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Theoarides

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 Mailing address: 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 during stimulation.
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
anti-inflammatory products.

Nutramax Laboratories, Inc
(Edgewood, MD 21040, USA;
Algonot, LLC Sarasota, FL 34242, USA; Phone:
800-Algonot or 941-346- 5304; www.algonot.com) Cosamin DSTM (pills)
Let Nature Ease Your Pain
ArthroSoft® (soft gel capsules for arthritis)
Life Extension
(Ft. Landerdale, FL 33309, USA;
ArthroSoft® cream for arthritis
ArthriProsystemTM
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
conditions.

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®
CystoProtek®
Desert Harvest (Colorado Springs, CO 80907,
(softgel capsules for interstitial cystitis) • Aloe Vera dry powder (capsules)
600 mg of freeze- dried aloe vera from whole NutriCology, Inc. (Hayward, CA 94544, USA;
Phone: 510-487-8526)
ProstaProtek®
Quercetin (pills)
(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.
Quercetin
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 • Rutin
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 quercetin, 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 glucosamine sulfate 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® can be 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).
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inflammation models of a polyphenol-supplemented virgin

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