Rheumatoid Arthritis

Introduction:

Rheumatoid arthritis (RA) is a chronic disease related to an autoimmune process (body’s immune system attacks healthy cells) which results in inflammation and pain in the joints. This type of arthritis occurs as a symmetrical distribution of joint inflammation most commonly in fingers, wrists, feet, ankles and knees. Other characteristics of the disease include morning stiffness, finger deformities, nodules under the skin, and may also involve the lungs. It is diagnosed by clinical presentation and a test for rheumatoid factor. Erythrocyte sedimentation rate is used to follow disease activity. It is usually treated with non-steroidal anti-inflammatory drugs such as ibuprofen or naproxen and disease modifying anti-rheumatic drugs such as methotrexate.

Rheumatoid arthritis and omega-3 fish oil:

Omega-3 fatty acids are considered essential fatty acids necessary for human health require to be obtained through food. Omega-3 oils consist of three types which include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-Linolenic acid (ALA). The principal sources of EPA and DHA available include fish oil, algal oil, and krill oil. ALA is found in flax seed oil, canola oil and soybean oil. For the purpose of this report, when omega-3 is mentioned, it is referring to a fish oil source of omega 3.

 

Rheumatoid arthritis, omega-3 fish oil, joint stiffness, pain, and grip strength:

A review of studies on Rheumatoid Arthritis (RA) by James MJ et al indicated that omega-3 fatty acid intake may help improve RA symptoms. Improvements in morning stiffness, pain index, and grip strength have been reported with intake of omega-3 fatty acids. Evidence exists to advise RA patients in food choices that provide substantial amounts of omega-3 fatty acids (fish products, omega-3 rich seeds, and vegetables) and to avoid foods that are very rich in omega-6 fatty acids (polyunsaturated oils and animal fats). (1)

 

Dietary fish oil supplementation and rheumatoid arthritis:

Results of a meta-analysis showed that after 3 months, dietary fish oil supplementation was associated with a statistically significant modest improvement in Rheumatoid Arthritis (RA). There was a reduction noted in tender joint count and morning stiffness in patients with RA. Ten randomized, double-blind placebo-controlled trials were included in the meta-analysis which concluded that fish oil is beneficial for RA. (2)

 

Omega-3 fish oil, joint stiffness and joint tenderness:

Improvements in morning stiffness and joint tenderness with the regular intake of fish oil was reported in a study of 66 patients with Rheumatoid Arthritis (RA) or inflammation of the joints and surrounding tissues. After discontinuing diclofenac, a non-steroidal anti-inflammatory drug at a dose of 75 mg oral twice daily, researchers administered fish oil at a high dose (130 mg/kg/day) to one group of patients and corn oil (9 capsules/day) to the other group for 8 weeks after stopping their regular medications. Patients on fish oil showed significant improvement in their arthritis measured by the reduction in number of tender joints (-5.3) and duration of morning stiffness (-67.7 minutes). (3)

 

Rheumatoid Arthritis, omega-3 fatty acids, and joint pain:

Taking 2.6 mg of omega-3 fatty acids daily was associated with a significant improvement in pain assessment in patients suffering from Rheumatoid Arthritis (RA). Participants (n=90) received either 2.6 gm of omega-3, or 1.3 gm of omega-3 + 3 gm of olive oil, or 6 gm of olive oil. Improvement in patient and doctor evaluation of pain was only significant with 2.6 gm of omega-3. Furthermore, more people were able to reduce their use of anti-rheumatic medication while taking 2.6 omega-3. (4)

 

Rheumatoid arthritis, omega-3 fatty acids, joint swelling, and joint pain:

A study of patients (n=23) with moderate to severe Rheumatoid Arthritis, which affects the joints, showed that IV omega-3 therapy performed on these patients significantly improved associated symptoms such as joint tenderness and swelling. For the first 2 weeks, patients received daily IV administration of either treatment (0.2 g of fish oil emulsion/kg) or placebo (0.9% saline). This was followed by 20 weeks of oral administration (capsules) of 0.05 g of fish oil/kg (treatment) or paraffin wax (placebo). At the end of the study, compared to the placebo group, those on omega-3 therapy had significantly lower swollen and tender joints. (5)

 

Meta-analysis of fish oil use on 8 measures of arthritis severity:

A meta-analysis was conducted which included 10 double-blind, randomized, placebo-controlled studies aimed at determining the effect of fish oil supplementation on 8 measures of arthritis severity including the number of tender joints, number of swollen joints, extent of morning stiffness, grip strength, erythrocyte sedimentation rates, and overall global assessment of disease severity. The studies involved a total of 368 participants who took fish oil supplements for at least three months. The meta-analysis revealed a highly significant decrease in the number of tender joint count (rate difference [RD] or absolute difference between groups = -2.9) and a significant shortening in the duration of morning stiffness (RD=-25.9) among patients supplementing with fish oils compared to dietary control oils. No statistically significant changes were observed for the other measured indicators of disease severity. (6)

 

Omega-3 fish oil and rheumatoid arthritis (RA):

The effects of the consumption of fish oil supplements and consumption of oily fish on the risk of RA and inflammation of the joints was tested in this population-based case-controlled study. Relevant dietary data was obtained from 1,889 individuals with RA and 2,145 control subjects without RA in Sweden from 1996 to 2005. Compared with subjects who never or seldom consumed oily fish, individuals who consumed oily fish 1-7 times per weeks had a 20% reduced risk of developing RA. Results were similar among individuals consuming oily fish 1-3 times a month. There was no difference in the consumption of fish oil supplements between the treatment or control group. (7) A review of trials using omega-3 fatty acids for rheumatoid arthritis (RA) or osteoarthritis (OA) was performed by Rosenbaum. Researchers reviewed 16 clinical trials, one meta-analysis and one review article in order to evaluated supplements in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Multiple studies reported that omega-3 fatty acids might help treat RA. Studies have used combinations of EPA and DHA for treatment of RA. Most studies showed improved clinical symptoms in patients including the number of tender joints, duration of morning stiffness, and/or physician pain assessment score. Total EPA/DHA omega-3 fatty acids combined daily doses ranged from 1.04 g to 7.1g (mean, 3 g). Treatment periods ranged from 12 to 52 weeks (mean, 16 wks). NSAIDs and slow-acting anti-rheumatic drugs were continued throughout the trials with EPA/DHA. Overall, a trend was seen toward a benefit of improved symptoms. (8)

 

Omega-3 fish oil adverse reactions and interactions:

A total of 10 studies were reviewed by Villani AM et al to determine potential serious adverse effects of fish oil at a dose of under 1.86 grams per day (21 It was found that there were no serious adverse effects reported in 994 adults over 59 years of age and other non-serious adverse effects were not significantly different from placebo (21). Fish oil has been reported to affect platelet aggregation, reduce vitamin K dependent factors which may be associated with an increased anticoagulation (reduce blood clotting) effect. Consumption should be avoided when taking anticoagulants like aspirin, warfarin, or ticlopidine because of the potential increased risk of bleeding (20). A case of a 67-year old woman taking warfarin (1.5 mg/day), an increase in her fish oil intake from 1 g/day to 2 g/day was associated with an increase in time for blood to clot as measured by the international normalized ratio (INR) which went from 2.8 to 4.3 within 1month, and decreased to 1.6 after the fish oil dose was reduced (17). An intake of 6 grams per day of docosahexaenoic acid (DHA) found no significant difference found in blood coagulation, platelet function, or thrombotic parameters including prothrombin time, activated partial thromboplastin time, antithrombin-III levels, and platelet aggregation (19). Fish oil may contain harmful contaminants such as heavy metals including mercury, dioxins, and polychlorinated biphenyls (PCBs). This risk can be reduced by purchasing fish oil that has undergone a purification process specified on the label (approved by the FDA, EPA, or US Pharmacopeia) (18).

 

Diet treatment for rheumatoid arthritis (RA):

The effect of diet on patients with rheumatoid arthritis (RA) or inflammation of the joints was studied in a controlled, single-blind trial. Participants in the treatment group (n=27) fasted for 7-10 days, followed by an individually adjusted gluten-free vegan diet for 3.5 months, followed by a 9-month lactovegetarian diet. The control subjects consumed an ordinary mixed food diet. Compared to the control group, those on the specified diet had a significant improvement in all clinical variables and most laboratory variables measured. A year later, the patients were re-examined. Researchers found that vegetarians who had benefited from the diet showed a significantly greater benefit than diet non-responders or control subjects. This suggests that the vegetarian diet positively influenced measures of inflammation and disease activity. (9)

 

Foods for reducing inflammatory markers:

In a small study of men aged 18 to 40 years, eating a cup (150 g) of boiled white potatoes, yellow potatoes (Yukon Gold), or purple potatoes every day for 6 weeks was associated with reduced inflammation and DNA damage (measured by plasma 8-hydroxydeoxyguanosine [8-OHdG], protein oxidation, lipid peroxidation, C-reactive protein [CRP], inflammatory cytokines, lymphoproliferation, NK cytotoxicity, and phenotypes). Researchers found that those who consumed the yellow and purple potatoes were much lower in oxidizing agents than the white potatoes. This study tested 8-OHdG which is an oxidized nucleoside of DNA excreted in the urine during DNA damage.  It is known to be a marker of oxidative stress and possibly linked to cancer and other diseases.  Level of 8-OHdG was lower in men who consumed either yellow or purple potatoes compared with white potatoes. The men who ate yellow potatoes had lower levels of IL-6 and exhibited less DNA damage compared with the men who ate white potatoes. Purple-potato eaters had lower levels of a different inflammatory marker, C-reactive protein, compared with white-potato eaters. Researchers suspect the rich pigments in colored potatoes help protect cells, tissue, and DNA from the free radical injuries that initiate inflammation. (10) Dietary change may improve markers of inflammation. Researchers randomly assigned 30 obese patients to two low calorie diets: calorie-restricted legume-free diet and calorie-restricted legume-based diet, prescribing 4 weekly different cooked-servings (160-235 g) of lentils, chickpeas, peas or beans. At the end of 8 weeks, people in both groups lost weight but weight loss was greater in the subjects in the legume-based diet (-7.8% vs. -5.3%; p = 0.024). The legume-based diet also resulted in a significantly higher reduction (% change from baseline values) in C-reactive protein (CRP) (~40% vs ~5% reduction in lab values) and complement C(C3) (~80% vs ~40%) both inflammatory markers. Even after the researchers controlled for the effects of weight loss on these markers, subjects in the legume-based diet had less apparent inflammation. (11)

 

Rheumatoid arthritis and curcumin:

Eight weeks of curcumin provided the same reductions in swelling and pain as the prescription drug diclofenac sodium, in a study of 45 people with rheumatoid arthritis. The participants were randomly assigned to receive curcumin (500 mg oral twice daily), diclofenac sodium (50 mg oral twice daily), or a combination of both. Using the Disease Activity Score (DAS), the researchers note that all groups showed improvements in various joint health measure, and there was a trend toward curcumin reducing the symptoms the most. (12)

 

Rheumatoid arthritis and Cat’s Claw:

Rosenbaum CC performed a review of studies entitled “Antioxidants and anti-inflammatory dietary supplements for osteoarthritis and rheumatoid arthritis.” The author found that three studies supported cat’s claw (either alone or in combination with other supplements) for OA. Cat’s claw refers to certain types of woody vines that grow in the Amazon. Two of the most commonly used species are Uncaria tomentosa and Uncaria guianensis (Uncaria guianensis has the greater antioxidant potency). Rosenbaum CC evaluated one study which involved 45 men with OA randomly receiving 100 mg daily (30 subjects) or placebo (15 subjects) for 4 weeks. For those taking cat’s claw, significant improvements were found compared to placebo for pain on activity, overall patient pain assessment, and overall physician pain assessment. No significant differences were found for pain at rest or at night or for knee circumference. Rosenbaum CC found that another study looked at 95 patients with OA which were randomly assigned to receive either glucosamine sulfate (1500 mg per day) or Reparagen (1800 mg per day), Reparagen capsules contain 300 mg Vincaria, a patented extract of Uncaria guianensis, (also called Cat’s Claw) with 1500 mg Lepidium meyenii, a vegetable from the Andes Mountains with IGF-I activation potential. The primary outcome was a 20% reduction in pain scores in most (90%) of both study groups determined by the Western Ontario and McMaster Universities Arthritis Index (WOMAC). WOMAC is the most widely used assessment in arthritis research which uses five different scores to rate pain and stiffness.  According to the author’s review in this study, cat’s claw can be recommended for patients with OA. Larger clinical trials need to be done to confirm benefit in rheumatoid arthritis since there was only one trial with 40 patients showing less pain but no change in swelling or stiffness. (8)

 

Rheumatoid arthritis and glucosamine:

Glucosamine may have some effect against rheumatoid arthritis, but research is limited with only one study located in a literature search which showed slight superiority of the compound 1-(p-chlorobenzoyl)-5-methoxy-2- methylindole- 3-acetic acid monohydrate glucosamide to indomethacin (22). This compound is a different form of glucosamine than the more commonly used glucosamine sulfate and is not available commercially. Glucosamine compounds have much more research supporting a benefit for osteoarthritis as opposed to rheumatoid arthritis.

 

 

Assessment and Plan: Rheumatoid arthritis

• The research evidence expressed supports advising rheumatoid arthritis patients to select foods that provide substantial amounts of omega-3 fatty acids (fish products, omega-3 rich seeds, and vegetables) and to avoid foods that are very rich in omega-6 fatty acids (polyunsaturated oils and animal fats). (1)

 

• Omega-3 oils consist of three types which include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-Linolenic acid (ALA). The principal sources of EPA and DHA available include fish oil, algal oil, and krill oil. ALA is found in flax seed oil, canola oil and soybean oil.

 

• Daily doses of omega-3 fish oil ranged about 1 to 9 grams with an average of about 3 g taken. Treatment periods ranged from 8 weeks up to a year. In many of the trials, omega-3 fish oil was continued along with other medications. The following benefits of omega-3 cold water fish oil was supported by research:

 

• Omega-3 fish oil consumption in the form of oily fish may prevent rheumatoid arthritis. Compared with subjects who never or seldom consumed oily fish, individuals who consumed oily fish 1-7 times per weeks had a 20% reduced risk of developing RA (7).

 

• Some indicators of disease activity which did not show statistically significant improvements with the use of fish oil include erythrocyte sedimentation rates, and overall global assessment of disease severity (6).

 

• Grip strength in some studies was improved (1).

 

• Was able to allow patients to reduce their use of anti-rheumatic medication while taking 2.6 grams of omega-3 daily. (4)

 

• Improved the pain index (1), and the physician pain assessment score (8).

 

• Reduced the swelling of joints (5)

 

• Lowered the number of tender joints (5,6,8)

 

• The duration of morning stiffness was reduced (1,2,3,6,8). In one study, morning stiffness was reduced almost 70 minutes more than corn oil after 8weeks with high doses of 130 mg per kilogram (3), and another study showed that it reduced morning stiffness by 25.9 minutes after 3 months (6).

 

• Omega-3 fish oil adverse reactions and interactions:

 

• A total of 10 studies were reviewed by Villani AM et al to determine potential serious adverse effects of fish oil at a dose of under 1.86 grams per day (21 It was found that there were no serious adverse effects reported in 994 adults over 59 years of age and other non-serious adverse effects were not significantly different from placebo (21).

 

• Fish oil has been reported to affect platelet aggregation, reduce vitamin K dependent factors which may be associated with an increased anticoagulation (reduce blood clotting) effect. Consumption should be avoided when taking anticoagulants like aspirin, warfarin, or ticlopidine because of the potential increased risk of bleeding (20).

 

• A case of a 67-year old woman taking warfarin (1.5 mg/day), an increase in her fish oil intake from 1 g/day to 2 g/day was associated with an increase in time for blood to clot as measured by the international normalized ratio (INR) which went from 2.8 to 4.3 within 1month, and decreased to 1.6 after the fish oil dose was reduced (17).

 

• An intake of 6 grams per day of docosahexaenoic acid (DHA) found no significant difference found in blood coagulation, platelet function, or thrombotic parameters including prothrombin time, activated partial thromboplastin time, antithrombin-III levels, and platelet aggregation (19).

 

• Fish oil may contain harmful contaminants such as heavy metals including mercury, dioxins, and polychlorinated biphenyls (PCBs). This risk can be reduced by purchasing fish oil that has undergone a purification process speciied on the label (approved by the FDA, EPA, or US Pharmacopeia) (18).

 

• Kjeldsen-Kragh J performed a study on rheumatoid arthritis patients who initially fasted for 7-10 days, then ate gluten-free vegan diet for 3.5 months, followed by a 9-month lactovegetarian diet. Compared to a mixed food diet, those on the specified diet had a significant improvement in multiple clinical and laboratory variables. A year later, many of the patients had sustained benefit. (9)

 

• Some foods have been noted to improve the levels of inflammatory markers in the blood, but have not yet been researched well for benefits in inflammatory diseases such as rheumatoid arthritis. Yellow potato consumption was associated with lower levels of the inflammatory marker interleukin-6, and those who ate purple potatoes had lower levels of C-reactive in (CRP) (10). A legume-based diet resulted in a significantly higher reduction in the inflammatory marker, CRP (~40% vs ~5% reduction in lab values) and complement (C3) (~80% vs ~40% reduction in lab values) (11).

 

• A study by Hermsdorff HH et al, 45 people with rheumatoid arthritis who received 8 weeks of curcumin at a dose of 500 mg resulted in the same reduction of swelling and pain as the prescription drug diclofenac sodium at a dose of 50 mg (12).

 

• Adverse reactions of turmeric/curcumin  include but not limited to: A theoretical increase risk of bleeding with antiplatelet effects is possible although less than that caused by aspirin was reported (13).

 

• One study reported the following with doses of 1-4 grams per day: gastrointestinal complaints, falls, dizziness, respiratory tract infection, delusions, edema, and hearing impairment. Sodium, potassium, urea, creatinine, protein, albumin, bilirubin, alkaline phosphatase, and alanine aminotransferase/glutamic-pyruvic transaminase were followed without evidence of toxicity (14).

 

• There was one case reported where transient complete atrioventricular block occurred with taking 20-30 pills containing turmeric 50% (about 75 mg), mulberry leaves 10%, garlic 10%, black soybean 20%, and arrowroot starch 10% (15).

 

• One study on dose escalation showed that no toxicity was observed up to 8000 mg/day (16).

 

• Rheumatoid arthritis and cat’s claw: Cat’s claw refers to certain types of woody vines that grow in the Amazon. Two of the most commonly used species are Uncaria tomentosa and Uncaria guianensis (Uncaria guianensis has the greater antioxidant potency). Rosenbaum CC performed a review of studies entitled “Antioxidants and anti-inflammatory dietary supplements for osteoarthritis and rheumatoid arthritis.” The author found that three studies supported cat’s claw (either alone or in combination with other supplements) for OA, but larger clinical trials need to be done to confirm benefit in rheumatoid arthritis since there was only one trial with 40 patients showing less pain but no change in swelling or stiffness (8).

 

• Rheumatoid arthritis and glucosamine: Glucosamine may have some effect against rheumatoid arthritis, but research is limited with only one study located in a literature search which showed slight superiority of the compound 1-(p-chlorobenzoyl)-5-methoxy-2- methylindole- 3-acetic acid monohydrate glucosamide to indomethacin (22). This compound is a different form of glucosamine than the more commonly used glucosamine sulfate and is not available commercially. Glucosamine has much more research supporting a benefit for osteoarthritis as opposed to rheumatoid arthritis.

 

 

References:

1.James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum. 1997 Oct;27(2):85-97. http://www.sciencedirect.com/science/article/pii/S0049017297800091

2.Fortin P R, Lew R A, Liang M H, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. Journal of Clinical Epidemiology 1995; 48(11): 1379-1390. http://www.ncbi.nlm.nih.gov/pubmed/7490601

3.Kremer JM, Lawrence DA, Petrillo GF, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs: clinical and immune correlates. Arthritis Rheum 1995;38(8):1107–14. http://www.ncbi.nlm.nih.gov/pubmed/7639807

4.Geusens P, Wouters C, Nijs J, Jiang Y, Dequeker J. Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis. A 12-month, double-blind, controlled study. Arthritis Rheum. 1994 Jun;37(6):824-9. http://www.ncbi.nlm.nih.gov/pubmed/8003055

5.Bahadori B, Uitz E, Thonhofer R, et al. omega-3 Fatty acids infusions as adjuvant therapy in rheumatoid arthritis. JPEN J Parenter Enteral Nutr. 2010 Mar-April; 34(2):151-5. http://www.ncbi.nlm.nih.gov/pubmed/20375422

6.Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC, Sperling RI. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. Clin Epidemiol. 1995 Nov;48(11):1379-90. http://www.ncbi.nlm.nih.gov/pubmed/7490601

7.Rosell M, Wesley AM, Rydin K, Klareskog L, Alfredsson L; EIRA study group. Dietary fish and fish oil and the risk of rheumatoid arthritis. Epidemiology. 2009 Nov;20(6):896-901. http://www.ncbi.nlm.nih.gov/pubmed/19730266

8.Rosenbaum CC. Antioxidants and anti-inflammatory dietary supplements for osteoarthritis and rheumatoid arthritis. Alternative Therapies in Health and Medicine. 2010 Mar-Apr;16(2):32-40. http://www.encognitive.com/files/ANTIOXIDANTS%20AND%20ANTIINFLAMMATORY%20DIETARY%20SUPPLEMENTS%20FOR%20OSTEOARTHRITIS%20AND%20RHEUMATOID%20ARTHRITIS.pdf

9.Kjeldsen-Kragh J. Rheumatoid arthritis treated with vegetarian diets. Am J Clin Nutr. 1999 Sep;70(3 Suppl):594S-600S. http://www.ncbi.nlm.nih.gov/pubmed/10479237

10.Kaspar KL, Park JS, Brown CR, Mathison BD, Navarre DA, Chew BP, 2011, Pigmented potato consumption alters oxidative stress and inflammatory damage in Men, American Society for Nutrition, 141:108-111. http://www.ncbi.nlm.nih.gov/pubmed/21106930

11.Hermsdorff HH, Zulet MA, Abete I, Martinez JA. A legume-based hypocaloric diet reduces proinflammatory status and improves metabolic features in overweight/obese subjects. Eur J Nutr 2011 Feb;50(1):61-9. Epub 2010 May 25. http://www.springerlink.com/content/9m645tr105424g3n/?MUD=MP

12.Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012 Nov;26(11):1719-25. http://www.ncbi.nlm.nih.gov/pubmed/22407780

13.Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002 Dec;27(6):391-401. http://www.ncbi.nlm.nih.gov/pubmed/12472978

14.Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb;28(1):110-3. http://www.ncbi.nlm.nih.gov/pubmed/18204357

15.Lee SW, Nah SS, Byon JS, Ko HJ, Park SH, Lee SJ, Shin WY, Jin DK.Int J Cardiol. Transient complete atrioventricular block associated with curcumin intake. 2011 Jul 15;150(2):e50-2. http://www.ncbi.nlm.nih.gov/pubmed/2699615

16.Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001 Jul-Aug;21(4B):2895-900. http://www.ncbi.nlm.nih.gov/pubmed/11712783

17.Buckley, M. S., Goff, A. D., and Knapp, W. E. Fish oil interaction with warfarin. Ann Pharmacother. 2004;38(1):50-52. http://www.ncbi.nlm.nih.gov/pubmed/14742793

18.Bays HE. Safety considerations with omega-3 Fatty Acid therapy. Am J Cardiol. 2007;99(6A):S35-43. http://www.ncbi.nlm.nih.gov/pubmed/17368277

19.Nelson GJ, Schmidt PS, Bartolini GL, Kelley DS, Kyle D. The effect of dietary docosahexaenoic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans. Lipids. 1997 Nov;32(11):1129-36. http://www.ncbi.nlm.nih.gov/pubmed/9397397

20.Ramsay NA, Kenny MW, Davies G, Patel JP. Complimentary and alternative medicine use among patients starting warfarin. Br J Haematol. 2005 Sep;130(5):777-80. http://www.ncbi.nlm.nih.gov/pubmed/16115136

21.Villani AM, Crotty M, Cleland LG, James MJ, Fraser RJ, Cobiac L, Miller MD. Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature. BMC Geriatr. 2013 May 1;13(1):41. http://www.ncbi.nlm.nih.gov/pubmed/23634646

22.Giordano M, Capelli L, Chianese U. The therapeutic activity of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid monohydrate glucosamide in rheumatoid arthritis (double blind trial). Arzneimittelforschung. 1975 Mar;25(3):435-7. http://www.ncbi.nlm.nih.gov/pubmed/1098671