Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                

Osteoarthritis (OA) - CM Plex Cream Study by DR Kraemer

Download as pdf
Download as pdf
You are on page 1of 9

J Rheumatol 2002;29:1708-12

Cetylated Fatty Acids Improve Knee Function in Patients with


Osteoarthritis
ROBERT HESSLINK Jr, DAVID ARMSTRONG III, M.V. NAGENDRAN, SRINAN SREEVATSAN, and
RAJ BARATHUR
ABSTRACT.

Objective. To determine the benefit of cetylated fatty acids (CFA) on knee range of motion and function in
patients with osteoarthritis (OA).
Methods. Sixty-four patients with chronic knee OA were evaluated at baseline and at 30 and 68 days after
consuming either placebo (vegetable oil; n = 31) or CFA (CeladrinTM; n = 33). Evaluations included physician
assessment, knee range of motion with goniometry, and the Lequesne Algofunctional Index (LAI).
Results. After 68 days, patients treated with CFA exhibited significant (p < 0.001) increase in knee flexion
(10.1°) compared to patients given placebo (1.1°). Neither group reported improvement in knee extension.
Patient responses to the LAI indicated a significant (p < 0.001) shift towards functional improvement for the
CFA group (-5.4 points) after 68 days compared to a modest improvement in the placebo group (-2.1 points).
Conclusion. Compared to placebo, CFA provides an improvement in knee range of motion and overall function
in patients with OA of the knee. CFA may be an alternative to the use of nonsteroidal antiinflammatory drugs
for the treatment of OA.

From Hesslink Ventures and ClinCyte, San Diego, California, USA, and the Medical Center, Manipal, India.
Supported in part by a research contract awarded to ClinCyte by Imagenetix, Inc., San Diego, CA, USA.
R. Hesslink Jr, ScD; D. Armstrong III, PhD, Hesslink Ventures; M.V. Nagendran, MD, Medical Center,
Manipal; S. Sreevatsan, PhD; R. Barathur, PhD, ClinCyte.
Address reprint requests to Dr. R. Hesslink Jr, PO Box 501691, San Diego, CA 92150. Submitted July 27,
2001; revision accepted February 14, 2002.

Dietary fatty acid composition is important for the prevention of chronic disease1-4. Results of epidemiological
research indicate that individuals consuming diets high in fish oils have a lower incidence of cardiovascular
disease2-4. It has subsequently been shown that eicosapentaenoic acid (EPA) is the main component of fish oils
providing this protective benefit. EPA, an eicosanoid precursor, and docosahexaenoic acid (DHA) are omega-3
polyunsaturated fatty acids5-7. Epidemiological and clinical research indicates that individuals with rheumatoid
arthritis (RA) also benefit from dietary EPA and DHA supplementation8-11, although outcomes have been
variable. Recently, it was shown that a cetylated monounsaturated fatty acid (e.g., myristoleic acid) conferred
protection against adjuvant-induced arthritis in rats12. However, the mechanism of action was not established. A
recent study suggested that myristoleic acid may act by inhibition of 5-lipoxygenase13, a potent mediator of
inflammation14.
The incidence of osteoarthritis (OA) is rising among the elderly15. Nonsteroidal antiinflammatory drugs
(NSAID) including COX-2 inhibitors are commonly used treatments; however, longterm use of these agents
may lead to significant adverse events16-21. There is a need for alternative products that benefit patients with OA
without harmful side effects. Recently, several products containing cetyl myristoleate oil have become
available. However, well-controlled studies to investigate the efficacy of these products have not been
performed. We investigated the clinical benefits of a blend of cetylated monounsaturated fatty acids in a group
of patients with OA of the knee. We hypothesized that these patients would experience improvement in knee
range of motion and clinical status based on the Lequesne Algofunctional Index (LAI)22 questionnaire.
MATERIALS AND METHODS
Patients and consent. Two medical clinics were enlisted for recruitment of patients in an OA study approved by
the Maiya Hospital IRB in Bangalore, India. Of the 86 patients expressing interest, 66 patients were selected
due to their diagnosis of knee OA (placebo: n = 33; CFA: n = 33). Knee OA was diagnosed using American
College of Rheumatology guidelines23 by the treating physician and confirmed by the clinical investigator
(MVN).
Study design. Subjects were randomized to study intervention. Subjects and investigators were blinded to
treatment assignment. Amber colored soft gel capsules identical in shape and size were used to blind study
participants. Patients were asked to consume 6 capsules per day with makeup days allowed for missed dosages.
Subjects were asked to consume 3 capsules in the morning and 3 in the evening (total = 408 capsules).
After initial clinical assessment, the patients were asked to maintain their daily dietary and medication routine.
Subjects receiving medication for other ailments were asked to maintain their current dosing regimen. In
addition, patients currently taking medication for knee OA were asked to continue their medication (Table 1).
Patients unable to adhere to this requirement were dropped from the study. The patients returned after 30 days
for their second clinical assessment and after 68 days for their final assessment.
Clinical assessment. Patients were assessed on basic measures during 3 visits (baseline, Day 30, and Day 68) to
the main clinic. One clinical investigator (MVN) interviewed and evaluated each patient by physical
examination. Observations for pain, stiffness, and discomfort were recorded. Patients were asked to lie supine
for assessment of knee range of motion, and while lying supine the patient was asked to extend both legs
straight. Patients were then asked to flex each knee as far as possible until discomfort. The angle was then
measured using a standard goniometer with the measurement rounded in 5° increments (e.g., 72° rounded to 70°
and 83.5° rounded to 85°).
Patients were then asked a series of questions. The same staff member met with the patient during each visit.
These questions were taken from the LAI, which has been used extensively in European OA studies since 1980.
Basically, the LAI includes 3 sections with a total of 10 questions and a total of 24 points (Appendix). The first
section addresses pain and discomfort (8 points), the second section addresses walking distance (8 points), and
the third section addresses physical function (8 points).
Nutritional intervention. Patients in the placebo group received capsules containing 500 mg of soy lecithin
(ADM Company, Decatur, IL, USA). The treatment group received capsules containing 350 mg CeladrinTM
(Imagenetix Inc., San Diego, CA, USA), 50 mg soy lecithin, and 75 mg of a standard fish oil blend containing a
total omega-3 concentration of 37%, with EPA 17.56% and DHA 12.63% (Arista Industries, Wilton, CT, USA).
CeladrinTM is a blend of olive oil (30%) and cetylated fatty acids (cetyl myristoleate, cetyl myristate, cetyl
palmitoleate, cetyl laurate, cetyl palmitate, cetyl oleate).
Statistical analysis. Demographic and knee flexion data were analyzed using ANOVA with repeated measures
(JMP, SAS Inc., Cary, NC, USA). The responses to the LAI questionnaire were analyzed using a one-way
analysis of variance assuming continuous data and an ordinal logistic regression, which estimates the
cumulative probability of being at or below each individual response level. All statistics were 2 tailed and
significance was set at p < 0.05.
RESULTS
The variety of medications taken during the trial was similar between groups (Table 1). The 2 groups were
similar on baseline measures of age, weight, height, and sex. History of OA was significantly different between
the 2 groups (p < 0.004) (Table 2). Two patients were dropped from the placebo group due to compliance
issues.
Table 1. Summary of patient medications during study period.

Medications CFA Group Placebo Group


 (n) (n)

Aspirin 6 5
Ibuprofen 8 8
Ketoprofen 6 7
Celecoxib 3 0
Nimesulfide 1 6
Diclofenac 3 4
None 6 1

Table 2. Patient demographics (data presented as mean ± standard deviation).

 CFA Group Placebo Group

 n = 33 n = 31

Age (yrs) 58.1 ± 6.3 55.5 ± 6.8


Weight (kg) 74.8 ± 9.0 78.0 ± 8.1
Height (cm) 163.3 ± 8.5 166.10 ± 8.4
M:F 22:11 17:14
Years of OA* 6.94 ± 1.89 5.54 ± 1.84

* Significant difference (p < 0.004).


Physical examination by the clinical investigator revealed minimal improvements in swelling over the course of
the study. Fifteen percent of the CFA group experienced reductions in swelling, compared to none of the
placebo group. In the CFA group 58% of patients experienced a reduction in pain compared to 32% of patients
given placebo. Neither group exhibited changes in morning stiffness.
There was a significant (p < 0.001) improvement in knee flexion (Figure 1) for the CFA group at Days 30 and
68, whereas knee extension remained unchanged for both groups. Power analysis from observed changes in
knee flexion revealed that a minimum of 12 patients per group would have detected a 3.7° difference between
groups with a power of 90% (α = 0.05, 2 tailed).
Figure 1. Knee range of motion in patients consuming cetylated fatty acid supplements for 68 days. Data represented
as mean ± SE. *Significant difference (p < 0.001) compared to placebo.

The LAI categorized both treatment groups as initially having extremely severe OA (LAI > 14). Table 3 shows
the average subject response to the LAI. When analyzed as continuous data, all 4 response categories declined
significantly (p < 0.001 versus baseline) for the CFA group by Day 68. This was not observed in the placebo
group. Moreover, treatment interaction was significant for the pain category (p < 0.049) but not for distance or
activity. The total category suggested an improvement in the CFA group compared to placebo (p < 0.055).
Power analysis of the observed data at Day 68 revealed a power of 61% (α = 0.05, 2 tailed). To achieve 90%
power from the observed data, 66 subjects per group would be required.
Table 3. Lequesne Algofunctional Index of knee OA. Each value, mean ± SE, is the average sum of the Lequesne
questions for all subjects in each group. The range of averages is in parentheses. The CFA group noted improvement
resulting in a lower total response compared to placebo.

  CFA Group   Placebo Group

 Baseline Day 30 Day 68 Baseline Day 30 Day 68

Total 15.6 ± 0.6 10.6 ± 0.7 10.2 ± 0.7* 15.8 ± 0.7 13.7 ± 1.07 13.7 ± 1.07
 (14.4-16.7) (9.0-12.0) (8.7-11.8) (14.3-17.3) (11.5-15.9) (11.5-16.0)
Pain 6.0 ± 0.1 4.0 ± 0.3 3.9 ± 0.3** 6.1 ± 0.2 5.1 ± 0.4 5.1 ± 0.4
 (6.0-6.4) (3.3-4.7) (3.2-4.6) (5.6-6.6) (4.2-6.0) (4.2-6.0)
Walking 4.7 ± 0.3 3.5 ± 0.3 3.4 ± 0.3 4.9 ± 0.3 4.6 ± 0.4 4.6 ± 0.4
 (4.1-5.4) (2.9-4.1) (2.7-4.0) (4.2-5.6) (3.8-5.4) (3.8-5.3)
Activity 4.6 ± 0.2 3.5 ± 0.3 3.1 ± 0.3 4.8 ± 0.2 4.2 ± 0.3 4.2 ± 0.3
 (4.1-5.1) (2.5-3.7) (2.5-3.7) (4.2-5.2) (3.6-4.8) (3.5-4.8)

* p < 0.055; ** p < 0.049 determined by one way analysis of variance with repeated measures.
The LAI was further analyzed for noncontinuous data using ordinal logistic regression. This technique allows
for the determination of probability estimates for the observed to predicted responses. The probability estimates
shown in Table 4 reflect the treatment interaction between groups at baseline and Day 68. All questions
achieved probability estimates less than 0.05 except when patients responded to the question regarding pain
after standing. These data show that, overall, the CFA group tended to produce a greater positive influence on
patient perception as noted by their individual responses to each question.
Table 4. Probability estimates for Lequesne Algofunctional Index.

Question* Variable Estimates** Standard Error Probability

Nocturnal 0.987 0.170 < 0.0001


Morning stiffness 0.181 0.160 < 0.0057
Pain after standing 0.591 0.338 > 0.08
While ambulating 0.410 0.148 < 0.0056
Getting up 0.486 0.173 < 0.005
Maximum distance 0.554 0.145 < 0.0001
Upstairs 0.340 0.194 < 0.0388
Downstairs 0.424 0.154 < 0.0057
Able to squat 0.381 0.153 < 0.0128
Walk uneven 0.819 0.204 < 0.0001

* See Appendix for complete Lequesne questions, ** In the ordinal model, data are fitted to the cumulative
response probabilities of the logistic distribution function of a linear model using maximum likelihood.
Likelihood ratios are provided for the whole model. The above probability estimates test for differences
between those subjects receiving CFA and those receiving placebo.
DISCUSSION
Diehl and May12 reported in 1994 that the cetylated fatty acid, cetyl myristoleic acid, afforded significant
protection against adjuvant induced arthritis in rats. Although many products containing cetyl myristoleic acid
are now available, research based evidence of their efficacy has been lacking. Our placebo controlled study
documents the clinical benefits of a cetylated monounsaturated fatty acid blend for the treatment of patients
with OA of the knee. The intervention used in this study consisted of cetylated monounsaturated fatty acids with
nominal amounts of fish oil and olive oil used for suspension. CFA treated patients exhibited improvements in
knee flexion and function as measured by the LAI.
Epidemiological surveys provided the initial data that highlighted the value of marine fish oils in treatment of
chronic diseases1-7. Considerable data show the benefits of fish oil for RA but little information exists about
treatment of OA. The rationale for fish oil supplementation is that these fatty acids alter the lipid content of
membrane phospholipids and reduce the production of the eicosanoids that mediate inflammation. Fish oils also
reduce cytokine synthesis and suppress cell activation7,24. It is generally recognized that a minimum of 3 g/day
of EPA and DHA is required to derive expected benefits25, although it has been suggested that levels as low as
2.25 g/day of EPA and DHA can manipulate neutrophil fatty acid composition26. Since our subjects received
only 0.45 g/day fish oil, the fish oil probably had a very minimal role in producing the benefits achieved by our
patients.
Monounsaturated fatty acids like olive oil have been shown to inhibit endothelial activation27,28 and to reduce
tissue responsiveness to cytokines29-31. In addition, cetylated myristoleic acid confers protection in adjuvant
induced arthritis12. While the mechanism of action for cetylated myristoleic acid is beyond the scope of this
discussion, a recent study using an extract from the native herb saw palmetto (Serenoa repens) was shown to
induce cell death in human prostate cells13. The main component of this extract appears to be myristoleic acid
and the authors speculated that this apoptosis may be due to de novo ceramide formation and/or 5-lipoxygenase
inhibition. It is this inhibition of 5-lipoxygenase that may explain in part the action of myristoleic acid and its
cetylated form in our study. The byproducts of 5-lipoxygenase are potent mediators of inflammation and
allergic reactions14,32. Indeed, it was suggested as early as 199514 that lipoxygenase byproducts may participate
in inflammatory processes leading to joint destruction in RA.
The salient feature of our study is that our patients achieved appreciable increases (+10.1°) in knee range of
motion that were above the detectable level determined via power analysis. The ability of individuals with knee
OA to ambulate is compromised compared to healthy individuals. Walker, et al33 reported that knee flexion in
patients with OA (98.6°) was reduced significantly compared to controls (137.5°) during all activities.
Comparable knee flexion data for monounsaturated fatty acids and marine fish oils do not exist. However, when
compared with traditional medications used for knee OA, the data presented here are equivalent. For example,
in an early study investigating the benefit of naproxen and diflunisal, it was shown that patients with OA
achieved significant improvement in knee flexion of 7.5° after 12 weeks34. Another trial investigated traditional
NSAID (e.g., etodolac and piroxicam) in degenerative knee joint disease. Improvements from 6.0° to 7.7° were
reported after 6 weeks of treatment35. A recent study evaluated aceclofenac and piroxicam in OA patients over a
2 month period36. These patients experienced knee flexion improvement of 12.4° and 8.1°, respectively. In
addition, these patients experienced a reduction in the LAI. Patients receiving aceclofenac experienced a
decrease of 4.6 points whereas patients receiving piroxicam experienced a decrease of 5.0 points. Herrmann, et
al37 reported that diclofenac and oxaceprol elicited decreases in the LAI after 21 days (-2.8 and -2.5,
respectively).
Patients using the CFA in our study noted a reduction (-5.0) in the overall LAI after 30 days, which remained
unchanged after 68 days (-5.4). Analyzed as continuous data, the overall treatment interaction tended to suggest
an improvement (p < 0.055) compared to the placebo group. However, ordinal logistic regression showed an
almost overwhelmingly positive response to LAI with CFA compared to placebo. It is worth noting that power
analysis proved conclusive for our knee flexion data but suggested that an increased group sample size would
have benefited the LAI data set.
The CFA provided relief even for those individuals also receiving traditional medications (Table 1). These
results are even more impressive considering a recently published 5 year study showed only a minimal
improvement in LAI (-0.53 points) in patients given intraarticular injections of a glycosaminoglycan peptide
complex compared to controls (-1.53 points)38.
OA is due to a combination of mechanical, biochemical, and genetic factors that contribute to the breakdown of
the articular cartilage39. Because NSAID including the new COX-2 inhibitors have potentially serious side
effects16-21, more patients are seeking nontraditional treatments. Results of many of these have not been
conclusive40, although more recent data have shown the beneficial use of glucosamine41. Our results suggest
that cetylated fatty acids are effective in improving the symptoms of OA and therefore should be considered as
a viable option for treatment of this condition.
In summary, the use of a cetylated fatty acid complex improved knee range of motion and function in patients
with OA of the knee of 5 to 6 years' duration. Further studies are warranted to determine whether these fatty
acids alter the 5-lipoxygenase enzyme through either substrate or inhibitory mechanisms and change subsequent
leukotriene production.
ACKNOWLEDGMENT
We wish to thank Jack Bookout, PhD, Daniel Gallaher, PhD, and Robert Zurier, MD, for their invaluable
insight during the preparation of this manuscript. We wish to thank Kristee Emens-Hesslink for her detailed
editorial assistance.
APPENDIX
Lequesne Algofunctional Index questions for knee OA. The subject is asked to respond on a 5 point Likert scale
(0, 0.5, 1, 1.5, and 2; 0 is without difficulty and 2 is with difficulty or discomfort).
Pain or discomfort
1. During nocturnal bedrest
None or insignificant
Only on movement or in certain positions
With no movement
2. Morning stiffness or regressive pain after rising
1 min or less
More than 1 but less than 15 min
15 min or more
3. After standing for 30 min
4. While ambulating
None
Only after ambulating some distance
Early after initial ambulation and increasingly with continued
ambulation
After initial ambulation, not increasingly
5. While getting up from sitting without help of arms
6. Maximum distance walked (may walk with pain)
Unlimited
More than 1 km, but limited
About 1 km (0.6 mi) in about 15 min
From 500 to 900 m in about 8 to 15 min
From 300 to 500 m
From 100 to 300 m
Less than 100 m
With one walking stick or crutch
With 2 walking sticks or crutches
Activities of daily living
7. Able to climb up a standard flight of stairs
8. Able to climb down a standard flight of stairs
9. Able to squat or bend on the knees
10. Able to walk on uneven ground
REFERENCES
1. Hornstra G. Dietary prevention of coronary heart disease. Effect of dietary fats on arterial thrombosis.
Postgrad Med J 1980;56:563-70.
2. Dyerburg J. Platelet vessel wall interaction: influence of diet. Philos Trans R Soc Lond B Biol Sci
1981;294:373-81.
3. Dyerburg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders.
Scand J Clin Lab Invest 1982;Suppl 161:7-13.
4. Horrobin DF. Low prevalences of coronary heart disease, psoriasis, asthma and rheumatoid arthritis in
Eskimos: are they caused by high dietary intake of eicosapentaenoic acid, a genetic variation of essential
fatty acid metabolism or a combination of both? Med Hypotheses 1987;22:421-8.
5. Calder PC. The effects of fatty acids on lymphocyte functions. Braz J Med Biol Res 1993;26:901-17.
6. Darlington LG, Stone TW. Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and
related disorders. Br J Nutr 2001;85:251-69.
7. Calder PC, Zurier RB. Polyunsaturated fatty acids and rheumatoid arthritis. Curr Opin Clin Nutr Metab
Care 2001;4:115-21.
8. Kremer JM, Bigauoette J, Michalek AV, et al. Effects of manipulation of dietary fatty acids on clinical
manifestations of rheumatoid arthritis. Lancet 1985;1:184-7.
9. Kremer JM, Jubiz W, Michalek A, et al. Fish-oil fatty acid supplementation in active rheumatoid
arthritis. A double-blinded, controlled, crossover study. Ann Intern Med 1987;106:497-503.
10. Stammers T, Sibbald B, Freeling P. Efficacy of cod liver oil as an adjunct to non-steroidal anti-
inflammatory drug treatment in the management of osteoarthritis in general practice. Ann Rheum Dis
1992;51:128-9.
11. Kremer JM. N-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71 Suppl:349S-
51S.
12. Diehl HW, May EL. Cetyl myristoleate isolated from swiss albino mice: an apparent protective agent
against adjuvant arthritis in rats. J Pharm Sci 1994;83:296-9.
13. Iguchi K, Okumura N, Usui S, Sajiki H, Hirota K, Kiran K. Myristoleic acid, a cytotoxic component in
the extract from serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells.
Prostate 2001;47:59-65.
14. Bonnet C, Bertin P, Cook-Moreau J, Chable-Rabinovitch H, Treves R, Rigaud M. Lipoxygenase
products and expression of 5-lipoxygenase and 5-lipoxygenase-activating protein in human cultured
synovial cells. Prostaglandins 1995;50:127-35.
15. Elders MJ. The increasing impact of arthritis on public health. J Rheumatol 2000;27 Suppl 60:6-8.
16. Rubin BR. Osteoarthritis. J Am Osteopath Assoc 2001;101 Suppl 4 Part 2:S2-5.
17. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J
Med 1984;310:563-72.
18. Sol AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer
disease. Ann Intern Med 1991;114:307-19.
19. Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of over-the-counter nonsteroidal anti-
inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med
1994;154:42-5.
20. Perneger TV, Wheiton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen,
aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994;331:1675-9.
21. Guthann S, Rodriguez G, Raiford D. Individual nonsteroidal anti-inflammatory drugs and other risk
factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997;8:18-24.
22. Lequesne MG. The algofunctional indices for hip and knee osteoarthritis. J Rheumatol 1997;24:779-81.
23. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis:
II. Osteoarthritis of the knee. Arthritis Rheum 1995;38:1541-6.
24. Whelan J. Antagonistic effects of dietary arachidonic acid and n-3 polyunsaturated fatty acids. J Nutr
1996;126:1086S-91S.
25. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71 Suppl 1:349S-
51S.
26. Healy DA, Wallace FA, Miles EA, Calder PC, Newsholm P. Effect of low-to-moderate amounts of
dietary fish oil on neutrophil lipid composition and function. Lipids 2000 35:763-8.
27. Mata P, Alonso R, Lopez-Farre A, et al. Effect of dietary fat saturation on LDL oxidation and monocyte
adhesion to human endothelial cells in vitro. Arterioscler Thromb Vasc Biol 1996;16:1347-55.
28. Perez-Jimenez F, Castro P, Lopez-Miranda J, et al. Circulating levels of endothelial function are
modulated by dietary monounsaturated fat. Atherosclerosis 1999;145:351-8.
29. Granato D, Blum S, Rossle C, Le Boucher J, Malnoe A, Dutot G. Effects of parenteral lipid emulsions
with different fatty acid composition on immune cell functions in vitro. J Parenter Enteral Nutr
2000;24:113-8.
30. Adam JM, Raju J, Khalil N, Bird RP. Evidence for the involvement of dietary lipids on the modulation
of transforming growth factor beta 1 in the platelets of male rats. Mol Cell Biochem 2000;211:145-52.
31. Patrick L, Uzick M. Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm:
HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of
the literature. Altern Med Rev 2001;6:248-71.
32. Steinhilber D. 5-Lipoxygenase: a target for anti-inflammatory drugs revisited. Curr Med Chem
1999;6:71-85.
33. Walker CR, Myles C, Nutton R, Rowe P. Movement of the knee in osteoarthritis. The use of
electrogoniometry to assess function. J Bone Joint Surg Br 2001;83:195-8.
34. Deal CL, Moskowitz RW. Efficacy of diflunisal versus naproxen in osteoarthritis of the knee: an open
study. Clin Ther 1986;9 Suppl C:1-14.
35. Dick WC, Bulstra S, Schardijn GH, Feenstra RM. Safety and efficacy of etodolac compared with
piroxicam in patients with degenerative joint disease of the knee. Clin Ther 1992;14:517-26.
36. Busquier MP, Calero E, Rodriguez M, et al. Comparison of aceclofenac with piroxicam in the treatment
of osteoarthritis. Clin Rheumatol 1997;16:154-9.
37. Herrmann G, Steeger D, Klasser M, et al. Oxaceprol is a well-tolerated therapy for osteoarthritis with
efficacy equivalent to diclofenac. Clin Rheumatol 2000;19:99-104.
38. Pavelka K, Gatterova J, Gollerova V, Urbanova Z, Sedlackova M, Altman RD. A 5-year randomized
controlled, double-blind study of glycosaminoglycan polysulphuric acid complex (Rumalon®) as a
structure modifying therapy in osteoarthritis of the hip and knee. Osteoarthritis Cartilage 2000;8:335-42.
39. Goldring MB. Osteoarthritis and cartilage: the role of cytokines. Curr Rheumatol Rep 2000:2:459-65.
40. Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydro-chloride in the treatment
of pain on osteoarthritis of the knee. J Rheumatol 1999;26:2423-30.
41. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis
progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251-6.

You might also like