When diets aren't enough – supplements and nutraceuticals (Proceedings)

Supplementation of diets may be necessary due to dietary imbalances or because of disease-specific therapeutic benefits of the supplement. Supplements are often used with homemade diets to help create a complete and balanced diet or to increase the intake of a therapeutic compound that may be present in the diet, but at less-than necessary levels.

Medical treatments for chronic disease problems often include advice concerning diet. Additionally, many dietary supplements are available for sale, some of which make health claims. These compounds may be sold as "nutraceuticals", or as "alternative" or "complementary" therapies. Complementary and alternative therapies are not intrinsically better or worse than conventional treatments, they are just different. Use of such therapy does not absolve one of the responsibilities to be a thoughtful, informed consumer, and caregiver to a pet. One of the many challenges facing caregivers today is finding and interpreting information that permits them to decide the proper role of these popular, sometimes heavily advertised and lucrative products.

The Dietary Supplement Health and Education Act of 1994 established a framework for labeling and providing information about nutrition-related products, herbs, and other botanicals. The act permits labels to contain a statement describing how the product affects structure and function or general well being in humans, but not to make specific health claims. The label must carry a disclaimer: "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease."

The AVMA defines nutraceuticals as "...micronutrients, macronutrients and other nutritional supplements" used as therapeutic agents. The AVMA Guidelines for Complementary and Alternative Veterinary Medicine further states: "Claims for safety and effectiveness ultimately should be proven by the scientific method. Circumstances commonly require that veterinarians extrapolate information when formulating a course of therapy. Veterinarians should exercise caution in such circumstances."

The National Animal Supplement Council (NASC) has developed a proposal to attempt to allow continued marketing of unapproved "nutraceutical" ingredients. Its proposal would:

• establish a reporting system for events in which supplements may have caused harmful side effects,

• require NASC members to adopt manufacturing and quality controls,

• fund research so ingredients would meet AAFCO's ingredient definition process, and

• start a self-policing enforcement program to ensure labels are accurate and do not include drug claims.

The proposal identified five non-approved ingredients for which the NASC will seek an AAFCO feed ingredient definition. These are glucosamine, chondroitin sulfate, MSM, garlic and rehmannia.

A discussion of all available nutraceuticals is beyond the scope of this presentation; however, several will be highlighted. Information can be found in many places including the Alternative Medicine Foundation (http://www.AMFoundation.org). Information contained in these proceedings was found in searching for controlled clinical trials in PubMed.

Glucosamine and chondroitin sulfate

Only 6 articles were found; however, no controlled clinical trial was found to document benefit for use of these compounds in dogs and cats. There is evidence from experimental studies inducing arthritis and synovitis and from studies utilizing biomarkers of arthritis. In a study by Moreau, et al, evaluating client-owned dogs with arthritis, neither owners nor veterinarians, including gait analyses, appreciated significant improvement with the nutraceutical compound, but improvement was observed with meloxicam and carprofen by the surgeons and meloxicam by the owners. In another study by Gunn-Moore and Slenoy, N-acetyl-glucosamine was not found to be better for cats with idiopathic cystitis when compared with placebo. Many pet foods contain these compounds and are marketed as 'joint friendly'; however, dietary levels are substantially lower than recommended therapeutic dosages.

Methylsulfonylmethane (MSM)

Methylsulfonylmethane (MSM, or dimethylsulfone) is an organic sulfur compound belonging to a class of chemicals known as sulfones. It occurs naturally in some primitive plants and is present in small amounts in many foods and beverages. MSM is also known as DMSO2, a name that reflects its close chemical relationship to dimethyl sulfoxide (DMSO), which differs only in the oxidation state of the sulfur atom. MSM is the primary metabolite of DMSO in humans, and it shares some of the properties of DMSO. MSM is sold as a dietary supplement that is marketed with a variety of claims and is commonly used (often in combination with glucosamine and/or chondroitin) for helping to treat or prevent osteoarthritis. Retail sales of MSM as a single ingredient in dietary supplements amounted to $115 million in 2003.

In performing a search for its use in dogs and cats, no articles were found searching on "(dog OR cat) AND (MSM OR methylsulfonylmethane)". Even searching without limiting to controlled clinical trials, no citations were found.

Garlic

Garlic is a perennial bulb belonging to the lily family and is related to leeks and onions. The proposed active compound is allicin. It has been evaluated in a few studies in human beings; however, its evaluation in dogs and cats is limited to experimental studies. It is purported to lower blood glucose and lipids, decrease blood pressure, possess antibacterial properties, and act as an antioxidant. Experimentally, it has been shown to increase Heinz body formation in dogs and cats. There are no published controlled clinical studies in dogs and cats.

Rehmannia

Rehmannia is a genus of six species of flowering plants in the order Lamiales, endemic to China. Sometimes known as Chinese Foxglove due to its superficial resemblance to the genus Digitalis, the species of Rehmannia are perennial herbs. The plants have large flowers and are grown as ornamental garden plants in Europe and North America, and are used medicinally in Asia. R. glutinosa is used as a medicinal herb for anemia, dizziness constipation, hypertension, and as a diuretic, . Rehmannia contains the vitamins A, B, C, and D, as well as other useful compounds. No citations were found in searching PubMed.

Milk thistle

Milk thistle is a European medicinal plant that contains silimarin (sylmarin, silibinin, sylibin). It is used with hepatobiliary disease because it thought to possess anti-oxidant activity, increase hepatic protein synthesis, stabilize hepatocellular membranes, chelate iron, and alter cholesterol metabolism. There are no published controlled clinical studies in dogs and cats. One experimental study documented anti-toxic effects of silibinin against deathcap fungus (Amanita) in dogs. Recommended dosages are 50-250 mg/day or 20-50 mg/kg/day.

Anti-oxidants

Anti-oxidants refer to a heterogeneous group of compounds that prevent free-radical damage to cell membranes. They may be beneficial with inflammatory diseases, aging, and certain cancers. While many studies failed to document benefit of a single anti-oxidant, more recent evidence suggests that utilizing a balanced, mixed source of antioxidants may provide benefit with certain diseases. A PubMed search on "antioxidants" and "controlled clinical trial or clinical trial" returned 28 citations. Anti-oxidant treatment improved cardiac functional parameters in dogs with chronic valvular disease, decreased cataract formation when applied topically, increased immune responsiveness to vaccination in young dogs, increased cognition in aged beagles, increased immune-responsiveness in healthy geriatric dogs, decreased oxidative stress of acetoaminophen on feline erythrocytes, and improved joint function and pain in dogs with arthritis; however, they failed to ameliorate muscle damage in sled dogs, Antioxidants may be beneficial with certain types of cancer, but controlled studies are lacking in dogs and cats.

Omega 3 fatty acids

Omega 3 fatty acids are derived from murine life and possess anti-inflammatory and anti-neoplastic properties. A PubMed search returned 14 citations. Omega 3 fatty acids have been shown to be beneficial in dogs with atopic dermatitis, pruritis, lymphoma, arthritis, and chronic valvular disease. Experimentally, omega 3 fatty acids are associated with decreased proteinuria in dogs with glomerular proteinuria and with sustaining glomerular filtration rate in dogs with induced chronic renal failure. Recently, the National Research Council has recognized omega 3 fatty acids as an essential nutrient for dogs and cats.

Probiotics and prebiotics

Prebiotics refer to starches and fibers that are resistant to digestion that select for enteric bacterial that can utilize them as substrates. Probiotics refer to live microbial cultures, typically Lactobacillus spp and Enterococcus spp. They have been recommended for 'normalizing' the gastrointestinal tract in patients with diarrhea, inflammatory bowel disease, and food allergies, but have also been recommended for use with atopic dermatitis, recurrent bacterial urinary tract infections, and chronic antimicrobial administration. Four citations were found through PubMed. In one study of dogs with tylosin-responsive diarrhea, Lactobacillus did not prevent relapse. In another study, pro-biotic treatment was associated with improvement in canine inflammatory bowel disease scoring when compared with placebo. Recently, a probiotic has become available for use in dogs with chronic renal failure and marketed as 'enteric dialysis'. No controlled data is available for this product, but the data that is available shows a slight reduction in blood urea nitrogen and creatinine. This concept is similar to 'nitrogen repartitioning' utilizing dietary prebiotics. This is not truly dialysis as it does not appear to affect electrolyte, acid-base, or mineral balance as hemodialysis or peritoneal dialysis does. More of a concern is a report from Consumerlab.com, which showed that 44% of probiotic supplements contained fewer viable organisms than claimed or generally known to be effective. Only 1 of 3 veterinary products contained a large enough dose of viable organisms.

Combination products

Recently, a commercially-available, product containing anti-oxidants, vitamins, minerals, and glucosamine was evaluated in a placebo-controlled, clinical trial of client-owned dogs. Administration of the "anti-aging" supplement resulted in improvement in overall behavior particularly interactions with family members, mobility, coat condition, and cellular DNA damage. In this study, no attempt was made to standardize diet and dogs were excluded if they were consuming an anti-oxidant or omega 3 fatty acid enriched diet.

Evaluating nutraceuticals

Since there is no regulatory body for manufacturing of nutraceuticals, it is difficult to assess quality. Drugs are regulated by the FDA and must meet specific manufacturing standards; however, nutraceuticals are not considered drugs. Often, nutraceuticals are mislabeled, may contain impurities, may have variable quantities of active ingredients, or the active ingredient may not be bioavailable.

Some guidelines for selecting products likely to be of better quality include (VIN: Evaluating Nutraceuticals and Supplements by Rischniw and Wynn):

1. Price. Cheaper compounds are less likely to be of high quality. This has been the general observation with chondroitin sulfate.

2. Lot number and Expiration Date.

3. Monograph within the US Pharmacopeia, documenting accuracy of ingredient labeling. There is a general USP veterinary page (for veterinary drugs, requires free registration) and the USP Dietary Supplement Verification Program page, which provides a list of suppliers that have voluntarily submitted their products for USP verification and approval. However, this does not mean that products not verified by USP DSVP are of poor quality.

4. Claims of safety or efficacy. If a nutraceutical claims a medical benefit on the label, there should be a New Animal Drug Application (NADA) number accompanying the product. While this is "mandated" by law, it is often ignored. A NADA tends to suggest higher quality, because the manufacturer has bothered to abide by FDA regulations for drug manufacture.

5. Ingredient list. All ingredients should be listed by order of magnitude based on weight.

6. Good instructions for use.

7. Scientific evidence supporting manufacturer's claims. Some manufacturers have begun providing data for their specific products through independent scientific studies. These studies should ideally be peer-reviewed and published. Importantly, they should be clinical studies, not in vitro studies. There are institutes, affiliated with universities and medical schools, who are beginning to investigate nutraceutical claims scientifically. These include The Nutraceuticals Institute, The Institute of Nutraceutical Research, and others.

8. Testimonials in place of valid research. Many companies provide testimonials from "satisfied clients". These should be ignored, and companies that promote these instead of scientific research supporting their claims, should be viewed skeptically.

9. Membership in National Animal Supplement Council (www.nasc.cc). This industry group has a close relationship with FDA and strict guidelines for member companies regarding quality control and adverse event recording. Member companies are likely to have better quality products.

Evaluating safety and efficacy of a product is difficult. Ask manufacturers about specific formulations. The best measure is results of controlled clinical studies. Dr Andrea Fascetti of UC Davis provides some useful guidelines that a clinician should ask prior to prescribing a nutraceutical:

1. "Does the product do what it claims to do?" "What studies have been done to prove this, or are testimonials the only proof?"

2. "Does the product contain what it claims it does, and if so, is the product bioavailable?"

3. "If studies have been conducted on the compound, were they in vivo or in vitro?"

4. "Were the studies done in the target species?"

5. "Did the studies employ the same dose as is contained in the product?"

6. "Were the studies well-controlled?"

7. "Were the studies published in a peer-reviewed journal or similarly reputable source?"

8. "What are the active ingredients in products containing multiple substances, and what is the potential they may interact in a negative manner?"

9. "What other medications is my patient receiving, and how might the nutraceutical in question interact with them?"

10. "What work has been done to verify the safety at the dosage of intended use?"

11. "Has a margin of safety (the difference between effective dose and maximum safe dose) been established?"

Several websites exist that may help a clinician investigate specific nutraceuticals:

www.quackwatch.com

www.consumerlab.com

www.herbalgram.org

www.biovalidity.com

nccam.nih.gov

www.acvn.org

www.navigator.tufts.edu/index.html