
purpose.
CLA has shown some anticancer effects in a number of
animal and in vitro studies. Proliferation of human malignant
breast, colorectal, prostate, melanoma and lung cell lines has
been inhibited by CLA. CLA has inhibited mammary
tumorogenesis in a number of studies that demonstrate its
efficacy in animal models independent of the amount and
type of fat in the diet. In other experimental animal studies, it
has significantly inhibited mouse forestomach neoplasia,
epidermal tumors in mice and aberrant crypt foci in rat
colon.
The mechanisms by which CLA exerts its anti-cancer effects
are not yet understood, but it is evident that, in some cases, it
appears to interact directly with carcinogens to reduce their
potency and that, in other instances, it protects specific
tissues through its interaction with those tissues, independent
of the carcinogen. It appears to modulate carcinogenesis in
all of its separate stages: initiation, promotion, progression.
At one time it was believed that CLA's anti-cancer and other
therapeutic effects were largely due to an anti-oxidant
property. More recent research demonstrated no significant
CLA anti-oxidant effect. Instead, it is now believed by some
that CLA exerts beneficial complex regulatory effects at the
molecular level through its influence, among other things, on
peroxisome proliferator-activated receptors (PPAR). The
PPARs are nuclear receptors that modulate gene expression
in response to fatty acids, some drugs and other substances.
It is also believed to modulate eicosanoid and cytokine
activity as well.
One group of researchers recently reported that high-CLA
diets reduce the quantity of terminal end buds out of which
mammary tumors develop. They further observe that CLA
seems to inhibit cancer by selectively inhibiting rapidly
dividing cells and by promoting programmed cell death or
apoptosis.
PDR FOR NUTRITIONAL SUPPLEMENTS
More animal data have continued to accumulate, but, so far,
meaningful clinical data related to a possible role of CLA in
human cancers is lacking. Safety studies in human cancer
conditions are needed before clinical trials can be launched.
Some have expressed fear that some isomers or combination
of CLA isomers might pose peril.
CLA's widely reported hypolipidemic effects (in animal
studies) are also believed to be linked to the substance's
influence on PPAR subtypes involved with lipid metaboliz-
ing enzymes and the modulation of plasma triglyceride
clearance, among other things. Beneficial effects on lipids
have been reported in rats, mice, rabbits, chickens, hamsters
and in other animal models. Atheromatous lesions have
regressed significantly in CLA-supplemented animals. And
CLA has significantly reduced free fatty acids and triglycer-
ides in Zucker diabetic fatty rats compared with fatty rats on
control diets.
Despite some preliminary positive results, as discussed
above, a recent review of the CLA atherosclerosis data
concluded that after a decade of research no consensus has
yet been reached on the potential for CLA to meaningfully
modify atherosclerosis in animals, let alone in humans,
where data is almost wholly lacking. There is no convincing
evidence at this time, these reviewers concluded, that CLA
reduces the incidence or severity of atherosclerotic lesions or
that CLA can improve plasma lipid and lipoprotein levels.
Moreover, as noted above, some researchers have observed
that, in some circumstances, at least one CLA isomer exerted
negative effects on lipid profile, glucose metabolism and
insulin sensitivity.
In view of the latter, some preliminary indications that CLA
might have benefit in a pre-diabetic animal model wiJJ need
particularly careful follow-up.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICA TlONS
CLA is contraindicated in those hypersensitive to any
component of the preparation.
PRECAUTIONS
Because of lack of long-term safety data, CLA supplements
should be avoided by children, pregnant women and nursing
mothers.
ADVERSE REACTIONS
At doses of up to 2 grams daily, occasional gastrointestinal
complaints, such as nausea, have been noted.
DOSAGE AND ADMINISTRATION
There are a few products with CLA available. The amounts
of the two most studied isomers of CLA,cis-9, trans-II and
trans-lO, cis-12 CLA, vary. Also, there are different amounts
of other isomers of CLA in the various preparations. Typical
SUPPLEMENT MONOGRAPHS
doses are I to 2 grams daily. Some use doses up to 6 grams
daily.
CLA is also being developed for use in functional foods.
LITERATURE
Banni S, Angioni E, Stefani a M, et al. Conjugated linoleic acid
and oxidative stress. J Am Oil Chem Soc. 1998;75:261-267.
Belury MA. Conjugated linoleate: a polyunsaturated fatty acid
with unique chemopreventive properties. Nutr Rev. 1995;53:83-
89.
Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of
linoleic acid and conjugated linoleic acid on human prostate
cancer in SCID mice. Anticanc Res. 1998;18:833-838.
de Deckere EA, van Amelsvoort JM, Mc Neill GP, Jones P.
Effects of conjugated linoleic acid (CLA) isomers on lipid
levels and peroxisome proliferation in the hamster. Br J Nutr.
1999;82:309-317.
Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric
mixture of conjugated linoleic acids but not pure cis-9, trans-
II-octadecadienoic acid affects body weight gain and plasma
lipids in hamsters. J Nutr. 2000;130:27-29.
Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et
al. Dietary conjugated linoleic acid normalizes impaired glucose
tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys
Res Commun. 1998;244:678-682.
Kelley NS, Hubbard NE, Erickson KL. Conjugated linoleic acid
isomers and cancer. J Nutr. 2007;137(12):2599-2607.
Lee KN, Kritchevsky D, Pariza MW. Conjugated linoleic acid
and atherosclerosis in rabbits. Atherosc/ero. 1994; \08: 19-25.
Lee KN, Pariza MW, Ntambi JM. Conjugated linoleic acid
decreases hepatic stearoyl-CoA desaturase mRNA expression.
Biochem Biophys Res Commun. 1998;248:817-821.
McCarty MF. Downregulaton of macrophage activation by
PPAR gamma suggests a role for conjugated linoleic acid in
prevention of Alzheimer's disease. J Med Food. 1998;1:217-
226.
Mitchell PL, McLeod RS. Conjugated linoleic acid and
atherosclerosis: studies in animal models. Biochem Cell Bioi.
2008;86(4):293-30 I.
Moya-Camarena SY, Belury MA. Species differences in the
metabolism and regulation of gene expression by conjugated
linoleic acid. Nutr Rev. 1999;57:336-340.
Ostrowski E, Muralitharan M, Cross RF. Dietary conjugated
linoleic acids increase lean tissue and decrease fat deposition in
growing pigs. J Nutr. 1999;129:2037-2042.
Pariza MW, Park Y, Cook ME. Conjugated linoleic acid and
the control of cancer and obesity. Toxicol Sci. 1999;51(2
Suppl): \07-1\0.
Pariza MW, Park Y, Cook ME. Mechanisms of action of
conjugated linoleic acid: evidence and speculation. Proc Soc
Exp Bioi Med. 2000;223:8-13.
COPPER /161
Pariza MW, Park Y, Kim S, et al. Mechanism of body fat
reduction by conjugated linoleic acid. FASEB J. 1997;II:AI39.
Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic
acid on body composition in mice. Lipids. 1997;32:853-858.
Plourde M, Jew S, Cunnane SC, Jones Pl Conjugated linoleic
acids: why the discrepancy between animal and human studies?
Nutr Rev. 2008;66(7):415-421.
Silveira MB, Carraro R, Monereo S, et al. Conjugated linoleic
acid (CLA) and obesity. Public Health Nutr.
2007; \0(1 OA):1181-1186.
van den Berg 11, Cook NE, Tribble DL. Reinvestigation of the
antioxidant properties of conjugated linoleic acid. Lipids.
1995;30:599-605.
West DB, Delany JP, Camet PM, et al. Effects of conjugated
linoleic acid on body fat and energy metabolism in the mouse.
Am J Physiol. 1998;275(3 Pt 2):R667-R672.
Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW,
Nelson GJ, eds. Advances in Conjugated Linoleic Acid
Research. Volume I. Champaign, IL:AOCS Press;1999.
Further information:
To keep track of CLA progress, an updated listing can be
found on the Internet at http://www.wisc.edu/fri/clarefs.htm.
Copper
DESCRIPTION
Copper is an essential trace mineral in animal and human
nutrition. Anemia, neutropenia and osteoporosis are found
with frank copper deficiency. Copper deficiency in humans
is rare but it does occur under certain circumstances, such as
in patients receiving long-term total parenteral nutrition
(TPN). Mild copper deficiency due to marginal copper intake
over a long period may also occur. In addition to possible
anemia, neutropenia and osteoporosis, manifestations of mild
copper deficiency may include abnormal glucose tolerance,
hypercholesterolemia, arthritis, myocardial disease, arterial
disease, cardiac arrhythmias, loss of pigmentation and
neurological problems.
Copper is a transition metal with atomic number 29 and an
atomic weight of 63.55 daltons. Its .symbol is Cu. Copper
participates in metabolism as a component of many metal-
loenzymes, including ceruloplasmin or ferroxidase I, cyto-
chromecoxidase, copper/zinc superoxide dismutase,
dopamine beta-hydroxylase, tyrosinase, monoamine oxidase,
diamine oxidase, lysyl oxidase (protein-lysine 6-oxidase),
peptidylglycine-alpha-amidating monoxygenase and ferroxi-
dase II.
Copper essentiality for humans was first demonstrated in
malnourished children in Peru. The children had an anemia