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EUROPEAN JOURNAL OF INFLAMMATION
Vol. 1, no. 1, 1-8 (2003)
DIETARY SUPPLEMENTS FOR ARTHRITIS AND OTHER
INFLAMMATORY CONDITIONS: KEY ROLE OF MAST CELLS AND BENEFIT
OF COMBINING ANTI-INFLAMMATORY AND PROTEOGLYCAN PRODUCTS*
Department of Pharmacology and Experimental Therapeutics
Tufts-New England Medical Center, Boston, Ma., USA
Received December 13, 2002 - Accepted March 4, 2003
Arthritis is estimated to affect over 30% of all adults and all the available drugs add considerable
morbidity and mortality of their own. A recent therapeutic approach targets the mast cells that are
currently considered critical in a variety of inflammatory diseases, especially arthritis. Mast cells could be
activated by many immune and neural triggers, as well as by many food substances and drugs leading to
secretion of numerous vasoactive and inflammatory molecules. Recent studies have shown that mast cells
can be inhibited by certain naturally occurring flavonoids, such as quercetin, and the sulfated proteoglycan
chondroitin sulfate. Glucosamine and chondroitin are present in many dietary supplements, but neither the
source nor the purity of the active substances is listed; moreover, these formulations do not permit
sufficient absorption, due to the high molecular weight and negative charge. Moreover, a common source
of chondroitin sulfate is cow trachea with the risk of spongioform encephalopathy (mad cow disease). A new
series of dietary supplements (Algonot-Plus®) are based on published scientific evidence and combine
quercetin, glucosamine sulfate and chondroitin sulfate of high purity in formulations that include kernel
olive oil to increase absorption of the inhibitory substances.
Many of the available dietary supplements
widespread problem of arthritis (The coming
contain a multitude of ingredients, some of which
epidemic of arthritis. Time
, Dec. 9, 2002) and the
may have biologic effects of their own or may
increasing use of alternative therapy (The Science
interact with other supplements or drugs. A number
of alternative medicine. Newsweek
, Dec. 2, 2002).
of these have recently been found inactive in spite
A publication from the US Center for Disease
of anecdotal reports to the contrary; for example,
Control (CDC) indicated that 1/3 of all adults in
Ginkgo has been promoted as a CNS stimulant,
the USA (almost 70 million) suffer from arthritis
but was recently shown to be ineffective in this
or chronic joint pain, up from 1/5 in 1993; the
regard (3). Worse yet, a number of OTC drugs, as
associated annual cost was estimated at $82 billion
well as prescription drugs, such as morphine, can
(Dembner, A. One-third of adults in US have
stimulate mast cell secretion of detrimental
arthritis, according to survey. The Boston Globe
molecules, especially histamine (4-6). Histamine
Oct. 25: A3, 2002) This number includes both
toxicity can also occur through bacterial histidine
osteoarthritis and rheumatoid arthritis (RA), the
decarboxylase in uncooked tuna burgers (7) or
latter of which is characterized by active joint
cis-Urocanic acid-induced gastrointestinal mast
inflammation. Due to the chronic nature of these
cell release of histamine and other mediators. A
conditions, as well as the serious adverse effects
prime example of dietary supplements that could
of many of the prescription drugs used, increasingly
activate mast cells is those containing Ma Huang
more individuals turns to dietary supplements for
extract that is rich in ephedra alkaloids. Ephedrine
has been associated with sudden cardiac death (8)
Key words: arthritis, inflammation, cytokines, chondroitin sulfate,
glucosamine sulfate, quercetin, mast cells, secretion
T.C. Theoharides, Ph.D., M.D.
Department of Pharmacology and Experimental Therapeutics,
This publication and/or article is for individual use only and may not be further
reproduced without written permission from the copyright holder.
136 Harrison Avenue, Boston, MA 02111, USA
Unauthorized reproduction may result in financial and other penalties
Phone: (617) 636-6866 - Fax: (617) 636-2456
T.C. THEOHARIDES ET AL.
and other vasoactive effects (9) that may derive
been called “piece-meal degranulation” or
“intergranular activation” (43). Mast cells are,therefore, now recognized as key cells in the
development of a number of inflammatory diseases
However, even reviews for clinicians have
(44), including the joints (13, 15).
consistently failed to address mast cells, whichhave recently emerged as key players in arthritis
(10). The evidence of mast cell involvement in
There are no effective clinically available
arthritis recently became indisputable since
mast cell inhibitors, even through disodium
inflammatory arthritis could not develop in mast
cromoglycate, doxandrozole, ketotifen and some
cell deficient mice (11-12). Increasing evidence
histamine-1 receptor antagonists have variable
indicates that mast cells are involved in the
inhibitory effects (45). Aloe vera has been reported
pathophysiology of arthritis (13-23). In fact, stress
to reduce mast cell secretion (46) and mast cell
has been shown to activate mast cells (6) and
infiltration in an inflamed synovial pouch model.
worsen arthritis (24-26). Moreover, corticotropin-
Chondroitin sulfate was recently shown to inhibit
releasing hormone (CRH) secreted immediately
activation of connective tissue mast cells (47).
after stress and its structural analogue urocortin,
Even though many publications reported an
have been shown to be increased in the joints of
inhibitory action of plant flavonoids on mast cells
rheumatoid arthritis patients (27-32). In this context,
(48), this inhibition is not shared by all of the
it is important to note that CRH receptors were
3,000 or so flavonoids known. It was recently
identified on mast cells from rheumatoid arthritis
shown that the inhibition by the flavones kaempferol,
joints (28) and CRH (33), as well as urocortin
q u e r c e t i n a n d m y r i c e t i n d e p e n d s o n t h e
(34), have been shown to activate mast cells.
hydroxylation pattern of their B ring (48). In fact,some flavonoids like morin do not have any
Mast cells are found in most parts of the body
inhibitory activity, while others may actually
and are well known for their involvement in allergic
and anaphylactic reactions (35-36) throughd e g r a n u l a t i o n . H o w e v e r , i n a d d i t i o n t o
immogobulin E and specific antigen, numerous
other non-immune triggers or conditions can activate
supplements containing D-glucosamine have
mast cells; these include anaphylatoxins,
become quite popular for arthritis; most recently,
neuropeptides, bee, ant and jelly fish venum, as
the proteoglycan chondroitin has also been added
well as physical and emotional stress. Upon
(50). However, there are a number of problems
stimulation, over 30 molecules (mediators) are
with the available preparations. Firstly, D-
secreted either preformed from almost 500 secretory
glucosamine and similar sugars normally found in
granules, or made de novo
glycosaminoglycans (GAGs) in joints and elsewhere
These molecules include arachidonic acid products,
could actually promote bacterial adhesion,
biogenic amines, chemoattractants, cytokines,
aggregation and inflammation (51). Glucosamine
growth factors, neuropeptides, proteoglycans and
is made from shellfish chitin and, if it not of high
proteolytic enzymes (37-38). However, the
purity, should be avoided by those allergic to
involvement of mast cells in the pathophysiology
shellfish. Moreover, a common source of chondroitin
of arthritis was missed because they did not appear
sulfate is from cow trachea with the risk, remote as
degranulated. Increasing evidence, however,
it may be, of spongi form encephalopathy (“mad
indicates that biogenic amines (39-40), arachidonic
cow disease”). Most importantly, very little oral
acid products (41), and cytokines (42) are released
chondroitin is absorbed in powder form due to its
from mast cells without degranulation, a process
high molecular weight (150,000 – 1,000,000 daltons)
termed “differential release”. The morphological
and the extensive negative-charge due to sulfation;
appearance of this process is characterized by a
in fact, the more sulfated the molecule, the better
more subtle process of changes within the electron
its beneficial effect, but the worse the absorption.
dense content of the secretory granules and has
Unfortunately, popular magazines and newsletters
Eur. J. Inflamm.
Tab. I. Example sof Cartilage rebuilding products.
Tab. III. Combination “cartilage rebuilding” and
Nutramax Laboratories, Inc
(Edgewood, MD 21040, USA;
Sarasota, FL 34242, USA; Phone:
800-Algonot or 941-346- 5304; www.algonot.com)
Let Nature Ease Your Pain
ArthroSoft® (soft gel capsules for arthritis)
(Ft. Landerdale, FL 33309, USA;
ArthroSoft® cream for arthritis
2 enterically coated fish and ginger oil softgels
*Acidity <0.5%; H O<5%; filtered through 0.5 mi-
These products are hypoallergenic, free from artifi-
cial colors or flavors, corn, milk products, preserva-
tives, salt, starch, sugar, wheat or yeast. There are 4
USA and 4 International patents pending.
Tab. IV. Other Algonot-Plus® products for inflammatory
Algonot, LLC (
Sarasota, FL 34242, USA; Phone:
800-Algonot or 941-346-5304; www.algonot.com)
Tab. II. Examples of single anti-inflammatory prod-
Let Nature Ease Your Pain®
(Colorado Springs, CO 80907,
(softgel capsules for interstitial cystitis)
• Aloe Vera dry powder
600 mg of freeze- dried aloe vera from whole
(Hayward, CA 94544, USA;
(softgel capsules for chronic prostatitis)
T.C. THEOHARIDES ET AL.
Tab. V. Beneficial Effects of Algonot-Plus® Products.
from reputable institutions neglect to mentionthese problems in articles addressed to the consumer.
In particular, less than 5% of chondroitin
sulfate is absorbed intact when administered orally
fava bean source that may cause hemolytic
(52, 53). For instance, after oral administration of
3H- chondroitin sulfate to the rat and dog, 70% of
the radioactivity was absorbed, but the high
molecular weight fraction, which is the one most
Inhibits mast cell and macrophageactivation
useful, was less than 10%. Additionally, if the
⇒ Inhibits histamine and tryptase release
degree of sulfation was high, the absorption was
⇒ Inhibits IL-6, IL-8 and TNF-α release
almost negligible. In another study, oraladministration of a small molecular weight
chondroitin sulfate (16,000 daltons) led to only
13% bioavailability, but when chondroitin sulfate
of about double the size (26,000 daltons) was
used, less than 4% the oral dose administered inrats reached the blood as intact chondroitin sulfate
• Chondroitin sulfate
(54). Other papers found no oral absorption of
⇒ From shark cartilage to avoid the most
chondroitin sulfate and concluded that any protective
effect in the joints after oral administration
Unfortunately, most of the companies that
market products containing glucosamine and/or
⇒ Acts as decoy for microbial adherence
chondroitin do not list the exact amounts, thesource, degree of sulfation or the purity of the
• Glucosamine sulfate
active ingredients (eg. Tab. I). The US Federal
⇒ Building block for cartilage synthesis
Trade Commission (FTC) only ensures that the
⇒ Acts as decoy for microbial adherence
label conforms to certain requirements, such asthat direct therapeutic claims are not made.
• Kernel Olive Oil
Nevertheless, many companies still make unfounded
⇒ Low acidity and special filtration from the
claims and simply change their labels, if pressed
to do so. It is, therefore, very important that health
⇒ Unsaturated fatty acids provide fluidity of
professionals familiarize themselves with which
products are safe, scientifically based and likely
Antioxidants protect against peroxidation
to be of benefit. Some products and their advantages
Polyphenols have anti-inflammatoryactions
or disadvantages are discussed briefly (Tab. I-III).
Mechanism of action: cartilage “rebuilding
⇒ Provides greater solubility and absorption
building block for new cartilage, while chondroitinsulfate presumably acts as “ready made” cartilage.
* Shark is caught for food and cartilage is
However, chondroitin sulfate has also anti-allergic
and anti-inflammatory properties, primarily through
NSAIDs = non-steroial anti-inflammatory
mast cell inhibition (47). It is particularly critical
that both the glucosamine and chondroitin must behighly sulfated
because the sulfated moleculeshave many negative charges that better inhibit thefunction of inflammatory cells (47). Moreover,the sulfated molecules act as decoys attracting
Eur. J. Inflamm.
bacteria and preventing them from adhering to the
Unique benefits of Kernel olive oil
cell surface and causing infection (51). A natural
Kernel olive oil
from the island of Crete is of
molecule that has been recently used is the flavonoid
low acidity and water content and undergoes special
, which has potent antioxidant and anti-
filtration to remove any particular matter. It is
inflammatory properties (48). Quercetin is
considerably richer than olive oil in all the well-
commonly obtained from fava beans that may lead
known antioxidant and other cytoprotective
to hemolytic anemia in G PD deficient persons.
components (58), such as polyphenols, that endow
olive oil with anti-inflammatory and anti-arthritic
Algonot – Plus ® combines “cartilage
actions (59-62) (Tab. V). In fact, olive oil has been
rebuilding” and anti-inflammatory products
reported to have beneficial in rheumatoid arthritis
While glucosamine sulfate may be incorporated
63)” (58, 63), as well as permit concurrent
into new cartilage, chondroitin sulfate appears to
administration of non-steroidal anti-inflammatory
block mast cell activation and the bioflavonoid,
drugs because of its gastric mucosa healing
quercetin, blocks mast cell secretion; the two
properties (58). A study just released also indicated
together lead to better inhibitory results, as published
that adherence to a Mediterranean diet rich in
recently (47, 48). The dietary supplements product
olive oil reduced inflammatory activity in
line, Algonot-Plus® operates under the slogan “Let
rheumatoid arthritis patients (64). Moreover,
Nature Ease Your Pain®”. It includes ArthrotSoft®
supplementation of olive oil with polyphenolic
softgel capsules and a cream. ArthroSoft® contains
compounds, such as those found in kernel olive
from shellfish chitin, together
oil, protected against experimental inflammation
with chondroitin polysulfate
obtained from shark
cartilage, instead of the most common source ofcow trachea extract, and quercetin from the saphora
plant to avoid fava beans. ArthroSoft® achieves
Arthritis now appears to affect about 70 million
increased absorption of all three ingredients, due
Americans with a staggering financial burden;
to the fact that the active substances are mixed
similar projections are made for other industrialized
with unprocessed Kernel olive oil. No side effects
countries. The use of alternative therapies for
arthritis has increased dramatically in the last few
The ArthroSoft® cream was developed to be
years with glucosamine and chondroitin being the
used together with ArthroSoft® capsules and would
most commonly used substances. Even though
also be useful for anyone with skin inflammation,
preliminary reports indicate a potential benefit in
especially psoriasis, which worsens by stress (56).
osteoarthritis, potential adverse effects and lack
The ArthroSoft® cream not only contains substantial
of sufficient absorption are not mentioned.
amounts of all the key ingredients found in
M o r e o v e r , t h e p r o b l e m o f o n g o i n g j o i n t
ArthroSoft® capsules, but delivers more of the
inflammation especially prevalent in rheumatoid
same locally due to the presence of kernel olive oil
arthritis is not addressed at all. The new series of
that increases skin absorption. ArthroSoft®
Algonot-Plus®, ArthroSoft®, CystoProtek® and
taken along with any treatments for several months
ProstaProtek® under the logo ”Let Nature Ease
your Pain®”, combine glucosamine sulfate, withchondroitin sulfate and quercetin of high purity
and from safe sources in a formulation with kernel
were just made available, CystoProtek® and
olive oil that increases absorption. A companion
ProstaProtek® (Tab. IV) for interstitial cystitis
skin cream also delivers more of the active
and chronic prostatitis, inflammatory conditions
of the urinary bladder and prostate, respectively.
ProstaProtek® also contains rutin, the glycoside
form of quercetin that also has anti-arthritisproperties (57).
2002. Complementary and alternative medi-
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Ú T M U T A T Ó HÁZIPATIKA ÖSSZEÁLLÍTÁSÁHOZ 1. Fájdalom-, lázcsillapítók 1. Paracetamol és kombínációi Általános ismertetés: a parecatamol fájdalom- és lázcsillapító hatóanyag, gyulladáscsökkentő hatása azonban – szemben az ún. nemszteroid gyulladásgátlókkal - gyakorlati szempontból jelentéktelen. Javallatok: paracetamol tartalmú gyógysze