DESCRIPTION
Methylsulfonylmethane, abbreviated
MSM, is an organic sulfur-containing compound that occurs naturally in
a variety of fruits, vegetables, grains and in animals, including
humans in at least trace amounts. MSM has also been found in such
plants as Equisetem arvense, also known as horsetail.
The biological role of MSM, if any, is not known. MSM is a metabolite
of dimethyl sulfoxide or DMSO (see Dimethyl Sulfoxide). It is believed
that some of the possible effects of DMSO could be attributed to MSM.
MSM is a water-soluble, solid
compound. It is also known as dimethyl sulfone, DMSO2,
sulfonylbismethane and methyl sulfone.
ACTIONS AND PHARMACOLOGY
ACTIONS
None known.
PHARMACOKINETICS
Little is known about the
pharmacokinetics of MSM in humans. Sulfur from MSM was found to be
incorporated into protein methionine and cysteine when fed to guinea
pigs. MSM was also detected in the brain of a normal 62-year old male,
following its ingestion, using in vivo proton magnetic
resonance spectroscopy. Thus, it appears that MSM gets absorbed and
can cross the blood-brain barrier.
INDICATIONS AND USAGE
Claims for MSM include pain relief,
particularly in arthritis, immune modulation in autoimmune disorders,
muscle repair, sleep aid and diabetes therapy. There is preliminary
research suggesting some possible MSM anti-cancer effects.
RESEARCH SUMMARY
Two animal studies showed that MSM
and other bipolar solvents can prolong latency period to time of tumor
appearance in chemically induced animal model cancers. In one of these
studies, there was no effect on tumor incidence; in the other, MSM
seemed to reduce the incidence of poorly differentiated tumors. More
research is indicated.
CONTRAINDICATIONS, PRECAUTIONS
ADVERSE REACTIONS
CONTRAINDICATIONS
None known.
PRECAUTIONS
MSM should be avoided by pregnant
women and nursing mothers.
ADVERSE REACTIONS
Reported adverse reactions include
nausea, diarrhea and headache.
OVERDOSAGE
There are no reports of overdosage.
DOSAGE AND ADMINISTRATION
Doses used are typically 1 to 8 grams
daily.
HOW SUPPLIED
Powder — 2600 mg/0.5
teaspoonful
Tablets — 1000 mg
LITERATURE
Childs SJ. Dimethyl sulfone (DMSO2)
in the treatment of interstitial cystitis. Urol Clin North
Am. 1994; 21:85-98.
Kandorf H, Chirra AR, De Gruccio A,
Girman DJ. Dimethyl sulfoxide modulation of diabetes onset in NOD
mice. Diabetes. 1989; 38:194-197.
Kocsis JJ, Harkaway S, Snyder R.
Biological effects of the metabolites of dimethyl sulfoxide. Ann NY
Acad Sci. 1975; 243:104-109.
Layman DL. Growth inhibitory effects
of dimethyl sulfoxide and dimethyl sulfone on vascular smooth muscle
and endothelial cells in vitro. In Vitro Cell Dev Biol. 1987;
23:422-428.
Morton JI, Siegel BV. Effects of oral
dimethyl sulfoxide and dimethyl sulfone on murine autoimmune
lymphoproliferative disease. Proc Soc Exp Biol Med. 1986; 183;
227-230.
O'Dwyer PJ, McCabe DP, Sickle-Santanello
BJ, et al. Use of polar solvents in chemoprevention of 1,
2-dimethylhydrazine-induced colon cancer. Cancer. 1988;
62:944-948.
Pearson TW, Dawson HJ, Lackey HB.
Natural occurring levels of dimethyl sulfoxide in selected fruits,
vegetables, grains and beverages. J Agric Food Chem. 1989;
29:1089-1091.
Richmond VL, Incorporation of
methylsulfonylmethane sulfur into guinea pig serum proteins. Life
Sci. 1986; 39:263-268.
Rose SE, Chalk JB, Galloway GJ,
Doddrell DM. Detection of dimethyl sulfone in the human brain by in
vivo proton magnetic resonance spectroscopy. Magn Reson Imaging.
2000; 18:95-98.
TRADE NAMES
Glucosamine is available from
numerous manufacturers generically. Branded products include Aflexa
(McNeil Consumer), Natures Blend Glucosamine (National Vitamin Co.),
GS-500 (Enzymatic Therapy), Glucosamine Complex (Schiff), Maxi GS
(Maxi-Health Research), NAG (Twinlab).
DESCRIPTION
Glucosamine is an amino
monosaccharide found in chitin, glycoproteins and glycosaminoglycans
(formerly known as mucopolysaccharides) such as hyaluronic acid and
heparan sulfate. Glucosamine is also known as 2-amino-2-deoxyglucose,
2-amino-2-deoxy-beta-D-glucopyranose and chitosamine. Glucosamine has
the following chemical structure:
Glucosamine
Glucosamine is available commercially
as a nutritional supplement in three forms: glucosamine hydrochloride
or glucosamine HCl, glucosamine sulfate and N-acetyl-glucosamine.
At neutral as well as physiologic pH,
the amino group in glucosamine is protonated, resulting in its having
a positive charge. Salt forms of glucosamine contain negative anions
to neutralize the charge. In the case of glucosamine hydrochloride,
the anion is chloride, and in glucosamine sulfate the anion is
sulfate. N-acetylglucosamine is a delivery form of glucosamine in
which the amino group is acetylated, thus neutralizing its charge. To
date, most of the clinical studies examining the effect of glucosamine
on osteoarthritis have been performed with either the sulfate or the
chloride salts of glucosamine. All three forms are water soluble.
The glucosamine used in supplements
is typically derived from marine exoskeletons. Synthetic glucosamine
is also available.
ACTIONS AND PHARMACOLOGY
ACTIONS
The actions of supplemental
glucosamine have yet to be clarified. It may play a role in the
promotion and maintenance of the structure and function of cartilage
in the joints of the body. Glucosamine may also have anti-inflammatory
properties.
MECHANISM OF ACTION
Until the specific actions of
supplemental glucosamine are determined, the mechanism of action in
relieving arthritic pain and in repair of cartilage is a matter of
speculation. However, we do know a great deal about the biochemistry
of the molecules in which glucosamine is found. Biochemically,
glucosamine is involved in glycoprotein metabolism. Glycoproteins,
known as proteoglycans, form the ground substance in the
extra-cellular matrix of connective tissue. Proteoglycans are
polyanionic substances of high-molecular weight and contain many
different types of heteropolysaccharide side-chains covalently linked
to a polypeptide-chain backbone. These polysaccharides make up to 95%
of the proteoglycan structure. In fact, chemically, proteoglycans
resemble polysaccharides more than they do proteins.
The polysaccharide groups in
proteoglycans are called glycosaminoglycans or GAGs. GAGs include
hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan
sulfate, heparin and heparan sulfate. All of the GAGs contain
derivatives of glucosamine or galactosamine.
Glucosamine derivatives are found in
hyaluronic acid, keratan sulfate and heparan sulfate. Chondroitin
sulfate contains derivatives of galactosamine.
The glucosamine-containing
glycosaminoglycan hyaluronic acid is vital for the function of
articular cartilage. GAG chains are fundamental components of aggrecan
found in articular cartilage. Aggrecan confers upon articular
cartilage shock-absorbing properties. It does this by providing
cartilage with a swelling pressure that is restrained by the tensile
forces of collagen fibers. This balance confers upon articular
cartilage the deformable resilience vital to its function.
In the early stages of degenerative
joint disease, aggrecan biosynthesis is increased. However, in later
stages, aggrecan synthesis is decreased, leading eventually to the
loss of cartilage resiliency and to most of the symptoms that
accompany osteoarthritis.
During the progression of
osteoarthritis, exogenous glucosamine may have a beneficial role. It
is known that, in vitro, chondrocytes do synthesize more
aggregan when the culture medium is supplemented with glucosamine. N-acetylglucosamine
is found to be less effective in these in vitro studies.
Glucosamine has also been found to have antioxidant activity and to be
beneficial in animal models of experimental arthritis.
The counter anion of the glucosamine
salt (i.e. chloride or sulfate) is unlikely to play any role in the
action or pharmacokinetics of glucosamine. Further, the sulfate in
glucosamine sulfate supplements should not be confused with the
glucosamine sulfate found in such GAGs as keratan sulfate and heparan
sulfate. In the case of the supplement, sulfate is the anion of the
salt. In the case of the above GAGs, sulfate is present as an ester.
Also, there is no glucosamine sulfate in chondroitin sulfate.
PHARMACOKINETICS
Pharmacokinetics of glucosamine are
derived primarily from animal studies. About 90% of glucosamine
administered orally as a glucosamine salt gets absorbed from the small
intestine, and from there it is transported via the portal circulation
to the liver. It appears that a significant fraction of the ingested
glucosamine is catabolized by first-pass metabolism in the liver. Free
glucosamine is not detected in the serum after oral intake, and it is
not presently known how much of an ingested dose is taken up in the
joints in humans. Some uptake in the articular cartilage is seen in
animal studies.
INDICATIONS
Glucosamine may be indicated for the
treatment and prevention of osteoarthritis, either by itself or in
combination with chondroitin sulfate (see Chondroitin Sulfate).
RESEARCH SUMMARY
Two recent meta-analyses have
confirmed that glucosamine is useful in the treatment of
osteoarthritis. One of these meta-analyses included all double-blind,
placebo-controlled trials that lasted four weeks or longer. This
meta-analysis also included trials that studied the effects of
chondroitin sulfate (see Chondroitin Sulfate). In all, there were l3
of these studies (six involving glucosamine and seven involving
chondroitin sulfate).
All l3 studies found positive results
in hip or knee osteoarthritis. The authors of the meta-analysis judged
a trial positive if there was 25% or more improvement in the treatment
group compared with placebo. The Levesque Index and global pain scores
were used to assess improvement. Very significant improvement was
associated with both glucosamine (39.5%) and chondroitin sulfate
(40.2%), compared with placebo.
In another recent meta-analysis of
nine randomized, controlled trials of glucosamine, glucosamine was
significantly superior to placebo in seven of the studies and was
superior to ibuprofen and equal to ibuprofen in the other two studies.
Recently, a long-term, randomized
placebo-controlled trial of glucosamine sulfate's effects on
osteoarthritis ended with the conclusion that the supplement halts
progression of structural joint damage and reduces symptoms of those
with osteoarthritis of the knee. The study involved 212 patients 50
years or older who received 1500 milligrams of glucosamine sulfate
daily or placebo.
Radiographic evidence, at a
three-year followup, showed joint space narrowing--the prime indicator
of arthritic joint damage--in the placebo group consistent with what
has been documented to be typical in untreated osteoarthritis. The
glucosamine-supplemented subjects, on the other hand, showed only a
non-significant increase in joint space at the same three-year
followup.
There has been one study
demonstrating an apparent synergistic effect using glucosamine and
chondroitin together. The combination was more effective than either
substance alone in inhibiting progression of degenerative cartilage
lesions in an experimental study.
Clinical research is needed to
determine if this effect is truly synergistic, additive or
non-existent. The National Institutes of Health has started a large,
multi-center study that may shed further light on this issue.
It is probably not surprising that
glucosamine may be helpful in osteoarthritis. Glucosamine is crucial
for the construction of glycosaminoglycans (GAGs) in articular
cartilage. Reduced GAG content in osteoarthritic cartilage matrix
corresponds with the severity of osteoarthritis. Oral glucosamine
appears to be capable of prompting the chondrocytes to secrete more
GAGs. This knowledge, derived from animal and in vitro studies,
has prompted clinical trials of glucosamine in osteoarthritis.
CONTRAINDICATIONS, PRECAUTIONS,
ADVERSE REACTIONS
CONTRAINDICATIONS
There are no known contraindications
to glucosamine supplementation.
WARNINGS AND PRECAUTIONS
Glucosamine may increase insulin
resistance. Glucosamine increases insulin resistance in normal and
experimentally diabetic animals. In these animals, intravenous
glucosamine significantly decreases the rate of glucose uptake in
skeletal muscle. In animals given oral glucosamine, this is not
observed.
Those with type 2 diabetes and those
who are overweight and have problems with glucose tolerance should
have their blood sugars carefully monitored if they use glucosamine
supplements. Because of insufficient safety data, children, pregnant
women and nursing mothers should avoid using glucosamine.
ADVERSE REACTIONS
Side effects that have been reported
are mainly mild gastrointestinal complaints such as heartburn,
epigastric distress and diarrhea. No allergic reactions have been
reported including sulfa-allergic reactions to glucosamine sulfate.
INTERACTIONS
Glucosamine may increase insulin
resistance and consequently affect glucose tolerance. Diabetics who,
under medical advisement, decide to use glucosamine supplements will
need to monitor their blood glucose and may need to adjust the doses
of the medications they take to control blood glucose. This needs to
be done under medical supervision. No other drug, nutritional
supplement, food or herb interaction is known.
OVERDOSAGE
None known.
DOSAGE AND ADMINISTRATION
The three forms of glucosamine
available commercially are glucosamine hydrochloride, glucosamine
sulfate and N-acetyl glucosamine. The usual dose used by those with
osteoarthritis is l,500 milligrams daily in divided doses. These three
forms of glucosamine are available in 500 milligram capsules.
The amount of glucosamine base varies
with the supplemental form. Pure glucosamine hydrochloride is about
83% in glucosamine base, pure glucosamine sulfate is about 65% in
glucosamine base, and pure N-acetyl glucosamine, about 75% in
glucosamine base. It is important that all clinical studies
standardize the glucosamine dose of the form used to glucosamine base.
Supplements are available containing
glucosamine and low-molecular-weight chondroitin sulfate. (See
Chondroitin Sulfate.)
It usually takes several weeks of
supplementation before effects, if any, are noted.
HOW SUPPLIED
Capsules — 500 mg, 550 mg, 750
mg, 1000 mg
Powder
Liquid — 500 mg/5 mL
Tablets — 340 mg, 500 mg, 1000
mg
LITERATURE
Deal CL, Moskowitz RW. Nutraceuticals
as therapeutic agents in osteoarthritis. The role of glucosamine,
chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North
Am. 1999; 25:379-395.
Drovanti A, Bignamini AA, Rovati AL.
Therapeutic activity of oral glucosamine sulfate in osteoarthritis, a
placebo-controlled double-blind investigation. Clin Ther. 1980;
3:260-272.
Houpt JB, McMillan R, Wein C, Paget-Dello
SD. Effect of glucosamine hydrochloride in the treatment of pain of
osteoarthritis of the knee. J Rheumatol. 1999; 26:2423-2430.
Leffler CT, Philippi AF, Leffler SG,
et al. Glucosamine, chondroitin, and manganese ascorbate for
degenerative joint disease of the knee or low back: a randomized
double-blind, placebo-controlled pilot study. Mil Med. 1999;
64:85-91.
McClain DA, Crook, ED. Hexosamines
and insulin resistance. Diabetes. 1996; 45:l003-l006.
Noack W, Fischer, M., Forster, KK, et
al. Glucosamine sulfate in osteoarthritis of the knee.
Osteoarthritis Cartilage. 1994; 2:51-59.
Pujalte JM, Llavore EP, Ylescupidez
FR. Double-blind evaluation of oral glucosamine sulfate in the basic
treatment of osteoarthritis. Curr Med Res Opin. 1980;
7:110-114.
Reichelt A, Forster K, Fisher M, et
al. Efficacy and safety of intramuscular glucosamine sulfate in
osteoarthritis of the knee. A randomized, placebo-controlled,
double-blind study. Arzneimittelforschung. 1999; 44:75-80.
Setnikar I, Giacchetti C, Zanolo G.
Pharmacokinetics of glucosamine in the dog and in man.
Arzneimittelforschung. 1986; 36:729-735.
Setnikar I, Palumbo R, Canali S,
Zanolo G. Pharmacokinetics of glucosamine in man.
Arzneimittelforschung.1993; 43:1109-1113.
Towheed TE, Anastassiades TP.
Glucosamine and chondroitin for treating symptoms of osteoarthritis.
Evidence is widely touted but incomplete. JAMA. 2000; 283:1483-1484.
Towheed TE, Anastassiades TP.
Glucosamine therapy for osteoarthritis. Editorial. J
Rheumatol l999; 26:2294-2297.
TRADE NAMES
Chondroitin sulfate is available from
numerous manufacturers generically. Branded products include Ramott
(Key Company) Chondroitin Sulfate Support (Natural Treasures), CSA (Twinlab),
Chonflex (American Health).
DESCRIPTION
Chondroitin sulfate belongs to a
family of heteropolysaccharides called glycosaminoglycans or GAGs.
Glycosaminoglycans were formerly known as mucopolysaccharides. GAGs in
the form of proteoglycans comprise the ground substance in the
extracellular matrix of connective tissue. Chondroitin sulfate is made
up of linear repeating units containing D-galactosamine and D-glucuronic
acid. Chondroitin sulfate is found in humans in cartilage, bone,
cornea, skin and the arterial wall. This type of chondroitin sulfate
is sometimes referred to as chondroitin sulfate A or
galactosaminoglucuronoglycan sulfate. The amino group of
galactosamines in the basic unit of chondroitin sulfate A is
acetylated, yielding N-acetyl-galactosamine; there is a sulfate group
esterified to the 4-position in N-acetyl-galactosamine. (Chondroitin
sulfate A is also sometimes called chondroitin 4-sulfate.) The
molecular weight of chondroitin sulfate ranges from 5,000 to 50,000
daltons and contains about 15 to 150 basic units of D-galactosamine
and D-glucuronic acid. It is represented by the following structural
formula:
|
 |
Chondroitin sulfate A R = SO3H R1
= H
Chondroitin sulfate C R = H R1 = SO3H
Chondroitin sulfate C, primarily
found in fish and shark cartilage, but also in humans, is also made up
of linear repeating units of D-galactosamine and D-glucuronic acid.
The amino group of D-galactosamine is acetylated to give N-acetyl-galactosamine,
and, in the case of chondroitin sulfate C, the sulfate group is
esterified to the 6-position in N-acetyl-galactosamine. Chondroitin
sulfate C is sometimes called chondroitin 6-sulfate. Chondroitin
sulfate B is also known as dermatan sulfate. It is abundant in skin
and is also found in heart valves, tendons and arterial walls.
Dermatan sulfate is made up of linear repeating units containing D-galactosamine
and either L-iduronic acid or D-glucuronic acid. Its molecular weight
ranges from 15,000 to 40,000 daltons.
The source of chondroitin sulfate
used in nutritional supplements includes the cartilaginous rings of
bovine trachea and pork byproducts (ears and snout). Shark cartilage
and whale septum cartilage have also been used to obtain chondroitin
sulfate. Chondroitin sulfate supplements are usually isomeric mixtures
of chondroitin sulfate A(chondroitin 4-sulfate) and chondroitin
sulfate C(chondroitin 6-sulfate).
ACTIONS AND PHARMACOLOGY
ACTIONS
The action of orally administered
chondroitin sulfate has yet to be clarified. Possible actions include
promotion and maintenance of the structure and function of cartilage
(referred to as chondroprotection), pain relief of osteoarthritic
joints and anti-inflammatory activity.
MECHANISM OF ACTION
Until the specific actions of
supplemental chondroitin sulfate are determined, the mechanism of
action is a matter of speculation. However, much is known about the
biochemistry and physiology of chondroitin sulfate and similar
molecules. Glycoproteins known as proteoglycans form the ground
substance in the extracellular matrix of connective tissue.
Proteoglycans are polyanionic substances of high molecular weight and
contain heteropolysaccharide-side-chains covalently linked to a
polypeptide-chain backbone. The polysaccharides, which include
chondroitin sulfate and hyaluronic acid, make up as much as 95% of the
proteoglycan structure.
The polysaccharides in proteoglycans
are called glycosaminoglycans or GAGs. Chondroitin sulfate and
hyaluronic acid are vital for the structure and function of articular
cartilage. Chondroitin sulfate and hyaluronic acid are fundamental
components of aggrecan found in articular cartilage. Aggrecan confers
upon articular cartilage shock-absorbing properties. It does this by
providing cartilage with a swelling pressure that is restrained by the
tensile force of collagen fibers. This balance confers upon articular
cartilage the deformable resilience vital to its function. Hyaluronic
acid, which is also found in synovial fluid, has lubricating
properties for the joint.
In the progression of degenerative
joint disease or osteoarthritis, aggrecan synthesis is decreased,
leading to the loss of cartilage resiliency and the pain and other
symptoms that accompany osteoarthritis.
Intra-articular injections of
hyaluronic acid, an FDA-approved drug, can relieve joint pain and
improve mobility. This type of therapy is called viscotherapy and is
believed to act by improving joint lubrication. If chondroitin sulfate
were delivered into joints, some similar effects would be expected.
Animal studies have shown that parenterally administered chondroitin
sulfate does get into cartilage tissue as does orally administered
chondroitin sulfate. There is some human data suggesting orally
administered chondroitin sulfate, particularly low-molecular-weight
chondroitin sulfate, is also delivered to articular tissue. There is
some indication that orally administered chondroitin sulfate leads to
increases in hyaluronic acid and viscosity of synovial fluid, as well
as decreases in collagenase in synovial fluid. That is, glucosamine
delivered into joints may inhibit enzymes involved in cartilage
degradation and enhance the production of hyaluronic acid.
PHARMACOKINETICS
Earlier studies using
high-molecular-weight chondroitin sulfate, concluded that there was no
significant absorption of this high-molecular-weight version of
chondroitin sulfate. More recent studies demonstrate that there is
probably significant absorption of low-molecular-weight chondroitin
sulfate. Absorption appears to occur from the stomach and small
intestine. There is also an indication that some chondroitin sulfate,
after absorption, does enter the joint space. Studies of the
pharmacokinetics of orally administered chondroitin sulfate are
ongoing.
It is of interest to note that a
molecule similar in many resects to chondroitin sulfate, pertosan
polysulfate, FDA-approved for the treatment of interstitial cystitis,
is given orally and is absorbed to some extent.
INDICATIONS AND USAGE
Low-molecular-weight oral chondroitin
sulfate may be indicated for the treatment and prevention of
osteoarthritis, either by itself or in combination with a glucosamine
supplement (see Glucosamine). There is a suggestion that chondroitin
sulfate may be helpful in atherosclerosis, but more research is needed
to determine if this is the case.
RESEARCH SUMMARY
Two recent meta-analyses indicate
that chondroitin sulfate may be useful in the treatment of
osteoarthritis. One of these meta-analyses included all double-blind,
placebo-controlled trials that lasted four weeks or longer. This
meta-analysis also included trials that studied the effects of
glucosamine (see Glucosamine) on osteoarthritis. In all, there were 13
of these studies (six involving glucosamine and seven involving
chondroitin sulfate).
All 13 studies found positive results
in hip or knee osteoarthritis. The authors of the meta-analysis judged
a trial positive if there was 25% or more improvement in the treatment
group compared with placebo. The Levesque Index and global pain scores
were used to assess improvement. Very significant improvement was
associated with both glucosamine (39.5%) and chondroitin (40.2%),
compared with placebo.
In another recent meta-analysis of
chondroitin sulfate, this one examining four randomized double-blind,
placebo- or NSAID-controlled studies of 227 patients, chondroitin
sulfate supplemented subjects showed at least 50% improvement,
compared with controls. Various studies have reported significant
reduction in NSAID use among osteoarthritis subjects supplemented with
chondroitin sulfate.
There is also radiological evidence
of chondroitin's possible efficacy in osteoarthritis. Knee joint space
decreased significantly in placebo subjects but remained unchanged in
those receiving chondroitin sulfate for a year. And, in another study,
those receiving chondroitin sulfate showed significantly fewer
instances of erosive osteoarthritis (compared with placebo controls)
on hand radiographs over a three-year period.
A significant synergistic effect has
been reported recently using combined glucosamine hydrochloride and
chondroitin sulfate in an experimental study. The combination was more
effective than either substance alone in inhibiting progression of
degenerative cartilage lesions. Longer term clinical studies are
needed to confirm or refute this synergy effect. A large multi-center
study directed by the National Institutes of Health is now underway
and may shed further light on this issue.
It is believed that chondroitin
sulfate's possible efficacy in osteoarthritis derives from the fact
that it is one of the two most abundant glycosaminoglycans (GAGs) in
articular cartilage. Supplementation with this GAG seems, in part at
least, to confer chondroprotection through its inhibitory action on
some of the enzymes that damage cartilage. Further, by inhibiting
other enzymes that can block transport of nutrients that nourish
cartilage, this GAG may promote cartilage replacement.
It has been known for some time that
injections of hyaluronic acid into arthritic joints can bring
significant pain relief and enhanced mobility. Thus it is logical to
assume that chondroitin sulfate, if it can reach the joints, may have
similar effects since this substance has the ability to bind to
receptor sites on synovial cell surfaces and thus induce production of
hyaluronic acid, crucial to joint mobility.
The question for some time was
whether a large molecule like chondroitin sulfate could achieve this
penetration. Recent studies demonstrate that a low-molecular-weight
version of oral chondroitin sulfate, of the sort used in all of the
U.S. clinical trials, is absorbed.
Some years ago, chondroitin sulfate
was investigated for its possible use in atherosclerosis. There was
some evidence that it could favorably lower lipid levels and protect
against blood clotting. Atheromatous aortic lesions were prevented in
animals on high-cholesterol diets.
In a clinical trial, 60 patients
suffering from coronary artery disease received 2 grams of oral
chondroitin sulfate daily for 900 days. During that period, 16 of 60
unsupplemented control patients suffered acute coronary incidents.
Only one of the chondroitin sulfate-treated subjects had an acute
coronary incident. The same research group later followed up with
similarly positive results.
More research is needed before any
conclusions can be drawn with respect to a possible role for
chondroitin sulfate in the treatment or prevention of atherosclerosis.
CONTRAINDICATIONS, PRECAUTIONS,
ADVERSE REACTIONS
CONTRAINDICATIONS
None known.
PRECAUTIONS
Because of insufficient safety data,
children, pregnant women and nursing mothers should avoid using
chondroitin sulfate. Because of the theoretical possibility that
chondroitin sulfate may have antithrombotic activity, those taking
warfarin and those with hemophilia should exercise caution in its use.
Those who need to restrict their salt intake should , if they use
chondroitin sulfate, use salt-free preparations.
ADVERSE REACTIONS
Side effects that have been reported
are mostly of the mild gastrointestinal variety, such as epigastric
distress, nausea and diarrhea. No sulfa-allergic reactions or other
allergic reactions have yet been reported.
INTERACTIONS
There are no known drug, nutrient,
food or herb interactions. Chitosan (see Chitosan) may form complexes
with chondroitin sulfate decreasing its absorption. Therefore,
chondroitin sulfate should not be used concomitantly with chitosan.
OVERDOSAGE
Overdosage of chondroitin has not
been reported in the literature.
DOSAGE AND ADMINISTRATION
Low-molecular-weight chondroitin
sulfate is available as a stand-alone supplement or in combination
with glucosamine (see Glucosamine). The usual dose used by those with
osteoarthritis is 1,200 milligrams daily in divided doses.
It usually takes several weeks of
supplementation before effects, if any, are experienced.
Chondroitin sulfate in combination
with hyaluronic acid is available as an FDA-approved drug. It is used
as a viscoelastic agent in cataract surgery. Hyaluronic acid itself is
FDA approved for the treatment of osteoarthritis. The two forms
presently available, Hylan G-F 20 (Synvisc, Wyeth-Ayerst) and sodium
hyaluronate (Hyalgan, Sanofi/Orthologic), are given by intra-articular
injection.
HOW SUPPLIED
Capsules — 250 mg, 400 mg, 500
mg
Powder
Tablets — 250 mg, 400 mg, 600
mg
LITERATURE
Baici A, Horler D, Moser B, et al.
Analysis of glycosaminoglycans in human serum after oral
administration of chondroitin sulfate. Rheum Int. 1992;
12:81-88.
Bartolucci C, Cellai L, Cordani D, et
al. Chondroprotective action of chondroitin sulfate. Competitive
action of chondroitin sulfate on the digestion of hyaluronan by bovine
testicular hyaluronidase. Int J Tiss Res. 1991; 13:311-317.
Bourgeois P, Chales G, Dehais J, et
al. Efficacy and tolerability of chondroitin sulfate 1,200 mg/day vs.
chondroitin 400 mg/day vs placebo. Osteoarthritis Cartilage.
1998; 6 SupplA:25-30.
Busci L, Poor G. Efficacy and
tolerability of oral chondroitin sulfate as a symptomatic slow-acting
drug. for osteoarthritis (SYSADOA) in the treatment of knee
osteoarthrosis. Osteoarthritis Cartilage. 1998; 6 SupplA:31-36.
Conte A, Volpi N, Palmiera L, et al.
Biochemical and pharmacokinetic aspects of oral treatment with
chondroitin sulfate. Drug Res. 1995; 45:918-925.
Deal CL, Moskowitz RW. Nutraceuticals
as therapeutic agents in osteoarthritis. The role of glucosamine,
chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North
Am. 1999; 25:379-395.
Leffler CT, Phillipi AF, Leffler SG,
et al. Glucosamine, chondroitin, and manganese ascorbate for
degenerative joint disease of the knee or low back: a randomized,
double-blind, placebo-controlled pilot study. Mil Med. 1999;
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TRADE NAMES
Asco-Caps-1000 (The Key Company),
Asco-Caps-500 (The Key Company), Ester-C (Swanson Health Products),
C-Time (Time-Cap Labs), C-Tym (Economed Pharmaceuticals), Fruit C (Freeda
Vitamins), Sunkist Vitamin C (Novartis Consumer Health), Cecon (Abbott
Pharmaceutical), Vicks Vitamin C (Procter & Gamble), Dull-C (Freeda
Vitamins), Mega-C (Merit Pharmaceuticals), C-Max (Bio-Tech Pharmacal),
Cemill (Miller Pharmacal), Cevi-Bid (Lee Pharmaceuticals), Honey C
Chews (Nature's Life), Halls Defense (Warner Lambert).
DESCRIPTION
VITAMIN C
The term vitamin C applies to
substances that possess antiscorbutic activity and includes two
compounds and their salts: L-ascorbic acid, commonly called ascorbic
acid, and L-dehydroascorbic acid. Ascorbic acid is the major dietary
form of vitamin C. The terms vitamin C, ascorbic acid and ascorbate
are commonly used interchangeably.
Vitamin C is a hexose derivative,
similar in structure to the six-carbon sugar glucose. It is an
essential nutrient for humans, and, as pointed out by Linus Pauling in
1970, "differs from other nutrients in that it is required in the diet
by only a few species of animals—man, other primates, the guinea pig,
an Indian fruit-eating bat, and the red-vented barbul and some related
species of Passeriform birds." It is also an essential nutrient for
Coho salmon, rainbow trout, carp and some insects. Most other animals,
all higher plant species and probably all algal classes can synthesize
vitamin C from glucose or other sugars. Molecules similar to ascorbic
acid are made by some fungi but not by bacteria. All vitamin C
requiring animals lack the enzyme L-gulano-gamma-lactone oxidase, the
final step in the synthesis of ascorbic acid from glucose.
The major deficiency syndrome of
vitamin C is scurvy. Symptoms of scurvy include inflamed and bleeding
gums, petechiae, ecchymosis, follicular hyperkeratosis, coiled hairs,
perifollicular hemorrhages, impaired wound healing, dry eyes and mouth
(Sjögren's syndrome), arthralgia, joint effusions, muscle weakness,
myalgia, fatigue, depression, frequent infections, anemia, anorexia,
diarrhea, and pulmonary and kidney problems that can lead to coma and
death. All systems of the body are affected by scurvy.
The antiscorbutic factor was isolated
from the ox adrenal cortex in 1928 by the Hungarian biochemist Albert
Szent-Györgyi and his colleagues. In 1932, the American biochemist
Glen King and his colleagues isolated this factor from lemon juice.
Structural studies revealed this factor to be a sugar acid and, before
it was named ascorbic acid, it was called hexuronic acid and godnose.
Many of the symptoms of scurvy,
particularly those having to do with connective tissue, can be
explained by the known biochemical roles of vitamin C, particularly
its role as a cofactor for prolyl and lysyl hydroxylase, enzymes
important in the formation of collagen. Collagen synthesized in the
absence of ascorbic acid—as occurs in scurvy—cannot properly form
fibers, resulting in blood-vessel fragility, among other defects. In
the prolyl and lysyl hydroxylase reactions, as well as in most of the
biochemical reactions ascorbic acid participates in, it acts as a
reducing agent. In these reactions, the vitamin reduces ferric and
cupric ions to their ferrous and cuprous states, forms which are
required for the reactions to proceed.
Ascorbic acid is also involved in the
biosynthesis of other connective-tissue components, including elastin,
fibronectin, proteoglycans, bone matrix and elastin-associated
fibrillin. It also appears to play a role in collagen gene expression
and cellular procollagen secretion.
The fatigue and weakness of scurvy
may be due to L-carnitine deficiency. Ascorbic acid is a cofactor for
crucial reactions in the carnitine biosynthetic pathway.
Ascorbic acid is involved in
modulating iron absorption, transport and storage. It aids in the
intestinal absorption of iron by reducing ferric iron to ferrous iron
and may stimulate ferritin synthesis to promote iron storage in cells.
It is involved in the biosynthesis of corticosteroids, aldosterone,
the conversion of cholesterol to bile acids and functions as a
reducing agent for mixed-function oxidases.
For all of this, ascorbic acid is
best known for its antioxidant properties and its possible role in the
prevention of certain chronic degenerative disorders, such as coronary
heart disease and cancer. In fact, ascorbic acid may be the most
important water-soluble antioxidant in the body.
The daily dietary intake of vitamin C
necessary to prevent scurvy is about 5 to 10 milligrams. Scurvy is
rare in developed countries, since most people living in these
countries typically consume much more than this amount.
About 90% of vitamin C in the average
diet comes from fruits and vegetables. Peppers—sweet green and red
peppers and hot red and green chili peppers—are especially rich in
vitamin C. Other good sources include citrus fruits and juices,
brussels sprouts, cauliflower, cabbage, kale, collards, mustard
greens, broccoli, spinach and strawberries. Nuts and grains contain
very little vitamin C. Cooking destroys vitamin C activity.
About 5% to 10% of the total vitamin
C content of fresh fruits and vegetables is comprised of
dehydroascorbic acid. In the case of processed foods, dehydroascorbic
acid makes up about 30% of the vitamin C content. D-ascorbic acid (erythorbic
acid or isoascorbic acid), the epimer of L-ascorbic acid, is
frequently added to food as an antioxidant preservative. Erythorbic
acid has very low vitamin C activity.
In addition to being known as
ascorbic acid and L-ascorbic acid, vitamin C is also known as 2,
3-didehydro-L-threo-hexano-1, 4-lactone,
3-oxo-L-gulofuranolactone, L-threo- hex-2-enonic acid gamma-lactone,
L-3-keto-threo-hexuronic acid lactone, L-xylo-ascorbic
acid and antiscorbutic vitamin. It is abbreviated AA. Ascorbic acid is
a crystalline, water-soluble substance with a pleasant (to some),
sharp acidic taste. Its molecular weight is 176.13 daltons, and its
molecular formula is C6H8O6. The
structural formula of vitamin C is represented as follows:
Vitamin C
The other form of vitamin C is the
oxidation product of L-ascorbic acid, L-dehydroascorbic acid or DHA.
VITAMIN C WITH BIOFLAVONOIDS
Vitamin C with bioflavonoids are
mixtures of vitamin C, either as ascorbic acid or as an ascorbate,
with flavonoids. Typically, the flavonoids are citrus flavonoids and
are derived from lemons, oranges and grapefruits. It is believed that
flavonoids work synergistically with vitamin C. This belief originates
from the work and writings of the Hungarian biochemist Albert
Szent-Gyögyi, the co-discoverer of ascorbic acid. Szent-Gyögyi also
isolated substances from citrus fruits and Hungarian paprika which he
called vitamin P. Vitamin P is now referred to as bioflavonoids or
flavonoids. Flavonoids are not vitamins.
Szent-Gyögyi believed that
bioflavonoids and vitamin C worked synergistically to maintain blood
capillary health and prevent capillary fragility. There is some in
vitro evidence that flavonoids and vitamin C do work
synergistically. One study showed that ascorbic acid acts
synergistically with the flavonoid quercetin to protect cutaneous
tissue cells in culture against oxidative damage induced by
glutathione deficiency. However, there is, as yet, no good evidence
that vitamin C and flavonoids work synergistically in vivo. A
recent study, in cell culture, suggested that flavonoids may even
inhibit the uptake of vitamin C into cells.
Flavonoids have biological effects
independent of any interaction with vitamin C. (See various monographs
on flavonoids.) Flavonoids from grapefruit include quercetin,
naringenin and kaempferol. Lemon flavonoids include hesperidin (hesperitin
7-0-beta-rutinoside) and eriocitrin (eriodictyol 7-0-beta-rutinoside).
These flavonoids, along with rutin and others, may be found in vitamin
C/bioflavonoid supplements. Some formulations use flavonoids from the
sour orange Citrus aurantium.
EFFERVESCENT VITAMIN C
Effervescent vitamin C is comprised
of L-ascorbic acid, citric acid and sodium bicarbonate. It is similar
to Alka Seltzer with ascorbic acid added. When the tablet is placed in
water, the citric acid reacts with sodium bicarbonate to form sodium
citrate and carbon dioxide. Also, some sodium bicarbonate reacts with
ascorbic acid to form some sodium ascorbate. Some find effervescent C
a more tolerable supplement than ascorbic acid.
ACEROLA VITAMIN C
Acerola vitamin C is vitamin C
derived from acerola fruit. Acerola is the fruit of the small tree or
shrub known as Malphighia glabra L. Malphighia glabra is
native to the Antilles and northern South America. Acerola is also
known as Barbados cherry, Antilles cherry, West Indies cherry, Puerto
Rican cherry, cereso, cereja-das-antilhas and cereja-do-para. In 1945,
the Barbados cherry was analyzed by researchers at the School of
Medicine, University of Puerto Rico, and was found to be very rich in
vitamin C. Interestingly, the analysis was inspired by the use of the
fruit for colds by the local people.
Acerola is one of the richest sources
of vitamin C in the world. The vitamin C content of the fruit depends
on ripeness, seasons, climates and localities. Content is highest when
the fruit is still green and lowest when ripe. The vitamin C content
of unripe fruits can range up to 4.7 grams per 100 grams of fruit or
4.7% and is about 2 grams per 100 grams or 2% in very ripe fruit. For
comparison, the vitamin C content of a peeled orange is 0.05% or 50
milligrams per 100 grams. Acerola also contains flavonoids, other
vitamins, such as thiamin, riboflavin, niacin, pantothenic acid and
beta carotene, and minerals, such as magnesium and potassium.
Malphighia glabra has also
shown active anti-fungal properties. Folk medicine uses of acerola
include treatment of liver ailments, diarrhea, dysentery, coughs,
colds and sore throats.
ROSE HIP VITAMIN C
Rose hips are the fruit of roses. The
rose hip is the swollen ovary of the flower which produces seed after
the petals of a blossom wither and fall. Once the petals have fallen
off a rose all that remains attached to the stem is the rose hip. Rose
hips are rich sources of Vitamin C. In fact, one species, Rosa
rugosa Thunb, contains the highest amount of vitamin C of any
organism in the world. Rosa rugosa Thunb rose hips can contain
up to 7 grams of vitamin C per 100 grams of rose hips or 7%. Acerola,
the next richest source of natural vitamin C produces up to 4.7%
vitamin C, and, for comparison, the peeled orange contains 0.05%
vitamin C.
During World War II, England, Norway
and Sweden were faced with a scurvy crisis. Since the war had
restricted normal shipping, the British could not obtain enough citrus
fruit for vitamin C. Children began showing the symptoms of early
scurvy. The British discovered rose hips to be an excellent source of
vitamin C and made the fruit of the rose into teas, soups and syrups.
The children received these supplements daily, and this prevented any
problem with scurvy.
Rose hips are the major source of
natural vitamin C. A few species are used to obtain the vitamin,
including Rosa canina, Rosa mosqueta and Rosa rugosa
Thunb. In addition to vitamin C, rose hips contain such carotenoids as
beta-carotene, lycopene, zeaxanthin, rubixanthin, gazaniaxanthin, beta
cryptoxanthin, gamma-carotene, lutein, violaxanthin, and
antheraxanthin. They also contain flavonoids, catechins, polyphenols,
procyanidins and pectins.
Rose hips have other applications.
The oil extracted from its seeds is included in many cosmetic
preparations for its high content of alpha-linolenic acid (45%-50%)
and linoleic acid (40%). The fruit has been used as food, mainly for
preparing jams, teas and alcoholic beverages.
REDUCED-ACIDITY VITAMIN C
Reduced-acidity vitamin C consists of
a mixture of 50% ascorbic acid and 50% sodium ascorbate. Some find
this form of vitamin C a more tolerable supplement than ascorbic acid.
Since the first pKa of ascorbic acid is 4.2, the pH of the mixture
dissolved in water would be 4.2. Reduced-acidity vitamin C is also
known as buffered vitamin C.
NON-ACID VITAMIN C
Non-acid vitamin C consists of an
ascorbate salt of sodium or calcium which has a neutral pH when
dissolved in water. The calcium salt consists of two molecules of
ascorbate and one atom of calcium. The molecular formula is C12H14CaO12.
Calcium ascorbate is freely soluble in water. The sodium salt consists
of one molecule of ascorbate and one atom of sodium. The molecular
formula is C6H7NaO6. Some find sodium
ascorbate and calcium ascorbate more acceptable forms for vitamin C
supplementation.
ASCORBATE AND VITAMIN C METABOLITES
Ascorbate and vitamin C metabolites
refer to marketed vitamin C supplements containing vitamin C in a salt
form, typically as calcium ascorbate, and vitamin C metabolites.
Vitamin C metabolites can include the aldonic acids L-threonic acid,
L-xylonic acid and L-lyxonic acid. Typically, the vitamin C metabolite
present in these products is L-threonic acid, also known as 2, 3,
4-trihydroxy- [threo] butanoic acid. L-threonic acid is usually also
present as the calcium salt or calcium L-threonate, and the percentage
of calcium L-threonate in the product is usually 1% of the amount of
ascorbate. That is, a tablet supplying 500 milligrams of ascorbate
would supply 5 milligrams of L-threonate.
Ascorbate and vitamin C metabolites
are sometimes referred to as metabolite-supplemented ascorbate. Some
in vitro studies have shown that the addition of L-threonate to
ascorbate enhances the transfer efficiency of ascorbate into cells.
Animal studies have reported increased absorption and higher retention
of vitamin C when the animals were supplemented with ascorbate plus
threonate than when supplemented with ascorbate alone. One
cell-culture study showed that the addition of threonate to ascorbate
enhanced the production of collagenous protein and mineralized tissue
when compared with ascorbate alone. The authors concluded that this
finding could have relevance with respect to wound healing and bone
regeneration.
Although the in vitro and
animal studies appear interesting, what is wanting are well-designed
and well-executed clinical trials in humans to determine if vitamin C
metabolites, such as L-threonate, positively affect vitamin C status.
ACTIONS AND PHARMACOLOGY
ACTIONS
Vitamin C has antioxidant activity.
It may also have anti-atherogenic, anticarcinogenic, antihypertensive,
antiviral, antihistaminic, immunomodulatory, opthalmoprotective and
airway-protective actions. Vitamin C may aid in the detoxification of
some heavy metals, such as lead and other toxic chemicals.
MECHANISM OF ACTION
Vitamin C is arguably the most
important water-soluble biological antioxidant. It can scavenge both
reactive oxygen species and reactive nitrogen species. Ascorbic acid
or, more specifically, ascorbate is an excellent reducing agent, and
it acts as a cofactor in various biochemical reactions to reduce the
transition metals, iron and copper.
Ascorbate can be oxidized by most
reactive oxygen and nitrogen species thought to play roles in tissue
injury associated with various diseases. These species include
superoxide, hydroxyl, peroxyl and nitroxide radicals, as well as such
non-radical reactive species as singlet oxygen, peroxynitrite and
hypochlorite. By virtue of this scavenging activity, ascorbate
inhibits lipid peroxidation, oxidative DNA damage and oxidative
protein damage.
Ascorbate is oxidized by reactive
oxygen and nitrogen species to the semidehydroascorbate radical that
is either reconverted to ascorbate via the enzyme NADH
semidehydroascorbate reductase or is converted to dehydroascorbate
Dehydroascorbate in turn can be
converted back to ascorbate via glutathione-dependent enzymes or
catabolized.
Ascorbate can act as a secondary
antioxidant. At least in vitro, ascorbate regenerates the major
lipid antioxidant alpha-tocopherol from the alpha-tocopheroxyl radical
form. Ascorbate may also participate in regenerating and sparing
alpha-tocopherol in vivo, though this has not been clearly
demonstrated. Vitamin C does preserve intracellular reduced
glutathione concentrations.
The possible anti-atherogenic
activity of vitamin C may be explained in a few ways. Oxidation of
low-density lipoprotein (LDL) is thought to be a key early step in
atherogenesis. Vitamin C protects against LDL peroxidation by
scavenging peroxyl radicals in the aqueous phase. Vitamin C may
enhance endothelial function by promoting the synthesis of nitric
oxide (also known as NO and EDRF for endothelium-derived relaxing
factor) or by preventing its inactivation by scavenging superoxide
radicals. Superoxide reacts with nitric oxide to form peroxynitrite.
High concentrations of vitamin C are required to prevent the
interaction of superoxide with nitric oxide, extracellularly. Although
such high plasma concentrations are feasible if vitamin C is given
parenterally, they are likely not to occur with oral administration of
vitamin C.
As noted above, vitamin C helps
preserve intracellular reduced glutathione concentrations. This
activity likely helps maintain nitric oxide levels and potentiates its
vasoactive effects. Oral vitamin C can reach high enough
concentrations intracellularly to scavenge superoxide radicals. Thus,
intracellular sources of superoxide that impair nitric oxide may be
scavenged by oral vitamin C. Recently, it has been found that ascorbic
acid enhances nitric oxide synthase activity by increasing
intracellular tetrahydrobiopterin.
Vitamin C may modulate prostaglandin
synthesis to favor the production of eicosanoids with antithrombotic
and vasodilatory activity. The possible sparing and regeneration of
alpha-tocopherol by vitamin C could be yet another factor in the
vitamin's possible anti-atherogenic action.
Vitamin C's possible anticarcinogenic
effects may be accounted for, in part, by its ability to detoxify
carcinogens, as well as its ability to block carcinogenic processes
through its antioxidant activity. Vitamin C can prevent the formation
of such carcinogens as nitrosamines in foods and in the
gastrointestinal tract and can detoxify such chemical mutagens and
carcinogens as anthracene, benzo[a]pyrene, organochlorine pesticides
and heavy metals. High concentratins of ascorbic acid in gastric juice
may reduce the risk of gastric cancer by inhibiting, as noted, the
formation of carcinogenic N-nitroso compounds. Additionally, increased
oxidative stress to the gastric mucosa has been reported in
Helicobacter pylori-associated gastritis, a condition that
predisposes to gastric cancer. There is preliminary evidence that
vitamin C can inhibit growth of Helicobacter pylori.
Evidence appears to suggest that
vitamin C may have cancer-preventive activity, at least for certain
types of cancer. However, the role of vitamin C, if any, in the
treatment of cancer remains very unclear. A recent cell-culture study
of human breast carcinoma lines showed vitamin C to improve the
antineoplastic activity of doxorubicin, cisplatin and paclitaxel. The
mechanism of the effect may be pro-oxidant, not antioxidant, activity
of the vitamin in potentiating the effects of these chemotherapeutic
agents. Another study suggests that the pro-oxidant form of vitamin C
may upregulate some of the enzymes involved in DNA repair. This
possible activity may play some anticarcinogenic role.
Vitamin C may have anti-hypertensive
activity in some. The mechanism of this possible effect is a matter of
speculation. Some in vitro studies show that vitamin C
increases the synthesis of the vasodilatory prostaglandin PGE1.
However, this may not have relevance in the regulation of vascular
tone in humans. As observed above, vitamin C may help maintain nitric
oxide levels and potentiate its vasoactive effects. There is an
indication that vitamin C may improve endothelial-dependent
vasodilation in those with essential hypertension, as well as in those
with hypercholesterolemia, and may help restore nitric oxide-mediated
flow-dependent vasodilation in those with congestive heart failure.
There is some evidence that vitamin C
inhibits the replication of human immunodeficiency virus 1 (HIV-1)
in vitro. One study showed upregulation of the expression of
glucose transporter 1 (Glut1) in HIV-infected cells Glut1 is one of
the transport proteins for ascorbic acid. Increased cellular
concentrations of ascorbate may be toxic to HIV-infected cells due to
degradation of the viral nucleic acid by the action of the pro-oxidant
form of vitamin C. The mechanism of the anti-HIV effect of the vitamin
in vitro, however, is unclear, as is the relevance of
this finding to HIV-positive individuals.
There is no evidence that vitamin C
affects the replication of the viruses that cause the common cold
in vivo. There is some evidence that vitamin C supplementation
decreases the incidence, severity and duration of common cold symptoms
in some. It is thought that this is due, at least in part, to
antihistaminic activity of vitamin C.
The possible immunomodulatory
activity of vitamin C may also be due, in part, to an antihistaminic
effect of the vitamin. Vitamin C may enhance neutrophilic chemotaxis
indirectly by reducing immunosuppressive effects of histamine. Some
studies have shown that vitamin C, in vitro, enhances mitogen-stimulated
lymphocyte proliferation, delayed-type hypersensitivity (DTH) response
to skin antigens, natural killer cell activity and neutrophil
chemotaxis. However, other studies have shown no effect of the vitamin
on these and other indices of immune function.
Some studies suggest a protective
effect of vitamin C supplementation against cataracts. Age-related
lens opacities are thought to be due to oxidative stress. Ocular
tissue concentrates vitamin C, and the antioxidant action of the
vitamin could account for its possible effect in protection against
cataracts.
Vitamin C may protect against asthma
and other obstructive pulmonary diseases, as well as protect the
airways against the effects of allergens, viral infections and
irritants in some. Allergens, viruses and irritants, including ozone,
nitrogen oxides and sulfur oxides, subject the airways to increased
oxidative stress which can lead to bronchoconstriction. The possible
protective action of vitamin C appears clearly due to its antioxidant
properties.
The antioxidant properties of vitamin
C can also account for its role in protecting against the
tissue-damaging effect of some toxic chemicals and heavy metals. High
serum levels of ascorbic acid have been reported to be associated with
a decreased prevalence of elevated blood lead levels. The mechanism of
the possible lead-lowering action of vitamin C is unclear. One study
compared the chelating properties of ascorbic acid and the known
lead-chelating agent EDTA and found them to have equivalent activity
with respect to lead.
PHARMACOKINETICS
Absorption of vitamin C from the
lumen of the small intestine depends on the amount of dietary intake.
At a dietary intake of 30 milligrams daily, the vitamin is nearly
completely absorbed from the lumen of the small intestine into the
enterocytes. At an intake of 30 to 180 milligrams daily, about 70% to
90% is absorbed. About 50% of a single dose of 1 to 1.5 grams is
absorbed. The percentage of a single dose absorbed decreases with
increasing amounts. For example, only 16% of a single dose of 12 grams
is absorbed. Maximum vitamin C absorption of large doses is attained
by ingestion of several spaced doses throughout the day rather than by
a single large dose. Further, sustained-release forms of large doses
will give a higher efficiency of absorption than an equivalent dose
that is not sustain-released. The type of food consumed does not
appear to affect the absorption of supplemental vitamin C or vitamin C
found in food.
The intestinal absorption of vitamin
C from foods and from supplements, up to about 500 milligrams, occurs
via a sodium-dependent active transport process. At doses higher than
500 milligrams, diffusion processes come into play. The major
intestinal vitamin C transporter is SVCT1 (sodium-dependent vitamin C
transporter 1). Some ascorbic acid may be oxidized to dehydroascorbic
acid and transported into enterocytes via glucose transporters.
Dietary dehydroascorbic acid is absorbed from the lumen of the small
intestine into the enterocytes in such a manner. All dehydroascorbic
acid within the enterocytes is reduced to ascorbic acid via reduced
glutathione, and ascorbic acid leaves the enterocytes to enter, first,
the portal and, subsequently, the systemic circulation. Ascorbic acid
is distributed to the various tissues of the body.
Higher levels of ascorbic acid are
found in the pituitary gland, the adrenal glands, the various white
blood cells and the brain. Ascorbic acid itself cannot cross the
blood-brain barrier. In order to enter the brain, ascorbic acid is
first oxidized to dehydroascorbic acid or DHA. DHA is then transported
across the blood-brain barrier by facilitative diffusion via glucose
transporter 1 (GLUT1). DHA is next transported through GLUT1 at the
surface of the blood-brain barrier endothelial cells. DHA is
transported out of the endothelial cells through GLUT1. DHA in the
brain is reduced to ascorbic acid. Ascorbic acid, once formed, is
essentially trapped in the brain since it cannot be transported
through GLUT1.
Ascorbic acid appears to be
transported into intestinal cells, liver cells and kidney cells by a
sodium-dependent active transport process via SVCT1 (sodium-dependent
vitamin C transporter 1). The transporter SVCT2 (sodium-dependent
vitamin C transporter 2) appears to aid in the transport of vitamin C
into the aqueous humor of the eyes. Uptake of ascorbic acid into
neutrophils appears to be by facilitative diffusion via GLUT1.
Regarding the metabolism of ascorbic
acid, it is oxidized to dehydroascorbic acid which can either be
reduced back to ascorbic acid or hydrolyzed to diketogulonate. Other
metabolites include oxalic acid, threonic acid, L-xylose and
ascorbate-2-sulfate. The principal route of excretion of ascorbic acid
and its metabolites is via the kidney. In order to maintain ascorbic
acid homeostasis, very little unmetabolized ascorbate is excreted with
dietary intakes up to about 80 milligrams daily. Renal excretion of
ascorbate increases proportionately with higher doses. As mentioned
earlier, as the dose of supplemental ascorbic acid increases, the
percentage of its absorption proportionately decreases. Consequently,
there is significant fecal excretion of ascorbic acid with high
supplemental intakes of the vitamin.
INDICATIONS AND USAGE
Vitamin C may be helpful in chronic
diseases characterized by oxidative damage to biological molecules.
Though vitamin C also has a pro-oxidant potential under some
circumstances, fears raised in that regard in recent years appear
overblown. There is currently no credible evidence for vitamin C
pro-oxidant damage in humans except, possibly, in rare circumstances
involving iron overload.
Vitamin C's antioxidant activity, on
the other hand, is well established, and that activity may be helpful
in the prevention of some cancers and cardiovascular disease. Vitamin
C may also be helpful in protecting against some of the lipid
oxidation caused by smoking. Vitamin C's demonstrated ability to
reduce some forms of oxidative DNA damage and indications that it may
also reduce protein oxidation under some circumstances further suggest
that it may be of benefit in smokers and some with chronic stress and
disease, in general.
Vitamin C may also be useful as an
immune stimulator and modulator in some circumstances. Claims that it
is a "cure" for common colds are unsubstantiated, although several
studies have shown that vitamin C can significantly reduce the
duration and severity of colds in some and reduce incidence in others.
There is also preliminary evidence that vitamin C can be useful in
ameliorating some other respiratory infections.
Vitamin C may help prevent cataracts.
Recently it was demonstrated that
vitamin C can inhibit growth of Helicobacter pylori and may
thus be protective against some ulcers and gastric carcinomas. There
is also the suggestion in a recent report that low serum levels of
ascorbic acid may be associated with a higher incidence of gall
bladder disease in women. In another recent report, vitamin C
supplementation was associated with reduced risk of reflex sympathetic
dystrophy after wrist fracture. It may be of benefit in some burn
victims and may be helpful, generally, in promoting wound healing and
gum health. It has also shown benefit in some with asthma.
RESEARCH SUMMARY
Vitamin C's antioxidant effects are
well established. It has been reported to protect plasma lipids from
oxidative damage. It also significantly protects DNA and protein from
various oxidative processes, as demonstrated in numerous studies.
There is still controversy around
claims that vitamin C can be a dangerous pro-oxidant in humans. These
claims are now generally discounted, and the research that led to
these fears has been widely challenged as being flawed in a number of
respects. One researcher recently reviewed this controversy and
concluded: "there is nothing in current data to worry members of the
public who take ascorbate supplements."
Other researchers have also recently
reviewed this controversy, noting that in vitro observations of
DNA damage arising in the presence of vitamin C and redox-active
transition metal ions are unlikely to have relevance in vivo.
The damaging effect demonstrated in vitro, these researchers
point out, "requires the availability of free, redox-active metal ions
and a low ratio of vitamin C to metal ion, conditions unlikely to
occur in vivo under normal circumstances. Furthermore, it was
shown recently that in biological fluids such as plasma, vitamin C
acts as an antioxidant toward lipids even in the presence of free,
redox-active iron ... there is no convincing evidence for a
pro-oxidant effect of vitamin C in humans."
On the other hand, vitamin C's
antioxidant activity is marked and appears to play an important role
in its possible cardioprotective activity. Several studies have shown
that vitamin C, either alone, or in combination with other nutrients
significantly inhibits LDL-cholesterol oxidation. This effect is most
consistent when vitamin C is combined with vitamin E and/or
beta-carotene, but it has also been observed when vitamin C is used
alone. In the latter case, some hypothesize that it works by sparing
or recycling vitamin E, an activity that has been observed in vitro.
Results have been mixed in smokers in whom lipid oxidation is a
serious problem. One of the better designed studies, utilizing a
particularly sensitive measure of lipid oxidation, found that heavy
smokers benefited from 2,000 milligrams of vitamin C administered for
only five days, as measured by a significant reduction in a specific
lipid oxidation marker, the F2 isoprostane 8-epi-PGF2-alpha.
Where there have been discrepancies
in results from lipid (and other) biomarkers studies, some researchers
attribute these, in part, to the failure of some investigators to
differentiate between subjects whose tissues are already saturated
with vitamin C at baseline and those whose tissues are not thus
saturated. Even dietary, non-supplemental, vitamin C intake, they
argue, can readily result in saturation sufficient to rule out further
reductions in oxidative damage, no matter what supplemental dose is
administered.
Vitamin C supplementation has also
been shown, in some studies, to significantly reduce total serum
cholesterol. Some others have not shown this benefit. And there have
been several observational reports associating high plasma vitamin C
concentrations with higher levels of HDL-cholesterol.
Platelet aggregation has been reduced
in two studies utilizing 2,000-3,000 milligrams of vitamin C daily for
one to six weeks. No effect was noted on platelets in another study
using 250 milligrams of vitamin C daily for eight weeks. Leukocyte
adhesion to endothelium, an activity implicated in atherogenesis, was
significantly inhibited in smokers receiving 2,000 milligrams of
vitamin C daily for ten days.
Several studies have shown that
vitamin C has positive effects on hypertension. Here, too, there have
been some conflicting results, but the preponderance of evidence
suggests a positive effect. Epidemiological studies also consistently
show that lower vitamin C intake is associated with hypertension. In
one recent randomized, double-blind, placebo-controlled study,
hypertensive patients received placebo or 500 milligrams of vitamin C
daily for 30 days. Vitamin C resulted in a 13 mm Hg reduction in
systolic blood pressure. Placebo had no effects.
Several other studies have shown that
both oral administration (1,000-2,000 milligrams) and intra-arterial
infusion with vitamin C can exert significant, positive effects on
vasodilation in coronary artery disease patients. Similar benefits
have been found in several other test groups, including smokers and
those with both type 1 and type 2 diabetes.
Vitamin C's potential impact on
incidence of heart attack, stroke and death related to cardiovascular
disease may be quite significant according to the findings of several
epidemiological studies. In an analysis of findings from the First
National Health and Nutrition Examination Survey, researchers found
that "the relation of the standardized mortality ratio (SMR) for all
causes of death to increasing vitamin C intake is strongly inverse for
males and weakly inverse for females." Among males with the highest
vitamin C intake, SMRs were 0.65 for all causes, 0.78 for all cancers
and 0.58 for all cardiovascular disease. Among females with the
highest vitamin C intake, SMRs were 0.90 for all causes, 0.86 for all
cancers and 0.75 for all cardiovascular disease. Comparisons were made
relative to the U.S. white population, for which the SMR was defined
as 1.00.
In a 20-year followup study of a
cohort of randomly selected elderly people in Britain, Scotland and
Wales, mortality from stroke was highest in those with the lowest
vitamin C status, as measured by dietary intake and plasma ascorbic
acid concentration. Adjustments were made for age, sex and established
cardiovascular risk factors. The association noted was independent of
social class and other dietary variables. No association was found in
this study between vitamin C status and risk of death from coronary
artery disease, but the researchers noted this may have been due to
the age of their observed population. "Factors that may predict
premature death from coronary heart disease may become less important
when measured in a population of elderly survivors," they noted. The
subjects in this cohort were 65-74 years of age.
Recently, a five-year prospective
population study of 1,605 Finnish men aged 42-60, who were free of
atherosclerotic heart disease at baseline, concluded with these
results: risk of myocardial infarction was considerably higher among
those with the lowest baseline plasma vitamin C concentrations than
among those with higher levels; 13.2% of those with the lowest levels
suffered MIs versus 3.8% of those with higher levels.
What made this study particularly
significant was its finding that increased risk of MI, in relation to
plasma vitamin C concentrations, was confined to that group of
subjects who were frankly deficient in vitamin C. In men with normal
to high concentrations, there was no increased risk. This may have
significance for some other studies that found no benefit from vitamin
C in reducing cardiovascular disease risk.
It has been established by prior
research that the Finnish population suffers high mortality from
coronary heart disease and that many Finnish men have low plasma
ascorbate concentrations. A reviewer of the Finnish study thus
concluded that the finding in this study "that only individuals who
are vitamin C-deficient are at increased risk may explain to some
extent why no significant relationship was observed in many studies of
relatively well-nourished populations."
This observation might apply, some
believe, to the Nurses' Health Study and the Health Professionals'
Study, both followup investigations that showed a relationship between
increased vitamin E intake and reduced coronary heart disease risk but
no similar relationship with respect to vitamin C.
As the reviewer further observed:
"Both of these studies involved generally health-conscious study
subjects. The vast majority of antioxidant-disease studies, even
controlled intervention studies, involve generally healthy,
well-nourished populations, primarily because these populations are
much easier to study. The Finnish study results, therefore, provide a
special perspective that may help us to understand the mixed results
from past studies and better plan future studies."
Vitamin C has, experimentally,
demonstrated an ability to protect against various cancers, most
likely through its ability to inhibit DNA oxidation, through reactive
nitrogen species scavenging and other antioxidant actions, as well as
through its possible effects on the immune system, among other
activities. There are numerous epidemiological and case-control
studies showing a consistent relationship between higher dietary
intakes of vitamin C and lower incidence of cancer, particularly colo-rectal,
stomach, lung, breast, esophageal, oral cavity and larynx-pharynx
cancers. In one review of 75 epidemiologic studies, 54 found
significant evidence of reduced cancer risk in those with higher
dietary vitamin C intake.
Several in vitro and animal
studies have demonstrated benefits. Results of some animal studies
suggested that vitamin C therapy could reduce the toxicity and/or
increase the effectiveness of some standard cancer therapies.
Currently some researchers have expressed fear that vitamin C might
reduce the effectiveness of some radiation and cancer chemotherapies
by reducing their toxicity in cancer cells, as well as in normal ells.
This idea has neither been confirmed nor refuted in animal or human
studies and requires further investigation. Meanwhile, other
researchers have expressed doubts about this hypothesis. They point
out, as noted above, that several experimental studies indicate that
high doses of vitamin C not only protect normal cells from toxic
cancer therapies but may simultaneously fight the cancer cells, as
well.
Many population studies have found
evidence of a vitamin C protective effect against some cancers. Some
other studies, however, have been negative. One group of researchers
reported a significant 29% reduction in risk of all cancer in males
consuming 113 milligrams or more of vitamin C daily, compared with
males consuming less than 82 milligrams daily. Another found that
consumption of 300 milligrams of vitamin C daily, derived from diet
and from supplementation, was associated with a 21% reduction in risk
from all cancers in men compared with daily consumption of less than
49 milligrams daily.
In a review of many of the
epidemiological studies, the authors noted: "Interestingly, virtually
all of the studies in which vitamin C intakes were greater than 87
milligrams a day in the lowest intake group (quantile) found no or
nonsignificant effects on cancer risk reduction with higher intakes of
vitamin C .... More studies investigating cancer risk in persons with
lower vitamin C intakes are warranted."
Studies of those using higher dose
vitamin C supplements have generally not shown protective effects
against cancer, "possibly," these reviewers observed, "because the
dietary intake of vitamin C was already sufficient for tissue
saturation." Intervention trials with high dose vitamin C have also
been mostly negative.
At present, it appears that vitamin C
helps protect against a number of cancers, and the amounts of vitamin
C needed for this protection can generally be obtained from a diet
that includes several servings of fruits and vegetables daily—or from
low-dose vitamin C supplementation. More research will be needed
before vitamin C's role, if any, in treating, as opposed to preventing
cancer is established.
Vitamin C has shown a variety of
activities in the immune system. It has been shown, in animal and
in vitro studies, to favorably modulate lymphocytes and
phagocytes. It can regulate natural killer cells under some
circumstances and affect production of cytokines, antibodies and
complement components.
Because supplemental vitamin C was
not shown, in several studies, to reduce the incidence of the common
cold, many concluded that it was of no use whatever in colds. That is
still the impression of some physicians, but it is probably an
erroneous one. First, a few studies have, in fact, shown a reduction
in incidence of colds. Most studies have been done in normally
nourished subjects in western countries; these have, typically, shown
no effect on incidence. But in three trials of subjects under acute
physical stress, vitamin C supplementation resulted in a 50% reduction
in common cold incidence. And in four British trials, there was an
average 30% reduction in incidence among those receiving vitamin C.
Dietary vitamin C intake is known to be low in the UK.
Placebo-controlled trials have
consistently found that supplemental vitamin C, in doses of 1 gram or
greater daily, alleviated the duration and severity of cold symptoms.
In several of these studies, the alleviation has been significant. For
unexplained reason, there seems to be a greater effect in children
than in adults and possibly, a greater effect in males than in
females. The best results have been obtained with 2-gram (or greater)
daily doses. There was a 6% median reduction in cold duration in five
studies in which adults were administered 1 gram of vitamin C daily.
There was a median decrease of 26% in two studies of children given 2
grams of vitamin C daily.
Vitamin C has also been found to be
of benefit in patients with pneumonia and bronchitis. Incidence of
pneumonia was significantly reduced in three controlled vitamin C
studies, and substantial vitamin C treatment benefit was noted in
elderly UK patients hospitalized with pneumonia or bronchitis.
There is evidence that supplemental
vitamin C can inhibit the growth of Helicobacter pylori
in both in vitro and animal studies. Thus it might have the
potential to reduce the incidence of H. pylori-induced ulcers
and subsequent gastric carcinoma. In vitro, high concentrations
of vitamin C inhibited up to 90% of H. pylori growth. There was
also significant inhibition of growth in animal experiments using oral
administration of vitamin C.
High intake of vitamin C is strongly
associated with reduced incidence of cataracts, according to the
findings of case-control studies. In one study, intake of 300
milligrams or more per day was associated with a 70% reduction in
risk. Another study found a 75% reduction in risk with daily intake of
490 milligrams or more per day, compared with intakes less than 125
milligrams per day. An intervention study using 120 milligrams of
vitamin C daily produced a nonsignificant reduction in cataract risk
of 22%, but a significant 36% reduction was observed in the same trial
in subjects who consumed a multivitamin/mineral supplement.
Laboratory work has shown that
vitamin C can slow chemical reactions that lead to cataracts by
causing various lens proteins to aggregate. This has been demonstrated
in animal work and in the human eye.
In a study of women who took vitamin
C for at least ten years, incidence of cataract was significantly
reduced compared with controls who did not take vitamin C. The vitamin
C-supplemented women were only 23% as likely to develop cataracts
compared with the women who did not take supplements. In women not
taking supplements, mean daily dietary intake of vitamin C was 130
milligrams per day, about twice the recommended intake but still less
than one-third the average of women taking supplements.
Recently, serum ascorbic acid levels
were found to be inversely related to prevalence of gall bladder
disease among women but not among men. Previously, it was shown that
vitamin C-deficient guinea pigs have a high incidence of gallstones.
Further clinical investigation is warranted.
In another recent study, this one a
double-blind, placebo-controlled trial of vitamin C in patients with
conservatively treated wrist fractures, treatment with 500 milligrams
of vitamin C daily for 50 days significantly reduced the incidence of
reflex sympathetic dystrophy (RSD). Followup continued for one year.
The researchers proposed that "this simple and cheap means of
prevention could also be useful in the prophylaxis of RSD after other
injuries, such as trauma of the foot or ankle, talar and calcaneal
fractures, or crural fractures."
It was the use of vitamin C as an
antioxidant therapy in dermal burns that led the researchers to
believe that an antioxidant therapy might also be of benefit in
preventing post-traumatic dystrophy (after wrist fracture).
Researchers have found that vitamin C helps protect endothelial cells
and reduces capillary permeability by reducing lipid peroxidation
after burns. Some of these same mechanisms apparently account for
reported beneficial effects of vitamin C in a variety of wounds, in
addition to burns. There is some evidence that supplemental vitamin C
may decrease permeability of gum surface tissue and may, by that and
other mechanisms, help protect against periodontal gum disease.
Evidence that vitamin C can sometimes
counteract the symptoms of asthma comes, in part, from a study showing
that vitamin C (taken in a 500 milligram dose 90 minutes before
exercise) reduces bronchial spasms in some asthma sufferers and from
another study in which 1 gram of vi | 
