Nutraceuticals: myth or must? (Proceedings)

Close to 30% of pet owners have used or considered the use of novel ingredients (eg, nutraceuticals and herbs/botanicals) in their animals. In the USA, approximately 90% of veterinarians sell some type of novel ingredient and the current market of veterinary novel ingredients is between $20 and $50 million per year. The American Veterinary Medical Association recognizes the importance of these medicaments through its guidelines regarding complementary or alternative medicine, which includes veterinary nutraceutical therapy. In Europe and other nations, the use of herbs/botanicals in particular enjoys a long historical use of general acceptance. However, despite the economic and medical impact of novel ingredients, their use is and should be controversial. Much more than drugs, the use of novel ingredients is complicated by issues regarding their safety, efficacy and manufacturing. The term nutraceutical is not a legal term, but was coined in the 1980's by a physician referring to oral compounds were neither nutrients nor pharmaceuticals. The North American Veterinary Nutraceutical Council (now defunct) was formed in 1996 by interested persons in industry, practice and academia. It defined a veterinary nutraceutical as "a [non-drug] substance which is produce in a purified or extracted form and administered orally to a patient to provide agents required for normal body structure and function and administered with the intent of improving the health and well-being of animals." The commonality among novel ingredients products is that legally they are neither food, food additives nor drugs (as recognized by the Food and Drug Administration (FDA) of the USA). As such, they undergo no premarket approval process and neither safety, efficacy nor manufacturing is assured. At least two groups in the USA have formed in North America with an interest in veterinary nutraceuticals: the Nutraceutical Alliance (www.nutraceuticalalliance.com) based in Canada, and the National Animal Supplement Council (NASC; www.nasc.cc), based in the USA. The latter group has taken an aggressive approach in trying to implement voluntary actions among nutraceutical manufacturers that will cause regulators to respond to their products in a positive fashion.

Novel ingredients often are used without doctor supervision. Up to 70% of humans do not report herbal use to physicians, in part because of their failure to recognized the products as drugs. Likewise, pet owners often do not cite nutraceutical or herbal use when queried regarding drug therapy for their pet. The availability through medically recognized and trusted sources often leads the consumer to assume both their accuracy in labeling, efficacy and safety. Yet, the lack of regulations and guidelines should lead to the "buyer beware".

Labeling

No mechanism (other than voluntary) exits to hold a manufacturer accountable for the labeling of a novel ingredient. Yet, the novel ingredient that is inappropriately labeled negatively impacts both safety and efficacy. Strong consideration should be given to purchasing those products for which assurance in manufacturing can be obtained. Manufacturers should be queried about the accuracy of their label and all aspects of their manufacturing program, with an emphasis on which "Good Manufacturing Program" they follow. The manufacturer also should be queried regarding its participation in any of the programs that offer evidence of quality assurance, such as exists in the USA: ConsumerLab's (www.consumerlab.com) certification seal; the Institute for Nutraceutical Advancement, or trade associations (eg, NASC when available). Several sources of scientific information indicate the need to focus on those products whose quality assurance can be verified. Chondroitin sulfates (CDS), an expensive ingredient of many "joint" targeted products, offers an example of consistent mislabeling. A study, funded in part by Nutramax Laboratories, found deviations from label claims for CDS in 84% (9 of 11) of the products studied; the amount by which products were mislabeling ranged from 0 to 115%.3 Further, the study found products costing less than or equal to $1 per 1200 mg CDS were seriously deficient (than 10% of the label claim), suggesting that cheaper products should be avoided. However, expense did not guarantee accuracy. Several of the most expensive products also were found in this study to be mislabled. Consumer Lab has found similar results: at least 50% of products containing CDS are mislabled. Two of three veterinary products contained no chondroitin despite labels that noted otherwise. In contrast to CDS, glucosamine is much more likely to be accurately labled in regard to content. Consumer Laboratory (www.Consumerlabs.com) is a for-profit laboratory that offers a seal of "validation" for dietary supplements sold in the USA that are appropriately labeled. Products that pass analysis are allowed to place the ConsumerLab seal on the product label. The public can access selected information from the Consumer Lab web site for a fee ($20 annual at the time of this printing) for ingredients that have been tested. Criteria for passing and failing and reasons for failure for specific ingredients can be accessed, as can a list of proprietary products that have passed. Ten of the ingredients studied by Consumer Lab and listed at their web site have been used in veterinary medicine (although none of the products are veterinary). Yet, products of only four ingredients (glucosamine, co-enzyme Q, iron and methosulfone [MSM]) were accurately labeled at least 80% of the time. Reasons for failure ranged from unacceptable inaccuracy in labeling of product content to contamination (with heavy metals or pesticides). Among the pass products was Cosamine®, the human version of Cosequin® DS for dogs, manufactured by Nutramax Laboratories. The presence of a "seal of verification", unless from a recognized, reputable source, does not necessarily indicate sufficient quality in manufacturing. The presence of a lot number and expiration date offers some evidence of accuracy in labeling. Labels should contain a list of ingredients and the intended use of the product. Ingredients should be listed by their common name in decreasing order of magnitude based on weight. Note that for selected herbs, the total constituents may not be known. Additionally, the number of constituents in herbs can be overwhelming: garlic alone contains over 200 active ingredients. Because the ingredient content can vary with the portion of the plant, the source of the plant (leaf, flower, root, stem) should be included. Labeling techniques may contribute to the advent of adverse effects. Manufacturers may improperly identify plants. Even if properly identified, the consumer may have difficulty identifying a product as potentially dangerous because an herbal agent may be referred to by many different names or an herbal name may be used in lieu of the more easily recognized chemical name (eg, guarana for ephedrine or mahuang for caffieine). The FDA has become more proactive in directing manufacturers to list generic drug names in lieu of or in addition to herbal names; however, consumers may have to look closely.

Adequate directions for use also should be provided. Absence of any of this information should cause the user of the product to look for alternative products. Products whose labeling is accompanied by scare tactics, exaggerated claims and testimonials should be avoided as should products whose label includes medical claims, such as " for use in the prevention or treatment of", or intended to changes in body structure or function".

Safety of Novel Ingredients

"Above all else, do no harm" should be the primary directive regarding the use of novel ingredients. Harm to the patient from the use of novel ingredients can reflect adverse reactions to the active ingredient, excipients, or contaminants; or therapeutic failure, particularly if traditional therapy is overlooked or not pursued in the belief that the novel ingredient will be sufficient. Of these, adverse reactions are the most likely to contribute to harm. Lack of adverse event reports in the literature for a novel ingredient should not be interpreted as evidence of safety, particularly in light of the absence of an effective adverse event reporting system. In the US and elsewhere, unlike pharmaceutical manufacturers, manufacturers of novel ingredients are not mandated to report adverse events.

Studies which establish safety of novel ingredients can be implemented relatively easily. The outcome measures of adversity, or more ominously, toxicity (ie, clinical signs, clinical laboratory changes, evidence of histopathology in organs of excretion, teratogenicity etc) are more discreet and easily defined than are criteria of efficacy. However, toxicity studies can be costly, particularly if chronic dosing studies are implemented, and the cost of such studies is likely to be transferred to the consumer. None – the – less, the profession should demand and expect evidence of safety in the target species of any product marketed for animal use.

Despite their endogenous origin, nutraceuticals may be associated with adverse events. For example, creatine, a popular (presumed) ergogenic compound, is consumed by up to 28% of college athletes. However, it is metabolized to potentially toxic aldehydes, including formaldehyde, which may reach sufficient concentrations with chronic dosing to cause undesirable effects. Creatine also may be contaminated during industrial production. Creatine is produced by synthesis from sarcosine (often originating from bovine tissues) and cyanamide which may result in the the presence of contaminants such as creatinine, dicyanidiamide. These contaminants should be delineated on the label. Androstenedione is popular product used by atheletes because of its potential (perceived) conversion in the body to testosterone. Yet, neither efficacy nor safety of this product have been demonstrated despite the potential adverse effects documented for other anabolic steroids. L-tryptophan is an example of a natural, yet endogenous amino acid that is not necessarily safe. It is approved for use when added to proteins in small quantities to improve the quality of nutrition. In this form, it is presumably should be safe. Yet, when used as a sedative in the free amino-acid form, over 1500 users developed an eosinophilic myalgia syndrome, probably because of a contaminant during the manufacturing process. Close to 40 people died as a result of this effect. Phenyalamine is another amino acid that has been used in its free form. Essential in the diet, phenylalamine has been added to improve the quality of food; however, when used in large doses as an analgesic, it can cause severe amino acid imbalances.

Of the novel ingredients, herbal / botanical products may present a greater risk compared to nutraceticals, although the incidence of adverse reactions does not appear to be as high in human medicine as that for either prescription or over-the –counter drugs. Often described in advertisements as "mild" because they are "natural," the prudent user of herbal products will recognized that the products are natural to plants, not animals. Indeed, animals have developed sophisticated mechanisms (eg, efflux pumps, drug metabolizing enzymes) to prevent the absorption and accumulation of plant chemical products in the body. Many drugs originally were discovered because of their presence in plants. Herbal products may be unsafe for several reasons. Active ingredients, whether the intended ingredient or another chemical within the plant, may not be safe, particularly when used in excess. Five broad classes of active chemicals exist in plants: volatile oils (eg, catnip, garlic, citrus), fixed oils, resins, alkaloids, and glycosides. Of these, fixed oils, often used as emollients, demulcents and bases for other agents, are among the least toxic. Alkaloids are among the most pharmacologically active plant chemicals and include a wide range of potentially harmful products. Resins can be strong gastrointestinal irritants.

The risk of adverse effects to herbs is increased by the presence of many active ingredients in the same plant. Indeed, herbalists often used unpurified plant extracts because of the belief that different chemicals will interact synergistically. The portion of the plant (ie, leaf, flower, stem, root, seed) may impact safety. Herbalists often administer the whole plant in the belief that, in contrast to the purified extract, toxicity will be reduced by a buffering effect of the whole herb. During growth of the plant, environmental contaminants may become unintended residues during the manufacturing process. Microorganisms, including bacteria, fungi or molds, can either directly contaminate the product or produce contaminating toxins. Bacterial contamination is more likely with root – as opposed to flower or leaf – products. Heavy metals, such as lead, cadmium or mercury, increasingly are contaminating plants exposed to environmental pollutants. Further, unless organically grown, insecticides and pesticides can contaminate herbal products. Factors during production and storage, such as storage length and conditions can alter herbal potency and quality. Finally, herbal products might be supplemented with active ingredients (often referred to as an herb) such as benzodiazepines, ephedrine, caffieine, or fenfluramine (the latter ingredient being one of the two ingredients in the notorius Phen-Fen dietary supplements). Health Canada recently has issued a warning to Canadians to not used selected herbal products that contain undeclared prescription drugs, including indomethacin, diethylstilbestrol and alprazolam (an anti-anxiety drug). Finally, the risk of drug interactions in persons consuming herbs has caused the American Society of Anesthesiologists to generate a brochure for its members entitled "What You Should Know About Your Patients' Use of Herbal Medicine". Examples of potential interactions involving the CNS include enhanced stimulation by caffeine, ephedra, yohimbine, guarana, and ginseng; enhanced sedation by valerian, kava, and St. Johns Wort. Drug-induced hemostasis defects may be potentiated by garlic, ginger, gingko, ginseng, chamomile, feverfew and bromelain; whereas the effects of hypoglycemics may be exacerbated by bilberry, bitter melon, dandelion and garlic. Echniacea and astragalus may offset the immomodulatory effects of corticosteroids or other immunosuppressants.

A number of other herbs have been associated with adverse effect. In 1975, the FDA reported over 30 herbs prepared as teas to be unsafe. Excessive consumption of herbal teas containing senna, aloe, buckthorn and other laxatives has been associated with the death of four women The FDA also is currently investigating the potential association of hepatotoxicity and the administration of kava (kava kava, Piper methysticum), an herbal product used for a variety of disorders, including stress and anxiety. Recent regulatory actions offer evidence of the risks that can be associated with the use of these unapproved products. Adverse events have also occurred in veterinary patients. The Animal Poison Control Center (APCC) published a report of adverse reactions in 47 dogs that ingested a popular weight loss dietary supplement containing guarana (caffeine) and ma huang (ephedrine). Seventeen percent of the dogs died following clinical signs expected from these central and cardioactive compounds.

Efficacy of novel ingredients

Dosing of novel ingredients is often empirical and rarely, if ever, based on scientific studies. Establishing the pharmacokinetics of these products is difficult because of the multiplicity of ingredients, and, or nutraceuticals, inability to distinguish the endogenous from supplemented chemical. Radiolabeling studies can be helpful. For example, using radiolabling, the bioavailability of glucosamine hydrochloride in humans is 84%, suggesting most of the oral dose reaches systemic circulation. In contrast, oral bioavailability of the sulfate salt is only 47%, indicating that only half of the oral dose of this salt reaches systemic circulation. Thus, the oral dose of the sulfate salt should be approximately twice that of the hydrochloride salt. Labeling often may not provide doses adjusted for differences among the form of the active ingredient or preparations. Extrapolation of oral bioavailability data among species should be made carefully. Recently, the oral bioavailability of glucosamine in dogs was reported to be 10% after single dose, but 200% after multiple doses. The oral bioavailability of CDS markedly decreases with an increase in molecular weight; CDS of 17,000 or less is most bioavailable, yet product labels do not provide this information.

When assessing the validity of scientific information supporting the safety and efficacy of nutraceuticals, criteria which apply to clinical trials for drugs should apply to clinical trials for novel ingredients. The report must include a description of the study design and methods such as random assignment of treatments, placebo controls and blinding techniques that reduce the risk of scientific bias. The need for placebos in veterinary medicine can not be overemphasized. In humans, the placebo effect in studies evaluating pain can be profound, ranging from 30 to 40% or more. A similar, if not higher, placebo effect should be expected in veterinary medicine. The need for randomization, a placebo group and the avoidance of traditional therapies are examples of reasons why evidence of informed consent (not simply permission, but provision of truthful information) must be provided in the report. Other criteria of a well designed study should include methods to standardize treatment groups and appropriate statistical analysis. The larger the variability in the outcome measures, the greater the number of animals that must be studied in order to detect a significant difference. Care should be taken to not interpret the lack of a significant difference as an indication that the groups are the same unless the study investigators demonstrate that the study design provided sufficient power. Credence might be given to the results of a study that demonstrates or fails to demonstrate a clinical difference despite the lack of statistical difference. For example, products containing glucosamine and chondroitin sulfate cause significant decrease in the indices of red blood cells or platelet activity in dogs and cats, but these differences are within clinical normals and thus are not clinically relevant. Negative clinical trials also should be reported; manufacturers should be queried about their inclusion in distributed information. As with drugs, care should be taken when extrapolating information from studies in a species other than the one in which the compound is to be used.

Oral (Nutraceutical) Disease Modifying Agents.

These products may represent the most rational therapy for treatment of DJD in dogs and cats in that they may help prevent or (more likely) slow the progression of disease. Most compounds (those which are likely to modify disease) contain glucosamine and chondroitin sulfates (extracted or synthesized) in various complex forms. A large number of oral disease modifying agents are currently available for treatment of osteroarthritis Examples include synthesized glucosamine, chondroitin sulfates and manganes ascorbate) found in Cosequin® (Nutramax Laboratories, Inc) or the mussel exract that may contain mucopolysaccharides/mixed glycosaminoglycans/chelating metals/etc found in Glyco-flex® (components less certain). Those products which contain various forms of glycosaminoglycans (aggregates form proteoglycans, the major constituent of cartilage matrix) such as glucosamines or chondroitin sulfates appear most promising based on studies that have supported their efficacy. However, these products undero no approval process; neither safety, efficacy nor label ingredients are documented. Note that no mechanism exist to assure quality control of the manufacture of these products. Studies investigating the match between labeled and actual ingredients found that products that contain glucosamine were relatively accurately labeled. In contrast, those containing chondrotin sulfate are much more likely to be mislabeld regarding contents (84% mislabeled in one study), particularly the cheaper products. Usually, it is the chondroitin that is mislabled because it is the more expensive. Currently, the FDA has not implemented regulatory action (and they are unlikely unless mislabled with a drug indication) over these products. Because they are not drugs, feed additives or foods, yet are given orally, marketing of these products must be approved by individual state Feed Control Officers. Although non regulatory, the American Association of State Feed Officials provides guidelines for individual states regarding products not approved by the FDA, but given orally. Most states follow their guidelines. If a product has not been "approved" by AAFCO (described as an "ingredient"), their recommendation is that the product not be sold. None of the disease modifying agents are approved by AAFCO. AAFCO recently announced that they will recommending refusal of the sale of unapproved products; the rumor is that glucosamine will be the first "test" product to be denied sale and regulation will begin in April. At least two laboratories are addressing the labeled contents of these products: the United States Pharmacopiea (www.usp.org which is addressing primarily human dietary supplements; and www.consumerlab.com),. The latter is a for profit laboratory that tests products for accuracy in labeling, looking not only for correct amounts, but absence of contaminants, metabolites, etc. Although some information is provided free of charge, for a nominal fee of $20, the public can peruse information on those products that failed or passed their tests and reasons for failure. The site also contains an herb/botanical encyclopedia and links to the FDA's medwatch alert program.

Presumably, as precursor nutrients, chondrotin sulfates and glucosamines will administered orally are extracted from the serum by chondrocytes and be used to synthesize proteoglycans. Ascorbic acid is a reducing agent for enzymes which form residues important for fibril formation and cross-linkage of collagen fibers for the articular cartilage, joint capsule, tendons, ligaments and bone. During periods in which cartilage degradation exceeds cartilage formation, the need for precursor molecules may exceed availability and the repair process is inhibited. The availability of orally administered compounds not only increases the efficiency of the ability of the chondrocytes to repair damaged cartilage as is evidenced by increased synthesis, but also leaves less opportunity for formation of inappropriate molecules. Oral absorption (up to 70%) of chondroitin sulfate has been reported in a number of species administered radioactive materials. However, MW should be ≤ 17,000 MW in size (note only one product studied met this MW limit and was properly labeled). Bioavailability of glucosamine salts will vary, with the HCL salt being move bioavailable (87%) compared to the sulfate salts (47%); thus doses of sulfate salts should be higher. In dogs, bioavailability of glucosamine appears to be as little as 10%, but this probably reflects first pass metabolism of the compound to disaccharides or other compounds. Chondroitin sulfate has a "carry-over" effect such that bioavailability reaches 200% or more following chronic dosing. Both compounds appear to be taken up into the joint. Glucosamine / chondroitin sulfate products appear to be safe. Platelet function may change, but the clinical relevance of this finding is no obvious. Lethal doses can not be established in some animals (indicating the drugs are safe). Significant but normal changes in PCV and platelet function are the only side effects noted with 30 days therapy at therapeutic doses in dogs and cats. Glucosamine may actually protect the gastrointestinal mucosa. Questions have arisen regarding the safety of these compounds in diabetic animals. Although initial studies indicate glucosamine does not impact diabetes, diabetic patients might be more closely evaluated as they begin these products.

A number of sources documenting efficacy exist for these products. Invitro studies using chondrocyte cultures indicate incorporation of components by chondrocytes and more rapid growth. Orally supplemented precursors also may inhibit cartilage degradation. Glucosamines appear to modulate the inflammatory process, perhaps by scavenging oxygen radicals. Cartilage degradative enzymes are also inhibited. A questionnaire based study of Cosequin® found that veterinarians found the compound to be good to excellent; free of side effects; most effective in animals older than 4 to 5 years; and required 4 to 6 weeks to be effective. Nutramax supported studies using rabbit models of surgically – induced damage found clear histological and gross improvement in joints treated with a combination glucosamine-chondroitin product compared to placebo (at 375 mg/kg). In human medicine, two studies have been implemented in patients with mild to moderate OA of the knee. The first studied Cosamine® and found a significant improvement in the treated (52%) vs placebo (28%) group following 6 months of therapy based on reduction of clinical signs; both groups reported an approximate 20% side effect rate. The second study included a larger number of patients (n=300), treated with glucosamine sulfate, studied for three years and based on radiographic as well as clinical measurements. The study found that patients receiving glucosamine had no loss of joint space radiographically as well as improvement in clinical signs. A recent study published by the N EngJ Med followed a large number of patients with mild to severe disease and compared efficacy to celecoxib. Although findings were not significantly different from placebo for the DMA group, the placebo group reported an astounding 60% effect, making it difficult to statistically identify differences. Trends in efficacy, however, were found within the moderately affected group, supporting efficacy of these products.

Oral glucosamine / chondroitin compounds might be considered as "follow-up" to patients that have responded to injectable PSGAGs, with initiation of therapy occurring simultaneously with the injectable products. However, as with injectable PSGAG agents - they should be considered in any condition in which joint damage is suspected or anticipated, including trauma, over use, surgery, or infections or immune-mediated causes. Combination therapy with various products (including NSAIDs) (which can be chondestructive) should be considered. Dosing of these products might be based on Cosequin:500 mg glucosamine hydrochloride (1000 glucosamine sulfate), and 400 mg chondrotin sulfate (chondroitin 4 preferred) per 25 lbs twice daily. According to the American Rheumatologic Foundation, these compounds will not provide the same level of analgesia as NSAIDs, particularly in severe patients. Onset of action will be approximately 4 to 6 weeks. Because of a significant placebo effect, and a 3 month carryover effect between products, the Foundation suggests that a "when a supplement has been studied with good results", the product should be identified and used. The human medical profession has recognized the potential impact of these products and encourages the medical profession to become knowledgeable regarding these products.

Other potential indications for oral disease modifying agents in animals includes intersitial cystitis in cats, chronic urinary tract infections associated with deep-seated bladder infections, degenerative disc disease (discs are comprised of the component parts of PGAGs) and (early) collapsing trachea.

A recent systematic review of 16 clinical trials published prior to 2006 in peer reviewed journals that addressed the efficacy of NSAIDS and disease modifying agents in dogs described a "moderate" comfort level regarding the claims pentosan polysulphate; green-lipped mussels; polysulfated glycosaminoglycans; and a combination of chondroitin sulfate, glucosamine hydrochloride, and manganese ascorbate. An extremely low level of comfort was described for hyaluronan.

Other products

Interestingly (and frustratingly), NSAIDs remain the most commonly prescribed medication in humans for treatment of OA, despite the recognition of serious adverse events associated with their use and the fact that 1 out of 5 humans use non-prescribed alternative medications. Nutritional (endogenous?) compounds are more limited in their effects on biological targets, and better provide for physiologic (innate) interventions. A plethora of nutraceutical products are promoted for their efficacy in the treatment of prevention arthritis. Most of them target control of inflammation,and as such, should be used in combination with those that supplement building blocks (eg, glucosamine, chondroitin sulfates). Nutritional products were recently scientifically reviewed in human medicine.(Ameye LG, Chee WSS. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence Arthritis Research & Therapy 2006, 8:R127 (doi:10.1186/ar2016; open access, July 04, 2007). Reviewed were randomized (human or animal) clinical trials that focused on OA, that were published in peer reviewed journals and were based on non-synthesized (natural) orally administered products. SAMe was excluded because it is considered synthetic (it is not stable in its endogenous form) whereas chondroitin sulfates and glucosamine were excluded because of they are already well reviewed. A total of 52/2026 potential studies met all criteria and were scored on a scale of -2 (evidence of no efficacy) to 2 (very good evidence of efficacy) with 1.67-2 representing the highest category, followed by 1.34-.166; 1.01 to 1.33 (m oderate evidence), 0.5 to 1 (limited evidence), and -0.5 to 0.5 (no evidence due to conflicting results, poor study design).Funding sponsorship for the trial as a possible source of bias was not addressed. No positive effects were found in 11/52 trials. The major nutrients that emerged from the review and their respective scores are: avacodo soybean unsaponafiables (ASU score 1.58); MSM (1.21), a cocktail of plant extracts (SKI306X [1.21] versus 0.67 for Duhuo Jisheng Wan), Vitamins B3 or C (the latter is accumulated in articular cartilage, causing collagen cross-links (0.75), Lipids from green lipped mussels (0.58), boron (a non-metallic trivalent chemical whose concentration is less in femoral OA compared to normal OA; score of 0.50), cetyl myristoleate (a lipid of sperm whale and beaver gland [!!] origin; score of 0.58), a variety of (individual)plant extracts plant extracts (bromelain [0.53] Harpagophytum procumbens [0.54], ginger [0.42], and Boswellia serrata [.0.42]), Vitamin E (0.17), hyperimmune milk (-0.9), and collagen hydrosylate (-0.17), with the plant extract Salix sp. ranked as no evidence (-0.25).

Avacado-soybean unsaponified lipids: Four rigourous trials indicated symptomatic relief without side effects; none, however, offered evidence of structural changes in cartilage. Among the anabolic, anticatabolic and anti-inflammatory effects cited for ASU included; increased collagen / aggregan synthesis, decreased collagenase, aggrecanase and matrix metalloproteinase activity, and decreased production of ILs 6 and 8 and PgE2. activity. ASU increases transforming growth factor in normal canine synovial fluid. The most common r avocado to soybean ratio studied was 1:2; it was the most effective, followed by products with a ratio of 1:1; products with a ratio of 2:1 were less effective. In general, ASU appear to improve symptoms of OA after several months, and may slow down joint space loss. However, further studies are needed to confirm structure modifying effects and long term effects.

Methylsulfonylmethane (MSM, eg, Flexagen® [be careful: Flexagen also is the tradename for diclofenamic acid, a human NSAID. Life threatening gastroduodenal ulcers occurred in a dog mistakenly prescribed diclofenamic acid rather than MSM ) is the oxidized metabolite of DMSO; naturally, it occurs in very low concentrations of I fruits, corn, tomatoes, tea, coffee, and milk.

. As such, it might be expected to scavenge oxygen radicals and provide analgesic effects.One clnical trial in humans demonstrated improved efficacy compared to placebo. Another found improvement with MSM or MSM and glucosamine compared to placebo but the combined effect offered no statistical improvement.

Omega-n-3 fatty acids act by replacing arachidonic fatty-acids and other n-6 acids (eg linoleic acid) in cell membranes with eicosapentenoic acid (the number refers to the position of the last carbon double bond along the fatty acid chain). Metabolism of cell membrane fatty acids yields eiocosanoids (prostaglandins and leukotrienes) of the n-3 series (eg, (linolenic, eicosapentaenoic, and docosahexaenoic acids). Omega-3 occurs naturally in soybean and canola oils, flaxseeds, walnuts, and fish oils, whereas n-6 occurs in safflower, corn, soybean, and sunflower oils as well as in meat. The modern Western diet is relatively in n-3 PUFAs compared to n-6 (ratio of 1:25) compared to pre-industrialized or modern Eastern diets at 1:2. The n-6-derived eicosanoids) tend to be proinflammatory, whereas the n-3-derived eicosanoids tend to be anti-inflammatory. As such, a high n-3 intake correlates with a low incidence of cardiovascular and inflammatory diseases. Supplementation of Omega-3 fatty acids increases the proportion of 3-n fats in cell membranes in general, and in articular cartilage such that subsequent eiconsanoid products are much less inflammatory. In cartilage, derivatives of n-3 inhibit, whereas those of n-6 stimulate aggrecanase and collagenase activity; n-3 derivatives decrease synthesis of COX-2, 5-lipoxigenase, IL-1 and TNF. Additionally, n-3 oxygenated derivatives, called resolvins, are potent anti-inflammatory agents through binding to G-protein coupled receptors. Care must be taken to make sure the ratio of n-6:n-3 dietary fatty acids is not too low.

Green-lipped Mussel products contain omega n-3 fatty acids, vitamins, glycosaminoglycans and minerals. However, the evidence of efficacy in humans is limited, although the number of persons enrolled is small and the duration of study generally has been short (3 months). A clinical trial in dogs fed powder sprinkled on food, or directly incorporated in a dry diet (0.3%) improved total arthritic score, joint pain and swelling with more than 50% of dogs improving by 30% or more.

Hyperimmune milk has been studied in humans and dogs. The product is produced by immunizing milk producing cattle with intestinal bacterial antigens and as such, is enriched in high molecular weight immunoglobulins as well as low molecular weight anti-inflammatory products. Clinical trials in humans failed to find a significant effect, although study design was poor. Dogs responded better to the product compared to placebo, but study design may limit application.

Probiotics

The term "probiotic" refers to live microorganisms which when administered in adequate amounts confer a health benefit on the host. In contrast to probiotics, prebiotics refer to non-digestible food ingredients (including dietary fiber) that beneficially effect the bacterial population. They differ from other fermentable carbohydrates in that they interact with selective microorganisms. Synbiotics contain both pre and probiotics, with "syn" implying a synergistic effect of the prebiotic on the probiotic portion of the combination products. TThe natural microflora prevents invasion by foreign bacteria. Normal microbiota protects against invasion of pathogenic strains of bacteria, facilitating normal bowel smooth muscle function, supporting digestion of certain foods, and contributing to nutrition through the production of vitamins (vitamin K; vitamin B in some species) and other nutrients (eg, short-chain fatty acids). Microbes impact the maturation and maintence of the intestinal immune system, influence cell proliferation and facilitate energy salvage (eg, through conversion of nutrients to short chain fatty acids). Genera that are numerous in both the GI tract of restricted access dogs and humans include Lactobacillus, Bifidobacterium, Eubacterium, Bacteroides, and Peptostreptococcus. The proposed mechanisms by which probiotics work are several fold. Known effects of commensal intestinal bacteria include maturation and maintenance of the immune system, gastrointestinal epithelial cell proliferation, energy capture, and through production of metabolites, either both beneficial and detrimental health effects (Blaut 20007). Among the organisms most commonly cited as beneficial are Lactobacillus and Bifidobacterium. The major differences between dogs and humans among culturable bacteria are limited and include: 1. Bacterioids and Streptococcus as the most common isolates in the ilea and colon of the dogs; however, these isolates, while not the predominant isolate in humans, are present in a large proportion. 2. Fusobacterium is not as numerous in dogs compared to man. In the cat, Bifodobacteria appear to be even less numerous than in the dog. In dogs, Lactobacillus acidophilus has been deomonstrated to decrease the number of culturable Clostridum sp. Among the prebiotics, 1.5 g lactusucrose/d for 2 weeks increased Bifidobacteria and decreased Clostrdium sp in dogs. In cats, Bifidobacteria and Lactobacillus also increased and Clostridium and Enterobacteracea decreased (dose 0.75 g/day). Fructo-oligosaccharides at a rate of 0.75% in the diet of adult healthy cats for two weeks decrease Clostridium sp and E. coli.

The science behind the use of probiotics is profoundly complicated by the following: microbiota differ with diet, different regions of the gastrointestinal tract, species, age, and state of disease. The number of CFU ingested as probiotics is minor compared to the normal microbiota. However, they transit through regions of the gastrointestinal tract that are sparsely populated and as such, may transiently become the dominant microbe.

Table 1. Examples of novel ingredients associated with adverse effects

Therapeutic benefits of probiotics for which scientific evidence is reasonable (in humans) include gingival disease, gastric infections by Helicobacter pylorus (and thus medical conditions associated with infection), pancreatitis, antimicrobial-induced diarrhea, acute, infectious diarrhea (but not C. difficile colitis), inflammatory bowel disease, liver disease, bacterial translocation, UTI associated with uropathogens, and oxalate urolithiasis. Probiotics and related compounds are not approved drugs and undergo no premarket approval process. As such, data supporting quality assurance, safety and efficacy for each product may not exist. Consumer Laboratories (www.consumerlab.com) has reviewed issues specifically related to quality assurance of a probiotic product. These include: 1. Labels should list all types of bacteria or yeast, including genus and species, and the number of colony forming units (CFU); 2; numbers of viable organisms (note the dose is generally 1 to 10 billion [109 to 1010 ] CFU are recommended (in humans) per day. 3. Viability of organisms; 4. presence of contaminating (potentially pathogenic) organisms, including E. coli, Salmonella spp, Staphylococcus aureus and Pseudomnuonas aeruginosa (as per FDA requirements); and 5. the extent of enteric protection of selected organisms, including L. bulgaricus,S. thermophilus and Leuconostoc and Lactococcus sp. Organisms which generally do not need protection include most Lactobacillus, Bifidobacterium and Streptococcus, or organisms present as spores, including Bacillus and some Lactobacillus. Of 24 products (21 human, 3 pet) reviewed by Consumer Laboratories (October 2007), 5 (4 human, 1 pet) failed to contain the labeled amount of microbes, 6 (4 human, 2 pet) failed to provide at least 109 CFU per serving (generally those that also failed to contain labeled amount) and 1 (pet) failed due to microbial contamination (with mold). Two of the pet and 4 of the human products did not include the number of CFU on the label.

Table 2. Examples of Novel Ingredients with potentially scientifically supported beneficial effects. Doses are often not scientifically based.*mislabeling been documented for many products