Four Nutraceuticals Your Practice Should Not Be Without

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Four NutraceuticalsYour Practice Should Not Be
Without

• Wendy Blount, DVM

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Wendy Blount, DVM

• DVM TAMU 1992
• Private Practice Houston 2 years
• Small Animal
• Residency TAMU 1994-1997
• Small Animal Internal Medicine
• Private Practice Nacogdoches, TX
• 75 Referrals Internal Medicine and Herbal
  Medicine/Nutrition
• 25 General Practice

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Nutraceutical

• NAVNA - North American Veterinary Nutraceutical
  Association
• Non-drug substance
• Purified and extracted
• Administered orally
• Provides nutritional building blocks for normal
  body structure and function
• Intent is to improve health and well being

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NOT Nutraceuticals

• Whole herbs
• Unprocessed (raw) natural products
• Cartilage powders
• Applied topically or injected

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Four NutraceuticalsYour Practice Shouldnt be
Without

• Joint Supplements
• chondroprotectives
• Fish Oil
• Milk Thistle
• Silymarin, SilybinTM
• SAMe

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Quality Control

• Governmental regulation
• Dietary Supplement Health and Education Act of
  1994 - gives FDA power of enforcement over all
  dietary supplements
• Nutrition Labeling and Education Act of 1990 -
  FTC enforces label claims on all products sold in
  US

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Quality Control

• NASC Membership
• NADA Number if claims on the label
• Third Party Evaluation
• www.consumerlab.com
• Veterinary literature - clinical studies in the
  target species, not in vitro studies or lab
  animal studies
• USP

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Quality Control

• Other things to look for
• Price
• Ingredient List - Beware proprietary blends
• Nature of the claims
• Good instructions for use
• Studies provided by manufacturer are on their
  actual product, not ingredients

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National Animal Supplement Council

• www.nasc.cc
• Member companies submit themselves to rigorous
  independent inspections
• Work directly with FDA to improve best
  manufacturing processes and adverse event
  reporting
• Work closely with AAFCO
• Encourage research on animal supplements

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NADA - New Animal Drug Application

• Required by law if medical claims are on the
  label
• Often ignored
• NADA number means the manufacturer has bothered
  to abide by FDA regulations for drug manufacture

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ConsumerLabs

• www.consumerlabs.com
• Purchases and tests dietary supplements for
  potency and purity - published reports
• Compiles information on dietary supplements
• Compiles a list of recalls and FDA warning
  letters pertaining to dietary supplement
  manufacturers
• Look for the ConsumerLabs Seal on the label

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USP - United States Pharmacopeia

• Compiles a list of suppliers that have
  voluntarily submitted their products for USP
  verification and approval

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Why Chondroprotectives?

• NSAIDs treat symptoms powerfully, but do not
  address the primary disease process in any way
• Chondroprotectives do address disease
• support joint tissue health and repair

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Why Chondroprotectives?

• NSAIDs can cause side effects
• Mild, self limiting side effects are common
• Serious side effects are rare, but can include
  death
• Serious side effects can occur even when used
  appropriately
• Chondroprotectives are associated with minimal
  and mild side effects
• reduce need for NSAID therapy in clinical trials

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Why Chondroprotectives?

• NSAIDs intervene at a single point in the
  inflammatory cascade
• cyclooxygenase
• Chondroprotectives can intervene in multiple
  pathways that lead to arthritis
• Multiple opportunities for therapeutic
  intervention

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COX2 Selectivity

• THEORY
• COX1 is constitutive - responsible for normal
  activity
• COX2 is induced - kicks in during inflammation
• Drugs that selectively inhibit COX2 should have
  fewer side effects, because they dont affect
  homeostasis
• REALITY
• In vitro data do not always correlate with in
  vivo results
• Side effects are still significant even with very
  COX2 selective drugs.

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NSAID Side Effects

• suppress chondrocyte metabolism
• inhibit normal collagen and proteoglycan
  synthesis
• gastric ulceration and hemorrhage.
• renal damage/failure
• especially with long term use
• Especially when used with ACE inhibitors,
  diuretics
• Very rarely liver failure

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Chondroprotectives - What Do They Do?

• GAGs line the cartilage act as protectant and
  shock absorber
• Supplementation enhances cartilage metabolism
• Retard cartilage degradation (metalloproteinases)
• Retard production of inflammatory cartilage
  breakdown products (anti-inflammatory)

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Chondroprotectives - What Do They Do?

• Prevent periarticular thrombi formation
• Potential Anticoagulant effect, because heparin
  and GAGs are chemically similar
• Minor but clinically insignificant shifts in
  hemostatic parameters
• Long term use concurrent with platelet inhibitors
  should be monitored (aspirin, phenylbutazone)
• It can take up to 4-6 weeks to see maximum effects

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Chondroprotectives- GAGs, Amino Sugars,
Structural Proteins -

• Glucosamine sulfate
• Glucosamine HCl
• Chondroitin sulfate
• Hyaluronic acid
• Pentosan polysulphate (Elmiron)
• Hexosamine and Hexuronic acid - Adequan

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Chondroprotectives- Others -

• Animal Extracts collagen II, Perna
• Antioxidants
• Vitamins
• Minerals
• Amino Acids and Enzymes
• Herbs

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Chondroprotectives
Safety Studies Hematologic, hemostatic, and
biochemical effects in dogs receiving an oral
chondroprotective agent for thirty days.Am J Vet
Res 5791390-4 1996 SepMcNamara PS Barr SC
Erb HN Hematologic, Hemostatic, and Biochemical
Effects in Cats Receiving an Oral
Chondroprotective Agent for 30 DaysVet Ther
12108-117 Spring'00 Experimental Safety Study
PS McNamara SC Barr HN Erb LL Barlow
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Glucosamine Amino Sugar

• Extracted from crab shells (chitin)
• Can rarely cause hypersensitivities if not
  pharmaceutical grade
• Can also be extracted from corn
• Building block nutrient that is extracted from
  the serum by chondrocytes to form GAGs
• Decreased glucosamine synthesis by chondrocytes
  has been observed in early OA

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Glucosamine Amino Sugar

• Also stimulates synovial cell synthesis of
  hyaluronic acid
• May modulate joint inflammation by scavenging
  free radicals
• Recommended dose 125-250 mg per 20-25 lb daily
• Double the dose for the first 4-6 weeks
• CAUTION Glucosamine can potentially disregulate
  diabetics

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Glucosamine Amino Sugar

• Glucosamine sulfate vs Glucosamine HCl
• Glucosamine HCl is better absorbed in people
• Clinical studies show GS is effective despite
  this
• Do not know if there is a difference in
  absorption or efficacy in dogs and cats
• Both are proven efficacious
• HOWEVER N-acetylglucosamine less efficacious in
  cell culture

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Glucosamine Amino Sugar

• Glucosamine for Feline Idiopathic Cystitis
• GAGs line the bladder mucosa
• Theory is that the GAG layer may be deficient in
  those dogs and cats who suffer from
  chronic/recurring UTI and idiopathic cystitis
• No studies to support this yet

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Glycosaminoglycans Chondroitin

• Harvested from cartilage
• Extensive processing required for high quality
  product
• more expensive ingredient than glucosamine
• Some products dont actually contain as much
  chondroitin as is on the label
• ConsumberLabs found 73 of products tested
  contained less chondroitin than claimed on label

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Glycosaminoglycans Chondroitin

• 2 types of chondroitin sulfate
• Chondroitin-4-sulfate - mammalian
• Chondroitin-6-sulfate - shark

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Chondroitin-4-sulfate

• Binds to collagen in the cartilage matrix
• Contributes to resiliency and water holding
  properties of cartilage
• As animals age, they make less C4S and more of
  the more brittle GAGs
• Contributes to age related joint degeneration

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Chondroitin-4-sulfate

• Like glucosamine, inhibits metalloproteinases
• Decreases degradation of collagen and
  proteoglycans
• decreases interleuken 1 and blocks complement
• C4S released by platelets during normal clotting
• Decreased release with disease or age causes
  pathologic microthrombi in subchondral bone and
  other tissues

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Chondroitin-4-sulfate

• Has positive effects that last long after
  treatment discontinued (unlike glucosamine)
• Many think you can wean down to the lowest
  effective dose after 6-8 weeks.

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Hyaluronic Acid

• GAG Composed of glucuronic acid and glucosamine
• Can be injected IA or IV
• A few studies in dogs show no effect on recovery
  after experimental cruciate injury

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Pentosan

• GAG derived from a plant source (beechwood) and
  synthetically modified by adding sulfates
• Oral availability is not as good as glucosamine,
  chondroitin
• A few studies in dogs show no effect at treating
  experimental cruciate injuries

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Animal Extracts - Perna

• Perna canaliculus Green Lipped Mussel
• Antiinflammatory lipids more powerful than fish
  oil and some NSAIDs
• Exact active ingredients and mechanism of action
  have not been determined
• 2 studies in dogs demonstrate efficacy in
  controlling joint pain

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Animal Extracts Collagen II

• Hyaline cartilage is composed mostly of type II
• Collagen II is produced from extracts of animal
  cartilage
• some evidence that collagen II can improve
  clinical signs due to rheumatoid arthritis in
  people
• RA is sometimes caused by autoimmunity to
  collagen in the joints

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Animal Extracts Collagen II

• Two studies have shown autoantibodies to type II
  collagen in dogs with joint disease
• Bari SM, Carter SD, Bell SC, et al Anti-type II
  collagen antibody in naturally occuring canine
  joint diseases. Br J Rheumatol 28480-486,1989.
• Niebauer GW, Wolg B, Bashey RI, et al
  Antibodies to canine collagen types I and II in
  dogs with spontaneous cranial curciate ligament
  rupture and osteoparthritis. Arthritis Rheumatol
  30319-327, 1987.

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Animal Extracts Collagen II

• low doses PO of collagen II can produce
  "tolerance" to the joint collagen in some people
  with RA
• This mediates clinical signs of inflammatory
  arthritis
• Lab animal models have shown consistently good
  results
• human clinical trials have shown mixed results. 

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Animal Extracts Collagen II

• current theory is that the secret to success is
  found in giving LOW doses for RA. 
• Giving too much collagen II antigen may actually
  cause flare-ups with RA in people.

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Antioxidants

• Free radical damage and oxidation play a
  significant role especially in immune mediated
  arthritis
• Antioxidants should in theory help to minimize
  pathology in inflammatory arthritides
• CAUTION - High doses of single antioxidants can
  actually have pro-oxidant effects
• Broad spectrum combination antioxidants are
  probably preferred

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Antioxidants Vitamin C

• Important to enzymes involved in cross-linkage of
  collagen fibers necessary to repair joint tissues
• Some evidence that calcium ascorbate helps
  alleviate pain due to OA in people
• Some evidence that Vitamin C helps prevent immune
  mediated arthritis in people
• Popular Among Breeders

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Antioxidants Vitamin C

• Since dogs make vitamin C endogenously, adding
  vitamin C to the diet has been questioned
• Unlikely to cause serious toxicity unless very
  high doses used
• GI toxicity at high doses

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Antioxidants Vitamin C

• So whats the deal with Ester-C ?
• Wang et al, 2001
• DOG STUDY Compared pharmacokinetics of
  crystalline AA and Ester-C
• no significant differences found

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Antioxidants Vitamin E

• Decreases proinflammatory cytokines and lipid
  mediators
• Low vitamin E intake may be a risk for
  development of rheumatoid arthritis in people
• No evidence that vitamin E alone ameliorates
  symptoms of arthritis in people
• No studies in dogs or cats

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Antioxidants Methylsulfonylmethane (MSM)

• Oxidation product of DMSO
• Found naturally in Horsetail, fruits, vegetables,
  grains
• upregulates the proteoglycan synthesis of
  chondrocytes
• Provides a sulfur source for methionine
• Thought to reduce inflammation by acting as an
  antioxidant (though not proven)

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Antioxidants Methylsulfonylmethane (MSM)

• No toxicity has been reported
• No studies in dogs and cats

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Vitamins Niacinamide

• Used for many immune mediated skin diseases,
  along with doxycyline
• Fifty years ago, Kaufman reported that high-dose
  niacinamide was beneficial in OA and RA
• Niacinamide inhibits IL1, which contributes to
  pathology of arthritis
• No studies on arthritis in dogs and cats

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Minerals - Manganese

• Essential cofactor in GAG formation
• Often a limiting factor in joint repair
• Potentiates efficacy of glucosamine
• Also has an antioxidant effect
• No clinical studies in dogs and cats
• In many combination joint support products
• Cosequin

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Minerals - Selenium

• selenium may down-regulate cytokine signaling
  which contributes to pathology of arthritis
• Low selenium intake may be associated with
  development of immune mediated arthritis in
  people
• No studies on arthritis in dogs and cats

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Minerals - Zinc

• Positive effects probably due to antioxidant
  activity
• also may immobilize macrophages
• No studies on arthritis in dogs or cats

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Minerals - Calcium

• Popular among breeders
• No studies on calcium supplementation and
  arthritis in dogs or cats

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Amino Acids Enzymes

• Do Enzymes work if Given Orally?
• Pancreatic enzymes certainly work when given
  orally, even if not incubated on the food
• A number of small proteins (lt10kDaltons) are
  absorbed intact if given PO

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Amino Acids Enzymes - Creatine

• Large doses help muscle function in people
• Dose in veterinary products is typically very
  small
• Any potential benefit is unlikely
• No studies in dogs and cats
• In SynoviCre

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AA Enzymes Proteolytic Enzymes

• Inhibit pro-inflammatory compounds and
  fibrinolytic activity
• Bromelain, papain, trypsin, etc.
• People with arthritis or spinal pain showed
  similar pain reduction, whether they were treated
  with enzymes or the NSAID diclofenac
• Bromelain decreases swelling in people with
  sports injuries when taken in high doses every 4
  hours

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AA Enzymes - Superoxide Dismutase

• An enzyme that inhibits inflammation by
  inactivation of superoxide radicals and possibly
  stabilization of lysosomes
• Forms peroxide, which in turn must be neutralized
  by other enzymes catalase or glutathione
  peroxidase
• Extracted from bovine liver cells

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AA Enzymes - Superoxide Dismutase

• Oral absorption is poor
• because of its large size, penetration to target
  tissues after IM injection is poor
• Intra-articular injections show mixed results
• Considerable quality control issues
• 1998 study evaluated 6 SOD products, and found
  none to contain more than 5 of label claims

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Herbs - Boswellia

• Boswellia serrata (frankincense)
• May reduce pain and swelling by inhibiting
  lipooxygenase
• Excellent quality herbal source would be crucial,
  as whole herbs are not standardized
• 2 studies in dogs show positive effect on joint
  pain

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Herbs ASUAvocado Soybean Unsaponifiables

• stimulate the synthesis of matrix components by
  chondrocytes
• approved as a prescription drug in France
• introduced in Denmark as a food supplement
• Four randomized, double-blind, placebo-controlled
  clinical trials in people
• ameliorates symptoms of knee and hip
  osteoarthritis

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Herbs ASUAvocado Soybean Unsaponifiables

• In new product Dasuquin by Nutramax
• Early stages of research
• In vitro studies (cell culture)
• Preliminary studies in healthy dogs
• No clinical trails in dogs or cats yet

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Herbs Devils Claw

• Harpagophytum procumbens
• Inhibits TNF-alpha
• Few negative side effects
• Drug Doloteffin was derived from this herb
• No studies in dogs and cats

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Herbs Willow Bark

• Salix alba
• A source of salicylates
• Aspirin was derived from this tree bark
• Same side effects as aspirin
• Related plants Poplar (Poplar spp.), Sweet
  Birch (Betula lenta)
• A number studies supporting use of willow bark
  for OA in people

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Herbs Yucca

• Yucca schidigera
• Very popular, but not well studied
• Included in dog foods because of its interesting
  side effect decreases odor of dog feces.
• No evidence that it affects arthritis in any way

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Herbs Yam

• Wild Yam, Mexican Yam
• Contains diosgenin, which has been used as a
  precursor in the manufacture of commercial
  corticosteroids
• But does not appear to be converted to
  glucocorticoid by mammals
• Unstudied, and efficacy is questionable
• Concurrent use with NSAIDs could be unwise

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Combination products

• Combined glucosamine and chondroitin is thought
  to be synergistic
• Anabolic effects of glucosamine
• Anti-catabolic effects of chondroitin
• Different mechanisms of action
• Adding Manganese enhances rate limiting cofactor

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Dog/Cat Clinical Studies

• Experimentally produced ruptured cruciates,
  followed by corrective surgery
• Post-op DJD reduced by Cosequin
• Hulse DS, Hart D, Slater M, et al The effects
  of Cosequin in cranial cruciate deficient and
  reconstructed stifle joints in dogs. Proc Vet
  Orthop Soc64, 1998.

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Dog/Cat Clinical Studies

• Experimentally produced synovitis
• Pretreatment with Cosequin reduced inflammation
  and lameness
• Canapp SO, McLaughlin RM, Hoskinson JJ, et al
  Scintigraphic evaluation of Cosequin as a
  treatment for acute synovitis in dogs. Am J Vet
  Res.

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Dog/Cat Clinical Studies

• Survey of 3,000 small animal practitioners
• Perceived improved mobility, reduced pain,
  improved attitude
• Adverse effect - only 2 had GI upset
• Anderson MA, Slater M, Hammad TA, Brawner, WR
  Results of a survey of small animal practitioners
  on the perceived efficacy and safety of an oral
  chondroprotective nutraceutical. Prev Vet Med
  3865-73, 1999.

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Dog/Cat Clinical Studies

• Glucosamine for Feline Idiopathic Cystitis
• 125mg mg N-acetyl glucosamine per day x 6 months
• No difference in outcome
• Gunn-Moore AD, Shenoy CM. Oral glucosamine and
  the management of feline idiopathic cystitis. J
  Feline Med Surg August 20046(4)219-25.

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Dog/Cat Clinical Studies

• Clinical study compared carprofen, meloxicam and
  Synoquin for treating OA
• surgeons noted improvement with carprofen and
  meloxicam
• owners saw improvement only with meloxicam
• force plate analysis significantly improved by
  carprofen and meloxicam but not by the
  nutraceutical Synoquin

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Dog/Cat Clinical Studies

• Force plate values returned to normal only with
  meloxicam
• treatments well tolerated, except for a case of
  hepatopathy in a dog treated with carprofen.
• Synoquin (VetPlus Ltd) chondroitin, glucosamine
  HCL, N-Acetyl-D glucosamine, ascorbic acid and
  zinc.
• Moreau M, Dupuis J, Bonneau NH, Desnoyers M.
  Clinical evaluation of a nutraceutical, carprofen
  and meloxicam for the treatment of dogs with
  osteoarthritis. Vet Rec 15211323-9 2003 Mar 15

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Dog/Cat Clinical Studies

• Clinical study compared carprofen, meloxicam and
  Cosequin effect on thyroid function in dogs with
  OSA
• normal thyroid function at the outset
• None of the three had any significant effect on
  thyroid function
• Chastain CB, Panciera D. Effect of Meloxicam,
  Carprofen and a Nutraceutical on Thyroid function
  tests. SA Clin Endocrin. 2004 May-Aug14(2)6.

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Dog/Cat Clinical Studies

• Pentosan PO for 12 weeks had no benefit in
  animals recovering from cranial cruciate surgery
• Assessed by radiographs and owner impression
• Innes JF, Barr AR, Sharif M. Efficacy of oral
  calcium pentosan polysulphate for the treatment
  of osteoarthritis of the canine stifle joint
  secondary to cranial cruciate ligament
  deficiency. Vet Rec April 2000146(15)433-7.

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Dog/Cat Clinical Studies

• Pentosan SC for 4 weeks had no benefit in animals
  recovering from cranial cruciate surgery
• Assessed by lameness, rads, force plates at 6,12,
  24 and 48 weeks.
• Budsberg S, Bergh MS, Reynolds LR, et al.
  Evaluation of pentosan polysulfate sodium in the
  postoperative recovery from cranial cruciate
  surgery in dogs a randomized,
  placebo-controlled clinical trail. Vet Surg
  April 200736(3)234-44.

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Dog/Cat Clinical Studies

• Hyaluronan IA once a week x 5 weeks after
  experimental cruciate injury no benefit
• Assessed by arthroscopy force plates.
• Smith G, Myers SL, Brandt KD, et al. Effect of
  intraarticular injection on vertical ground
  reaction force and progression of osteoarthritis
  after anterior cruciate ligament transection. J
  Rheumotol. February 100532(2)325-34.

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Dog/Cat Clinical Studies

• Collagen II given at 1 mg or 10 mg per day for 90
  days, to dogs with OA.
• Lameness and pain assessed weekly for 120 days.
• Significant improvements in pain and lameness in
  both groups. Relapse after withdrawal for 30
  days.
• Deparle LA, Gupta RC, Canerdy TD, et al.
  Efficacy and safety of glycosylated undenatured
  type-II collagen (UC-II) in therapy of arthritic
  dogs. J Vet Pharmacol Ther August
  200528(4)385-90.

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Dog/Cat Clinical Studies

• Dogs with DJD were treated with Perna for 56 days
• Scored by owners and veterinarians
• No difference between the groups at 28 days
• Significant improvement in Perna group by day 56
• Pollard B, Guilford WG, Ankenbauer-Perkins KL, et
  al. Clinical efficacy and tolerance of an
  extract of green lipped mussel extract (Perna
  canaliculus) in dogs presumptively diagnosed with
  DJD. NZ Vet June 200654(3)114-8.

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Dog/Cat Clinical Studies

• Dogs with arthritis were treated with Perna added
  to a dry diet for 6 weeks
• Scored by veterinarians
• Significant improvement in Perna at 6 weeks
• Bui LM, Bierer TL. Influence of green lipped
  mussels (Perna canaliculus) in alleviating signs
  of arthritis in dogs. Vet Ther Winter
  234(4)397-407.

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Dog/Cat Clinical Studies

• Boswellia 400mg/10kg body weight SID x 6 weeks
• 71 of dogs with OA had improvement within 2
  weeks
• Assessed by grading lameness
• Innes JF, Fuller CJ, Grover ER et al.
  Randomised, double blind, placebo-controlled
  parallel group study of P54FP for the treatment
  of dogs with osteoarthritis. Vet Rec April
  2003152(15)457-60.

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Dog/Cat Clinical Studies

• Carprofen reduced progression of experimental OA,
  based on histology and chemistry
• No assessment of effect on lameness
• Pelletier JP, Lajeunesse, Javanovic DV, et al.
  Carporfen simultaneously reduces morphological
  changes in cartilage and subchondral bone in
  experimental dog osteoarthritis. J Rheum Dec
  200027(12)2893-902.

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Dog/Cat Clinical Studies

• Aragon CL, Hofmeister EH, Budsberg SC. Systematic
  review of clinical trials of treatments for
  osteoarthritis in dogs. JAVMA, Vol 230, No. 4,
  February 15, 2007.
• Meloxicam most effective at managing OA
• Moderately effective

• Carprofen
• Etodolac
• Pentosan

• Perna
• Boswellia

• GAGs
• Cosequin

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Studies - Conclusions

• Many studies are based on experimental models of
  OA, many on unstable knees
• Dont know how this correlates with natural
  disease
• No studies on glucosamine alone (without
  chondroitin) in dogs and cats
• No studies comparing different joint supplements
• LD50 for GAGs extremely high - gt5g/kg non-toxic

82
Studies - Conclusions

• Cosequin, Collagen II, Perna and Boswelia seem to
  work for joint pain of OA.
• Synoquin does not seem to help joint pain
• Cosequin helps recovery after cruciate surgery
• Pentosan PO/SC and IA hyaluronic acid do not seem
  to help recovery after cruciate surgery
• N-acetyl glucosamine does not improve idiopathic
  cystitis

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Studies - Conclusions

• Cosequin, Perna and Boswelia seems to work for
  joint pain
• Synoquin does not seem to help joint pain
• Cosequin helps recovery after cruciate surgery
• Pentosan PO/SC and IA hyaluronic acid do not seem
  to help recovery after cruciate surgery
• N-acetyl glucosamine does not improve idiopathic
  cystitis

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Fatty Acids

• Also referred to as PUFAs
• Omega-3 fatty acids
• Omega-6 fatty acids
• Omega-9 fatty acids
• oleic acid (181n-9)

87
Fatty Acids Omega-3

• DHA - docosahexaenoic acid (226n-3)
• EPA- eicosapentaenoic acid (205n-3)
• EPA and DHA in fish oil
• DHA also in blue-green algae
• ALA - Alpha linolenic acid (183n-3)
• precursor to EPA DHA
• Present in flax seed (linseed) oil

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Fatty Acids Omega-3

• ALA Not well converted to DHA and EPA in dogs and
  cats
• due to lack of delta-6-dehydrogenase
• Need fish oil for EPA and DHA benefits

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Fatty Acids Omega-3

• Powerful antiinflammatory effects
• decrease synovial IL-1 production, which
  contributes to pathogenesis of arthritis
• Necessary for mitochondrial function
• Residual effects for several weeks after
  discontinuing therapy

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Fatty Acids Omega-3

• Dermatologic effects
• Many studies showing benefits of EPA and DHA
  pruritic skin disease in dogs
• Improvement in cats with miliary dermatitis

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Fatty Acids Omega-3

• Antineoplastic effects
• Both fish oil and arginine increased survival
  time and disease free interval in dogs with LSA
• Decrease production of cytokines that mediate
  cancer cachexia
• Antinflammatory effects are accompanied by
  immunostimulant properties

92
Fatty Acids Omega-3

• Cardiovascular effects
• Primary treatment for hyperlipidemia
• Improves cardiac cachexia in dogs
• Protects against fibrillation and ischemic renal
  failure in ischemic models in the dog
• Reduces myocardial infarct size in a canine model
  of myocardial ischemia and reperfusion

93
Fatty Acids Omega-3

• Musculoskeletal effects
• Mediates signs of RA in people, especially early
  in disease
• Moderates symptoms, does not slow progression of
  RA in people

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Fatty Acids Omega-3

• Renal effects
• Slows progression of glomerular disease in people
• Undefined effect on chronic tubular renal failure

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Fatty Acids Omega-3

• Hematologic effects
• At very high doses, can cause coagulopathy
• Cats more sensitive to this than dogs
• Do not give 2-3 days perioperatively
• Monitor with
• Von Willebrands Disease or other coagulopathy
• NSAIDs or coumadin therapy (or toxicity)

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Fatty Acids Omega-3

• Neurologic effects
• DHA necessary for proper neurologic development
  in puppies, kittens and people
• Helps a number of mental disorders in people
• This includes retinal development
• DHA blood levels are low in poodles with RP
  (retinitis pigmentosa) and PRA

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Fatty Acids Omega-3

• Quality Control
• Contamination with heavy metals, dioxins and PCBs
  is a concern
• More of a problem with eating fish than fish oil
  supplements (stored in tissues)
• No fish oil products tested by ConsumerLab have
  ever been contaminated

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Fatty Acids Omega-3

• Quality Control
• Beware of rancidity of refrigerated, pressed oils
• Cod Liver Oil is not always the best source
• High in Vitamins A D

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Fatty Acids Omega-3

• Side Effects
• Inhibit platelet function
• Give with food to avoid GI upset
• Very high doses without antioxidant support can
  result in lipid peroxidation
• Most commercial products are preserved with
  antioxidants
• Anecdotal reports of pancreatitis and steatitis
  in cats

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Fatty Acids Omega-6

• LA linoleic acid (182n-6)
• Precursor to omega-6 fatty acids
• GLA - gamma-linolenic acid (183-n-6)
• Black Currant Oil
• Borage Oil
• Evening Primrose Oil

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Fatty Acids Omega-6

• Arachadonic acid (204n-6)
• Essential for cats
• Other sources rich in omega-6s
• Corn oil
• Safflower oil
• Soybean oil
• Canola oil

102
Fatty Acids Omega-6

• have some pro-inflammatory effects, as they can
  increase TNF IL6
• Use of omega-6 for inflammatory diseases is
  controversial
• GLA leads to production of PGE1, which has less
  inflammatory effects than other PGEs
• Also leukotriene production is inhibited

103
Fatty Acids Omega-6

• Omega-6 are good overall coat conditioners, and
  help seborrhea
• Omega-6 already plentiful in the diet
• Studies in people show some response of arthritis
  to EPO and Borage oil
• Study on Black Currant Oil showing no beneficial
  effect for arthritis in people

104
Fatty Acids Omega-6Omega-3 Ratio

• Response to omega-3 therapy is due to both
  omega-3 dose and omega 6ratio in the diet
• Ideal ratio is probably between 31 and 91
• Many diets gt301 some gt501
• The more omega-6s in the diet, the more
  omega-3s needed for therapeutic effect
• Presence of excessive omega-3s can suppress
  omega-6 production and vice versa

105
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106
Milk Thistle

• Silybum marianum Aster Family (daisies and
  thistles)
• Ripe seeds are used medicinally
• Silymarin is one of the active ingredients
• powerful antioxidant
• Anti-inflammatory inhibits lipooxygenase-5
• Most commonly used as an 70-80 standard
  extract

107
Milk Thistle

• Components of Silymarin (all are flavonolignans)
• silybin (silibinin) MOST ACTIVE
• Isosilybin (isosilibinin)
• silydianin (silidianin)
• silycrystine (silicristin)

108
Milk Thistle

• Components of Silymarin (all are flavonolignans)
• Bioavailability depends on substances in
  extract
• Proliposomes increase bioavailability in
  dogs
• Phosphotidyl choline increases
  bioavailability
• PC used in Nutramax Marin and DenoMarin

109
Milk Thistle

• Dose
• Dried herb 15-20mg/lb SID (1.5-3
  silymarin)
• Concentrated extract 2-5 mg/lb BID (70-80)
• Alcohol concentrated extract 2-5 mg/lb
  BID-TID
• (70-80)
• NOTE some extracts are whole herb extracts
• hard to dose these high enough to be
  effective

110
Milk Thistle

• Hepatic Effects
• Used for liver disease since the time of the
  Romans
• Some studies in people show improvement in liver
  enzymes, liver histology and survival in people
  with chronic active hepatitis
• No such benefit in people with viral hepatitis
• Equivocal results in people with alcoholic
  hepatitis

111
Milk Thistle

• Hepatic Effects
• Protective against Amanita mushroom toxicity in
  dogs
• Used as an antidote for Amanita toxicity in
  people
• 5 mg/kg IV over 1 hour
• then 20 mg/kg/day IV x 6 days
• IV prep not readily available in the US

112
Milk Thistle

• Hepatic Effects
• Also protective against carbon tetrachloride
  toxicity in dogs
• Protects against acetamenophen and phenytoin
  liver toxicity in people
• Many use it for hepatoprotective effects in dogs
  who take phenobarbital and primidone

113
Milk Thistle

• Endocrine Effects
• Reduces insulin resistance in people with
  coexisting diabetes and alcoholic cirrhosis
• May decrease blood sugar and LDL in people with
  type II diabetes

114
Milk Thistle

• Cardiovascular Effects
• Amiodarone generates free radicals that may cause
  toxicity
• Amiodarone used for ventricular arrhythmias in
  dogs
• Silymarin plus amiodarone protected against
  induced atrial flutter
• Silymarin and amiodarone alone provided no such
  protection

115
Milk Thistle

• Antiprotozoal Effects
• Treatment with metronidazole and silymarin was
  more effective than treatment with metronidazole
  alone
• Treatment with silymarin alone was not effective

116
Milk Thistle

• Side Effects
• Rare GI upset in people, dogs and cats
• Rare allergic rash in people

117
Milk Thistle

• Quality Control
• Only 2 of 9 products tested by ConsumerLab
  contained the expected amounts of silymarin
• Stick with a Brand you know
• The only Nutraceutical made for pets with milk
  thistle in it is Marin by Nutramax
• Denamarin combines Marin with SAMe (Denosyl)

118
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119
S-adenosyl-L-methionine (SAMe)

• SAMe is an amino acid which acts as a methyl
  donor
• transsulfates GAGs
• Used to make neurotransmitters
• dopamine and serotonin
• Absorption is better when given after a 12-hour
  fast in dogs
• Giving with food can prevent stomach upset.

120
S-adenosyl-L-methionine (SAMe)

• Present in protein rich foods
• First used to treat depression on people
• Positive side effect of treating arthritis pain
  in people was noted
• Promotes DNA, protein and proteoglycan synthesis
• May have antiinflammatory and analgesic
  properties
• May be a promising antidote for Tylenol toxicity

121
SAMe Hepatic Effects

• Improves hepatocellular function
• Improves bile flow
• Increases glutathione levels to fight
  inflammatory liver disease
• Powerful antioxidant
• In people, low glutathione levels lead to
  hepatitis, arthritis and depression

122
SAMe Hepatic Effects

• 50 of dogs and 80 of cats with hepatobiliary
  disease have low liver glutathione
• Denosyl is proven to increase liver glutathione
  levels in dogs and cats
• Bloodwork improvement can take up to 1-4 months

123
SAMe Hepatic Effects

• used to produce phosphatidyl choline, the main
  phospholipid in hepatocyte cell membranes
• When SAMe is depleted, hepatocyte cell membranes
  become less fluid
• leads to impaired bile secretion into bile
  canaliculi and cholestasis
• Bile acids are inflammatory, leading to chronic
  hepatitis

124
SAMe Hepatic Effects

• SAMe also promotes Na-K-ATPase that drives
  canalicular bile flow
• Low SAMe levels can also cause cholestasis this
  way
• SAMe is good for hepatic icterus

125
SAMe Musculoskeletal Effects

• Human clinical trials show SAMe effective in
  treating OA
• Positive results can persist for at least 2 years
  after treatment in people
• rabbit studies show some chondroprotective
  effects, by increasing proteoglycan synthesis

126
SAMe Dose

• 18 mg/kg/day
• Daily for 1-3 months for exposure to hepatotoxin
• Daily for 2-3 months for chronic active hepatitis
• Then QOD or twice weekly
• Twice weekly for protection against hepatotoxic
  therapy

127
SAMe - Quality Control

• SAMe is an expensive ingredient
• Nearly half of products contained less SAMe than
  labeled when ConsumerLab first tested in 2000
• All passed testing in April 2007
• SAMe is absorbed in the small intestine
• Should be enteric coated for better absorption
  and to prevent stomach upset

128
SAMe - Quality Control

• SAMe can break down with exposure to air
• Each tablet should be sealed in foil blister
• Can not be compounded into suspensions
• Broken tablets should be discarded
• Doses rounded to the nearest whole tablet

129
SAMe - Quality Control

• SAMe comes in different forms, according to the
  stabilizer used
• Tosylate
• disulfate tosylate
• disulfate ditosylate
• 1,4-butanedisulfonate (Actimet)

130
SAMe - Quality Control

• added compounds weigh as much as the SAMe
  molecule itself
• Interpret mg on ingredient list with care
• label is not always clear how much SAMe is in the
  product

131
SAMe - Side Effects

• GI upset mentioned previously
• Enteric coating can help
• Give with food if necessary
• No toxicity every reported no LD50 can be
  reached