THE EFFECT OF cis-9-CETYL MYRISTOLEATE (CMO) AND ADJUNCTIVE THERAPY ON THE COURSE OF ARTHRITIC EPISODES IN PATIENTS WITH VARIOUS AUTO-IMMUNE DISEASE CHARACTERIZED BY THE COMMON TERMINOLOGY, "ARTHRITIS" AND "PSORIASES"

A Randomized Clinical Trial

Dr. H. Siemandi, M.D., et al

Objective. Recent published reports offer anecdotal evidence that cis-9-cetyl myristoleate may provide significant amelioration of various arthritis conditions. We set out to perform controlled studies to determine if this material was efficacious, either in the short term, or in some measurable manner, over a much longer period.

Methods. A prospective, randomized study design was used to allocate patients to receive cis-9-cetyl myristoleate, cis-9-myristoleate plus gluscosamine hydrochloride (GH), sea cucumber (SC) and hydrolyzed cartilage (HC) and a placebo.

Results. At the start of this study, the duration, severity, and pattern of arthritic episodes were found to be similar in the 3 treatment groups. At the end of the study it was found that the number of episode-free time was significantly prolonged, in the two cis-9-cetyl myristoleate groups compared with the placebo group.

Conclusion. Cis-9-cetyl myristoleate treatment and cis-9-cetyl myristoleate plus GH, SC & HC were demonstrated to offer significant benefits over the placebo in the prevention of arthritic episodes. It was further determined that these results could not be obtained with other standard arthritic therapies based upon exhaustive reviews of patient records prior to opening of the study. Cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GH, SC, & HC treatment also seems to permit some relief to autoimmune inflammatory diseases which may prove to be long-term. This finding could provide additional evidence of the theory, reflected by the earlier anecdotal evidence as well as some animal studies, that cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GS, SC & HC may prove to be of major benefit in the future treatment of autoimmune diseases.

The terms arthritis and psoriasis have come to describe a series of conditions reflecting a wide range of symptoms, some permanent and some transient. Each condition, however, is typified by certain common elements such as some sort of inflammatory response with resulting pain, various forms of cellular degeneration and frequently, permanent loss of mobility and quality of life.

With the exception of osteoarthritis, most researchers are beginning to believe all arthritic conditions may have a common, albeit many-faceted, etiology-autoimmune dysfunction. Unfortunately the great number and complexity of immune system components and their diverse interplay has made this theory difficult to prove.

While it has not been proven, the original research done on sic-9-cetyl myristoleate at NIH indicates a direct connection between the observed effect of cis-9-cetyl myristoleate and some ability of cis-9-cetyl myristoleate to correct certain immune dysfunction, which may cause many arthritic conditions.

PATIENTS AND METHODS

Study design. The study was a 32 week (8 week cycle, 4 in hospital & 4 follow-up), multicentric, double-blind, randomized placebo-controlled parallel trial that compared the efficacy of cis-9-cetyl myristoleate alone, and cis-9-cetyl myristoleate plus GS, SC & HC, administered over a period of 30 days, with placebo, for the treatment of various forms of autoimmune diseases commonly characterized as arthritis and psoriasis. Out of a dose of 90 grams of total fatty acid esters, 18 grams constituted cis-9-cetyl myristoleate. Those study patients who received the support nutrients GS, SC & HC were given a total dosage of 18 grams each of these nutrients.

The study was conducted under the auspices of the Joint European Hospital Studies Program. This study was designed by a committee, which consisted of rheumatologists and biostatisticians experienced in the development and execution of clinical trials. Oversight of the study was accomplished by an executive committee, composed of the primary researcher and primary statistician, selected participating investigators, consultants; and an independent oversight committee consisting of two experienced federally controlled, state health department the rheumatologists and one state health department biostatisician.

Eligibility criteria. Patients were required to have inflammatory arthritis of at least one-year duration in at least one peripheral joint, excluding the shoulders and hips. Included in this parameter, affected joints must have had joint tenderness and joint tenderness and joint swelling of >2 on a four point scale and joint patient-physician overall assessment of involvement ranging from: none-mild-moderate-severe-very severe. The patients inducted into this trial for the purposes of psoriatic testing were chosen on generally the same criteria-involvement of epidermal involvement from: none-mild moderate-severe-very severe.

Criteria for exclusion included unwillingness to stop the use of tobacco and caffeinated beverages, at least for the duration of the trail. Tobacco caffeinated uses have been reported to greatly hamper the positive (if anecdotal) result of the use of cis-9-cetul myristoleate. It also should be noted here that the use of any other medication in al forms of arthritis as well as psoriasis were not excluded as it was determined this would limit participation. It was also demand advisable to approximate as much as possible, conditions that would be found in the average arthritic. One exception to this condition was the exclusion of patients showing sensitivity to salicylates or ibuprofen, which were used as excipients in the placebo. Potential participants with other severe chronic conditions were excluded. As it was the opinion of the primary investigator that this type of participant would limit the potential successful completion of the study period.

All patients had failed to respond to therapy with therapeutic dose of one of the NSAIDs. All patients who took NSAIDs during the trail were required to be on stable dosages for one month prior to entry and throughout the trail. No systemic or steroids were allowed.

Informed consent. The study protocol was reviewed and approved by the federally controlled state oversight committee. Prior to entry into this trial, each potential study participant was informed of the nature, duration, and purpose of the study to be administered, and all the potential benefits, inconveniences, and hazards that could reasonably be expected.

Study medication. Patients received either one-half liter of pleasantly flavored oral liquid containing 18grams of cics-9-ccetyl myristoleate or one-half litter of the same liquid sans cis-9-myristoleate. Both liquids were carefully compounded so as not to be able to be differentiated. Each patient was also given 180 capsules of the adjunctive medication containing a total each of 18 grams GL, SC and HC. Identical capsules containing the placebo compound were also distributed. The cis-9-cetyl myristoleate topical liquid was distributed as a 25% concentration in 60cccc. Lightly scented lotion and an identical placebo lotion sans cis-9-cetyl myristoleate.

The oral liquid was used with meals in one-teaspoon quantities, three times daily. Two capsules of GL, HC & SC were taken with each meal, three times daily. The topical lotion was used as needed and determined by each patient according to his or her own perceived requirement.

Clinical assessment. Outcome measures of disease activity and therapeutic efficacy were obtained at the time of screening (not more than four weeks before study entry), randomization at week zero, and thereafter at weeks; 1, 2, 3, and 4. Outcome measures included a variety of patient-reported, clinical, laboratory and radiographic assessments.

Patient self-assessment measures included morning stiffness, night pain, patient overall assessment and Mobility Functional Index as determined by this published procedure.

Clinician assessment measures included joint counts, dactylics, Enthesopathy Index. Spondylitis Auricular Index, chest expansion, modified Schober's test finger –to floor test and physician overall assessment as detailed elsewhere in this paper. Additionally, the presence of symptomatic keratoderma, phalangeal and digital deformation as measured from a normal range of vertical protrusion at rest were measured. These tests, singularly and collectively were then compiled into a patient-by-patient qualitative scale as; none = 0, mild =1, moderate=2, severe = 3 and very severe=4.

Laboratory assessment. Laboratory evaluation included a urinalysis and complete blood cell count, with leukocyte differential and reticulocyte count. Chemical surveys and a Westergren erythrocyte sedimentation rate (ESR) determination were done at every visit by secondary researchers daily in the two hospital settings. The C-reactive protein (CRP) level was evaluated at the first and last day of the hospital stay. At the screening times, blood was drawn for HLA-B27 typing and RF and ANA determinations.

Radiology assessment. At the screening visit, all patients had the following radiographs performed: anteroposterior views of the pelvises and oblique views of the sacroiliac joints.

Adverse drug reactions (ADR's). Patients were screened for ADR's at every secondary researcher’s visit. Patients were withdrawn from the study medication if any of the following were found; WBC less than 3000/mm, absolute polymorphonuclear count less than 100000/mm, acute or progressive decrease in hemoglobin or hematocrit, proteinuria less than 500 mg. For 24 hours, drug fever or significant rash.

Compliance. The patients were queried at each secondary researcher's visit regarding the dietary supplement or topical lotion they had used. A capsule count for the trial medication was done at each consultation to monitor compliance.

Biostatistical considerations. Each patient was classified as a treatment responder or nonresponder based on the following definition. Assessment measures were selected a priori, and criteria for clinical (improvement and worsening = increase by 1 category); joint pain/tenderness score and joint swelling score (improvement = decrease by 30%; worsening = increase by 30%). Treatment response was then defined as improvement in at least 2 of these 4 measures, one of which must be joint pain/tenderness or swelling, and ITO worsening in any of the 4 measures. The study was designated with a 90% power for detecting a placebo response rate of 30% compared with a cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GS, SC & HC response rate of 50%, assuming a 10% withdrawal rate. This resulted in a target sample size of 431 patients with an actual sample size of 382.

In short, the analytical method was the change in primary and secondary outcome measures form baselines to the last available follow-ups analyzed using t-tests for continuous data and chi-square tests for ordinal and categorical data. Mixed-model analyses were done to for continuous data and a program named MIXOR for categorical and ordinal data. All other analyses were conducted using SAS version 6.08. All statistic tests were two-sided and P < 0.05 was the criterion for statistical significance.

Patient population. Four hundred thirty-one patients entered the study. Of these, 106 were randomized to receive cis-9-myristoleate plus GS, SC & HC; 226 received a placebo. Fifteen psoriatics received cis-9-cetyl myristoleate plus GS, SC & HC, plus CM 25% concentration topical at a 3X-quantity ratio. Even though the study was sponsored by the owners of the respective private hospitals, recruitment was not limited to the typical fee-paying patients. Approximately 27% of the patients were actively recruited in the respective local area. Despite a prolonged accrual period and careful screening, the loss of approximately 11% of the starting participants occurred largely because of the inability to stop the use of tobacco and/or caffeinated beverages. Fulfillment of the final parameter of study size was accomplished by the substantial excess of volunteers wanting to enter the study this couple with the relatively short testing period required to validate the effects of cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GS, SC & HC.

Statistical Chart I outlines the baseline demographic, clinical, and laboratory variables. The duration of disease was 12 years. The Westergren ESR and CPR levels were mildly elevated. There were no statically significant difference in any of these baseline parameters between the patients taking cis-9-cetyl myristoleate and cis-9-myristoleate plus GS, SC & HC and those taking placebo.

Compliance. Compliance for both the cis-9-myristoleate and cis-9-myristoleate plus GS, SC & HC and placebo groups was quite high. There was a statistical trend toward those in the cis-9-cetul myristoleate plus GS, SC & HC and those taking more tablets per day (96 % compliance) than those in the placebo group (86 % compliance) (P=0.08). The probability of this observation was due to the rapid response of pain relief in the cetyl myristoleate groups.

Primary outcome measures. The Oversight Committee defined response based on a decision rule as outlined in Patients and Methods. Statistical Chart 1 shows that based on that definition of treatment response, using the last-visit analysis, response rates were 63.3% in the cis-9-myristoleate group and 87.3% in the cis-9-myristoleate plus GS, SC & HC group and 14.5% in the placebo group. Trends favoring cis-9-myristoleate and cis-9-cetyl myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 13.9% in placebo group. Patient overall assessment demonstrated 59.2% improvement in the cis-9-cetyl myristoleate alone group and 88.2% in the cis-9-cetyl myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with 16.1% in placebo group. Joint swelling scores improved in 47.2% in patients using cis-9-cetyl myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 21.1% in placebo group.

Secondary and laboratory outcome measures. Analysis of secondary outcome results (Statistical Chart 2) demonstrated a significant reduction in the Spondylitis Articular Index in the cis-9-cetyl myristoleate group and in the cis-9-cetyl myristoleate plus GS, SC, & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 16.1% in placebo group. Joint swelling scores improved in 47.2% in patients using cis-9-cetyl myristoleate alone and 77.2% in patients using cis-9-cetyl myristoleate plus GS, SC, & HC group were also see in a reduced duration of early stiffness and in an improvement in the fingers-to-floor result.

Laboratory outcome measures showed some statistically significant changes. Total neurophils decreased in the cis-9-cetyl myristoleate group in the cis-9-cetyl myristoleate plus GS, SC & HC group compared with the placebo group. The CRP values were not significantly different from the nonresponders.

Withdrawals and adverse drug reactions. Statistical Chart 3 summarizes the data of patient exits from the study. Forty-nine patients withdrew form the study before completing the study, 16 from the cis-9-cetyl myristoleate and 10 from cis-9cetyl myristoleate plus GS, SC & HC groups, 2 from the psoriatic group, and 21 from the placebo group. Follow-ups in all groups averaged approximately the same and these measurements were combined, combined average- (mean + SD 6.97 + 2.64 months) (P=.06). Withdrawal of consent was the most common reason for discontinuing the study. Seven patients withdrew because of no improvement or worsening disease. Two patients had to be withdrawn from the study because of concurrent illnesses requiring conflicting medication. The majority of withdrawals, however, were the result of patient addictions to nicotine, caffeine and alcohol and the patient inability to cease these activities during the study period.

Statistical chart 2 displays the percentages of study patients showing improvement in the primary outcome variables (columns 1-3). The numbers to the right display the significance levels of the significant levels for the differences between treatment groups (columns 4-6). All of the significant levels are much less than 0.05, which means the differences between groups are considered statistically valid. For all four primary outcome variables (treatment response, physician assessment, patient assessment and joint swelling score). cis better than placebo are much less than the cis-9-cetyl myristoleate group, and the cis-9-cetyl myristoleate group did significantly better than placebo.

The chart also displays the result for the secondary outcome variables. The averages (mean average as opposed to median or mode) are presented in columns 1-3 along with their standard deviations (statistical measurement of data variations). Again, the numbers to the right display the significance levels for the differences between treatment groups (columns 4-6). "NS" means that there was no significant difference any measured groups labeled as such. When the groups are significantly different from each other the significance is displayed. None of the secondary outcome variables were significantly better than placebo for duration of starting involvement, joint pain/tenderness score, joint swelling score, Enthesopathy index, spondylitis articular index and the modified Schober's test. The cis-9-cetyl myristoleate & GS, SC HC, group did better than cis-9-cetyl myristoleate alone for the joint pain/tenderness score and the modified Schober's test.

DISCUSSION

The results of this trial suggest that cetyl myristoleate and cetyl myristoleate supporting formulas may be beneficial in the treatment of many forms of arthritic based diseases, including psoriatic arthritis. The definition of response was determined a priori and included assessment of joint pain/tenderness and swelling as well as patient and physician overall assessments. Cetyl myristoleate & supporting formulas produced the best treatment response by a factor of 72.8% more patients than did placebo. Considering the components of response individually, cetyl myristoleate & supporting formulas resulted in 70.3% more patients having improved as assessed by physician, and 56.1% more having improved joint swelling. Therefore, while the amount of treatment response using cetyl myristoleate and cetyl myristoleate & supporting formulas seems to be consistent with the treatment affects on joint counts, it is obvious that there is a statistically significant improvement in the use of the CMO with supporting formulas.

The time-line based response rate of cetyl myristoleate and cetyl myristoleate supporting formulas, not adequately reflected in data, by patient, shoed the majority of patients responding to cetyl myristoleate and cetyl myristoleate supporting formulas beyond the study time limits and dispensed on request to 21 patients. These 21 patients were determined to have received only marginal benefits from cetyl myristoleate and cetyl myristoleate supporting formulas but one more course of treatment showed response approximately equal to the first patient response results.

Cetyl myristoleate and cetyl myristoleate supporting formulas were well tolerated in this trial. This finding was not unexpected as cetyl myristoleate and the cetyl myristoleate supporting formula components are naturally occurring and having been used as diet supplementation for many years and are widely available singularly and in various combinations.

In summary, cetyl myristoleate and cetyl myristoleate supporting formulas appear to be beneficial in the treatment of a wide Rengo of arthritic conditions including long standing and refractive cases.

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