FOOD: PROCEED WITH CAUTION
Educational Objectives
| The goals of this program are to optimize the benefits of diet and nutrition and to increase awareness about the
potential risks associated with dietary supplements. After hearing and assimilating this program, the clinician
will be better able to:
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 | 1. Describe the Mediterranean diet and its role in reducing inflammation.
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| 2. List foods and spices with demonstrated anti-inflammatory effects.
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| 3. Discuss the effect of diet on chronic inflammatory conditions, such as rheumatoid arthritis.
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| 4. Identify dietary supplements known to inhibit or induce important enzymes involved in drug metabolism.
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| 5. Educate patients about potential risks associated with dietary supplements.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning
committee reported nothing to disclose.
Acknowledgments
Dr. Leopold was recorded at 51st Annual Postgraduate Symposium, Family Medicine Update: 2008, presented by the
San Diego Academy of Family Physicians and held June 27-29, 2008, in San Diego, CA; Dr. Borgsdorf was recorded
at 35th Annual Irving M. Rasgon, MD, Family Medicine Symposium, presented by Kaiser Permanente, and held June
27-29, 2008, in Carlsbad, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
| FOOD AS MEDICINE: AN ANTI-INFLAMMATORY DIET —David C. Leopold, MD, Director, Integrative Medical Education,
Scripps Center for Integrative Medicine, La Jolla, CA
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| Inflammation: core component of many chronic disease states; pharmacologic approaches may reverse inflammation,
but anti-inflammatory diet prevents inflammation (improving many disease states)
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| Mediterranean diet: limited intake of red meat; protein sources include poultry and fish; increased intake of whole
grains and fresh fruits and vegetables; other components include daily physical activity and moderate intake of alcohol;
epidemiologic studies—old study looking at regional dietary patterns found significant benefit (eg, 90% reduction in
risk for cardiovascular [CV] disease) from Mediterranean diet, compared to Western diet; benefit not linked to single
food; different dietary components have synergistic effects; recent study also found significant reduction in heart disease
and other chronic conditions associated with Mediterranean diet plus regular exercise and smoking abstinence; goal—
by preventing formation of inflammatory mediators, anti-inflammatory diet improves overall health and may reduce
need for anti-inflammatory pharmacologic agents
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| Omega fatty acids: metabolism of omega-6 fatty acids generally increases proinflammatory mediators; metabolism of
omega-3 fatty acids results in less inflammation; dietary ratio—lower ratio of dietary omega-6 to omega-3 fatty acids
(2-4 to 1) associated with longer lifespan; typical American diet has high ratio (20-25 to 1); dietary recommendations—
decrease intake of saturated fats; always cook with monounsaturated fats (eg, olive oil [preferred], canola oil); increase
intake of polyunsaturated fats (omega-3 fatty acids); limit intake of omega-6 fatty acids
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| Diet, weight loss, and health: Dutch study concluded that poor diet associated with similar degree of health risk as
smoking; for most people, losing ≈3 kg of weight significantly decreases risk for many diseases; anti-inflammatory diet
not specific for weight loss, but many people lose weight with long-term compliance; lifestyle choices—smoking abstinence,
increasing intake of fruit and vegetables, exercising regularly, and having moderate intake of alcohol estimated to
increase lifespan by ≈14 yr
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| Beneficial foods and phytonutrients: genistein (from soy) and fish oils — have synergistic effects on cyclooxygenase-2
inhibition; green tea—component (epigallocatechin gallate) helps improve arthritis; betaine—present in beets
and red wine; may explain “French paradox” (ie, high intake of betaine-containing fruits and vegetables as well as red
wine in moderation counteracts intake of fatty foods, producing relatively low risk for heart disease); like folate, reduces
homocysteine levels; curcumin (curry spice)—has mild nonsteroidal anti-inflammatory effects; lowers cholesterol; inhibits
peroxidation of lipids; rosemary—inhibits thrombogenesis; may have anti--proliferative effect; down-regulates
nuclear factor (NF)-kappaB; flavonoids—induce apoptosis; have anticancer effects
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| Red meat and cancer: regular intake of red meat increases risk for cancers of lung, colon and rectum, liver, esophagus,
and pancreas (in men); eating \>1.5 servings of red meat daily doubles risk for breast cancer among women; high heat or prolonged
cooking causes cross-linkage of proteins and changes in DNA
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| Disease states: benefit of anti-inflammatory diet demonstrated for patients with rheumatoid arthritis or asthma; high intake
of foods fried in polyunsaturated oils (eg, snack chips) increases risk for asthma among children
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| More beneficial foods and phytonutrients: quercetin—present in apples and onions; has anticancer and anti-inflammatory
effects; olive oil—monounsaturated fat; oleic acid has anti-inflammatory effects; more on flavonoids—
have nonsteroidal anti-inflammatory effects; inhibit platelet aggregation and other processes mediated by prostaglandins;
more on curcumin—may have role for early intervention in patients with Alzheimer’s disease; ginger—anti-inflammatory
effects; berries—high levels of polyphenols and antioxidants; study showed reduced oxidative stress on central
nervous system; onions—contain quercetin and other compounds that inhibit platelet aggregation; dark chocolate—
improves insulin sensitivity and control of systolic blood pressure (BP)
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| Rheumatoid arthritis (RA): patients who fast then follow vegan diet have substantial subjective and objective improvements;
dietary noncompliance often results in RA flare, with regression after diet resumed; omega-3 fatty acids—
supple--ments or increased intake of cold water fish recommended (also beneficial in patients with lupus); fiber—
associated with decreased inflammation, C-reactive protein (CRP) levels, and risk for rheumatologic conditions
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| “Leaky gut” theory: intestinal dysbiosis; dietary components enter bloodstream and react with tissues (eg, myofascial
tissue, joints); reducing antigenic stressors in diet reduces cross-reactivity; anti-inflammatory diet avoids intake of dairy
products, meats, and poultry
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| Whole grains: positive correlation between high glycemic load and CRP levels (implications for patients with CV disease
or cancer); study showed daily intake of 2 to 3 servings of whole grains led to significant improvements in diabetes; flour vs
whole grains—flour has high glycemic index (quick release of glucose); whole grains release glucose more slowly, avoiding
spikes; whole grains also have high levels of antioxidant activity
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| Probiotics and prebiotics: Lactobacillus and Bifidobacterium, in presence of inulin, positively alter gut flora (reduce
Clostridium and increase beneficial microflora) and decrease tumor markers; study showed significant reduction in
clarithromycin-resistant Helicobacter pylori after probiotic supplementation; benefit also seen among patients with ulcerative
colitis (especially when used in combination with omega-3 fatty acid supplementation)
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| Disease prevention: cancer—flaxseed may have role in prevention and adjunctive therapy for prostate cancer; green
tea seems to prevent tumor formation; damage from ultraviolet (UV) radiation—zeaxanthin and lutein associated with
reduced UV damage to ocular lens
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| General approach: anti-inflammatory diet, exercise, and stress management form “triangle of health”; whole foods preferred
over supplements; supplements and medications added as necessary for treating specific problems; adherence —
often poor initially, unless patient highly motivated; may wax and wane over time; patients who adhere to diet and lifestyle
recommendations for ≈12 wk typically notice significant benefit
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| Questions and answers: cooking oils—olive oil preferred; canola oil acceptable for baking; heat oil slowly and avoid
smoke point; wine—red wine seems to have more benefit than white wine (possibly due to higher concentration of
polyphenols and antioxidants); fasting—most studies use 7-day fast; speaker recommends 1-day fast for inexperienced
patients and 3-day fast for more experienced patients; red meat—free-range, “organically” raised animals produce healthier
meat, high in omega-3 fatty acids; animals subjected to stress produce nutritionally inferior product; cooking process
(eg, charring) may increase levels of carcinogens; identifying foods that aggravate RA—celiac testing often results in
false-positive and false-negative findings; initial fast helpful, followed by anti-inflammatory diet (avoid dairy, wheat, and
other suspect foods); slowly reintroduce items and watch for reaction; permanently eliminate items that cause exacerbation
of symptoms
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| IS “NATURAL” ALWAYS SAFE? INTERACTIONS BETWEEN DIETARY SUPPLEMENTS AND DRUGS OR DISEASE
STATES —Lawrence R. Borgsdorf, PharmD, Ambulatory Care Pharmacist, Kern County Medical Center, Bakersfield,
CA
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| Regulation: Dietary Supplement Health and Education Act (1994) — dietary supplements not regulated by Food and
Drug Administration (FDA); manufacturers can make false claims of efficacy, as long as claim does not appear on packaging;
proof of safety and efficacy not required; no standards of purity or content; duty to warn (as required with pharmaceutical
products) does not apply; label must include disclaimer statement; few systematic studies looking at interactions or
adverse effects
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| Use of dietary supplements: studies report rates of 30% to 50% (likely underestimated); 70% of patients who use dietary
supplements underreport use to physician
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| United States pharmacopoeia (USP): independent nonprofit organization with established standards for drug purity
and content; USP-approved products—contents verified; quantities present within acceptable range; minimal levels of
contaminants; functional delivery system; manufacturing processes meet USP standards
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| Potential problems: research—limited database about interactions of dietary supplements with other agents; products
not approved by USP—questionable purity adds variable (ie, effects of contaminants); highly variable concentrations
of active ingredients; dosing—not prescribed by physician; patients often take supplements inconsistently;
combination products—many supplements contain \>1 active ingredient; little known about interactions
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| Absorption: presence of one drug or supplement may alter absorption of another (eg, pectin and oat bran bind statins, preventing
absorption); P-glycoprotein—efflux transporter protein in gut, facilitates excretion of many compounds; inhibited
or activated by some drugs and dietary supplements (affects serum concentrations of transported compounds); blood flow
and gut motility—affected by some agents, resulting in altered absorption; protein binding—affects serum concentration
of free drug; eg, rosemary (ingredient in many dietary supplements) inhibits binding of cyclosporine to P-glycoprotein, decreasing
elimination and increasing serum concentration
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| Phase-I metabolism: stage in which many drug-dietary supplement interactions occur; induction or inhibition of enzymes
involved in drug metabolism affects serum concentrations, efficacy, and risk for toxicity; effect of enzyme induction
evident within 2 to 6 wk after initiating agent and lasts several weeks after discontinuing agent; when using agent
known to affect metabolism of another drug, dose adjustments can be made to offset altered activity; example—
metabolism of cyclosporine increased by St. John’s wort (has led to rejection of transplanted organs); cytochrome P
(CYP)3A4—enzyme involved in metabolism of hundreds of drugs (eg, amiodarone, amlodipine, most statins, cyclosporine,
sirolimus, selective serotonin reuptake inhibitors); enzyme inducers include St. John’s wort and garlic supplements
(but not fresh garlic); inhibitors include berberine, chamomile, echinacea, and ginseng; enzyme inhibition may lead to accumulation
of toxic levels of drug in serum; CYP1A2—substrates include cloza-pine, cyclobenzaprine, melatonin, imipramine,
and ritonavir; inducers include St. John’s wort; inhibitors include caffeine, echinacea, and grapefruit juice;
CYP2C8, CYP2C9, and CYP2C10—sub-strates include carvedilol and warfarin; inducers include ginkgo biloba; inhibitors
include echinacea and ginseng; multiple actions—some herbal products (eg, ginkgo biloba) inhibit some enzymes
and induce others
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| Transporter proteins: P-glycoprotein—efflux transporter that facilitates excretion of drugs into intestinal lumen,
bile, and urine, and out of brain; induction decreases substrate levels; inhibition increases substrate levels, possibly resulting
in toxicity; organic anion transporter proteins—uptake transporters, involved in absorption; induction increases
uptake and serum levels; inhibition decreases absorption; substrates—P-glycoprotein involved with excretion of
amiodarone, estrogens, statins, some immunosuppressive agents, and protease inhibitors (among others); herbal
products—garlic supplements and St. John’s wort induce, and goldenseal and grapefruit juice inhibit P-glycoprotein
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| Pharmacologic interactions: warfarin plus ginkgo—ginkgo has antiplatelet effects, increasing risk for bleeding in
patients taking warfarin; loop diuretics and oriental ginseng—ginseng directly affects renal tubular cells, reducing effect
of loop diuretics (eg, furosemide); kava—increases sedative effects and impairment associated with alcohol, benzodiazepines,
and other sedating agents; more on ginkgo—increases sedative effect when combined with trazodone
(mechanism unknown); increases efficacy and decreases extrapyramidal symptoms associated with haloperidol (mechanism
unknown); more on St. John’s wort—reduces serum levels of sirolimus, cyclosporine, and digoxin; inhibits serotonin
reuptake, increasing risk for serotonin syndrome; interacts with methadone, paroxetine, and estrogen-containing
compounds, eg, oral contraceptives; more on ginseng—interacts with phenelzine and other monoamine oxidase inhibitors,
potentially causing manic-like symptoms; decreases efficacy of warfarin; inhibits CYP450 ; interferes with polyclonal
antibody assays for digoxin, yielding falsely elevated or depressed results; more on garlic supplements—
increase risk for bleeding when taken with warfarin; reduce efficacy of protease inhibitors; green tea—decreases efficacy
of warfarin (because of high content of vitamin K); dong quai—known carcinogen, increases action of warfarin;
milk thistle—reported to have benefit in patients with hepatitis; drug interactions recently reported
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| Interactions with disease states: bleeding disorders—herbs known to affect bleeding (usually increasing risk) include
bilberry leaves, black cohosh, chamomile, ginger, goldenseal, feverfew, ginkgo, and ginseng; hepatitis—many herbal
supple--ments have hepatotoxic effects; chronic kidney disease—herbal diuretics may increase potassium wasting; noni
juice high in potassium (hyperkalemia reported); immune issues—some herbal products interfere with immunosuppressive
therapy (eg, lupus, rheumatoid arthritis, organ transplantation)
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| Management and mitigation: identify all dietary supplements used (best if patient brings in packaging); enter supplements
into medical record; tools—Kaiser Permanente learning center (www.naturaldatabase.com) includes natural medicines
database with information about efficacy, safety, and interactions; educational information for patients available; Drug
Facts and Comparisons (on Kaiser Web site) also provides information about interactions between herbal products and
drugs or disease states; general advice—counsel patients taking high-risk medications (eg, warfarin, antiarrhy-thmics, immunosuppressive
therapy, protease inhibitors), for which altered levels and/or efficacy could have dire consequences, to
avoid use of dietary supplements; dietary supplements with many known interactions (eg, St. John’s wort, ginkgo biloba)
should be avoided or used with caution, and patients followed for potential adverse effects; discontinuation recommended if
interaction suspected
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| Case 1: man, 70 yr of age; herbal products used include black cherry leaf, omega-3, -6, and -9 fatty acid supplements, coenzyme
Q10, and gotu kola; medications include aspirin, niacin, simvastatin, cyclobenzaprine, and fluticasone; concerns —
potential hepatotoxicity; CYPA4 inhibition may lead to increased levels of simvastatin; potential exacerbation of hyperlipidemia
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| Case 2: man, 68 yr of age, with chronic atrial fibrillation, stable on 30 mg warfarin weekly (long-term); routine follow-up
showed elevated international normalized ratio (INR), but no bleeding, unusual bruising, weakness, or dizziness; patient
compliant with medications and reports no changes in diet, but mentions change in brand of saw palmetto (taken for prostate
symptoms); saw palmetto discontinued; after stabilization, he wants to continue saw palmetto, but is advised to return
to previous brand; conclusion — new brand of saw palmetto not approved by USP and likely had contaminant that
caused interaction
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Suggested Reading
Bent S: Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of
California, San Francisco Medical Center. J Gen Intern Med 23:854, 2008; Chilton FH et al: Mechanisms by which
botanical lipids affect inflammatory disorders. Am J Clin Nutr 87:498S, 2008; Elkan AC et al: Gluten-free vegan diet
induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine
in patients with rheumatoid arthritis: a randomized study. Arthritis Res Ther 10:R34, 2008; Gardiner P et al: Herbal
and dietary supplement-drug interactions in patients with chronic illnesses. Am Fam Physician 77:73, 2008; Gillies PJ:
Preemptive nutrition of pro-inflammatory states: a nutrigenomic model. Nutr Rev 65:S217; Giugliano D, Esposito K:
Mediterranean diet and metabolic diseases. Cur Opin Lipdiol 19:63, 2008; Griffen BA: How relevant is the ratio of dietary
n-6 to n-3 polyunsaturated fatty acids to cardiovascular disease risk? Evidence from the OPTILIP study. Curr Opin
Lipidol 19:57, 2008; Gurley BJ et al: Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects
of milk thistle, black cohosh, goldenseal, kava kava, St. John’s wort, and echinacea. Mol Nutr Food Res 52:755,
2008; Mohammed Abdul MI et al: Pharmacodynamic interaction of warfarin with cranberry but not with garlic in
healthy subjects. Br J Pharmacol 154:1691, 2008; Nowack R: Review article: cytochrome P450 enzyme, and transport
protein mediated herb-drug interactions in renal transplant patients: grapefruit juice, St. John’s wort, and beyond! Nephrology
13:337, 2008; O’Keefe JH et al: Dietary strategies for improving post-prandial glucose, lipids, inflammation, and
cardiovascular health. J Am Coll Cardiol 51:249, 2008; Simopoulos AP: The importance of omega-6/omega-3 fatty
acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 233:674, 2008; Sood A et al:
Potential for interactions between dietary supplements and prescription medications. Am J Med 121:207, 2008; Zhou SF,
Lai X: An update on clinical drug interactions with the herbal antidepressant St. John’s wort. Curr Drug Metab 9:394,
2008.
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