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EFFECTS OF ONCE-DAILY VERSUS TWICE DAILY DOSING OF CALCIUM FRUCTOBORATE ON KNEE DISCOMFORT. A 90 DAY, DOUBLE-BLIND, PLACEBO CONTROLLED RANDOMIZED CLINICAL STUDY

 

Z. Pietrzkowski1, A. Roldán Mercado-Sesma3, R. Argumedo1, M. Cervantes1, B. Nemzer2, T. Reyes-Izquierdo1

 

1. Bioresearch Lab, VDF Futureceuticals Inc.; 23 Peters Canyon Rd, Irvine, CA USA 92606; 2. VDF Futureceuticals Inc.; 2692 N. State Rt. 1-17., Momence, IL, USA 60954; 3. Departamento de Salud-Enfermedad, Centro Universitario de Tonalá, Universidad de Guadalajara. Av. Nuevo Periférico No. 555 Ejido San José Tatepozco, C.P. 45425, Tonalá Jalisco, México.

Corresponding Author: Tania Reyes-Izquierdo, 23 Peters Canyon Rd, Irvine, CA, 92606 USA, Phone +1 949 502 4496, Fax +1 949 502 4987, Email: treyes@futureceuticals.com

J Aging Res Clin Practice 2018;7:31-36
Published online February 22, 2018, http://dx.doi.org/10.14283/jarcp.2018.7

 


Abstract

Importance: Previous research showed that a twice-daily 108 mg dose of calcium fructoborate (CFB) improved knee discomfort during a 2-week supplementation period. This current double-blind, placebo-controlled randomized study investigates the effects of CFB supplementation on knee discomfort during 90 days of supplementation. Purpose: To evaluate the comparative effects of once-daily and twice-daily dosing of calcium fructoborate on knee joint discomfort for ninety days. Design: 120 participants with self-reported knee discomfort were recruited and randomized into three groups (each N=40). Participants received: 108 mg CFB twice per day (CFB-G1); or, 216 mg CFB in a single dose (CFB-G2); or, placebo. Setting: Subjects were recruited through advertisement in local papers. The researchers assessed intake and within-study levels of knee discomfort by using the McGill Pain Questionnaire (MPQ) and the Western Ontario and McMaster University Arthritis Index (WOMAC). Results: 62 female and 59 male subjects completed the study. Subjects’ average age was (52.84 ± 8.19 years) and average BMI was (26.76 ± 2.50 kg/m2). Statistical differences between groups were calculated using a two-sided, two-sample t-test. Analysis of variance (ANOVA) was used to estimate within-group changes in mean WOMAC and MPQ scores as well as against the control group. When compared to placebo, CFB-G1 showed a significant decrease in reported discomfort on day 14 (P=0.02,) day 30 (P=0.003), day 60 (P<0.0001) and day 90 (P<0.0001) according to WOMAC Scores. A similar decrease was observed for CFB-G2 WOMAC Scores on day 14 (P=0.02), day 30 (P=0.0003), day 60 (P<0.0001) and day 90 (P<0.0001). When compared to placebo, the MPQ score for CFB-G1 group decreased on day 7 (P=0.002), day 14 (P=0.001), day 30 (P<0.0001), day 60 (P<0.0001) and day 90 (P<0.0001). MPQ score decreases were also observed for CFB-G2 group on day 7 (P=0.02), day 14 (P=0.01), day 30 (P<0.0001), day 60 (P<0.0001) and day 90 (P<0.0001). When comparing CFB-G1 and CFB-G2, no significant differences were observed. Importantly, no changes were observed in the WOMAC and MPQ scores within the placebo group. Conclusion: Both CFB groups showed early and significantly improved levels of knee comfort. Knee comfort continued to significantly improve throughout the duration of this 90-day study. No significant differences were observed between the once-daily and the twice–daily doses of CFB.

Key words: Calcium fructoborate, knee discomfort, WOMAC, McGill.


 

Introduction

Frequent knee pain is a common condition that affects 25 percent of adults. The leading cause of knee pain is a degenerative joint disease, known as degenerative arthritis or osteoarthritis(OA); which is the most prevalent joint disorder in the United States (1). Symptomatic osteoarthritis of the knee affects approximately 10 percent of men and 13 percent of women aged 60 and older (2). The prevalence of osteoarthritis of the knee and other sources of knee pain is increasing (1, 3). Although OA occurs in people of all ages, it is most commonly found in older people. Common risk factors include increasing age, obesity, previous joint injury, overuse of the joint, weak thigh muscles, and genetics.
According to the Arthritis Foundation, rheumatoid arthritis, gout, psoriatic arthritis, lupus, and fibromyalgia, can also cause knee pain (4). Knee pain not only interferes with an individual’s ability to engage in physical exercise, but can also interfere with other basic daily activities. Typically, individuals experiencing knee discomfort have resorted to use of analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for the relief of symptoms. Unfortunately, NSAIDS have been associated with undesirable side-effects and have been reported to be potentially dangerous for some individuals. Consequently, many active adults prefer a more natural solution for their joint discomfort. Therefore, longer-term use of an effective, natural and safe dietary supplement may be a healthier alternative. Previous research suggests that some nutritional supplements such as vitamins (vitamin C and E, D and B), glucosamine, chondroitin sulfates, trace elements (boron, selenium, zinc and copper) and fish oil can improve symptoms of knee discomfort (5-7). More recently, nutraceuticals have been considered as an alternative to stimulate production of needed components of articular cartilage or by slowing down cartilage damage in people with OA (8).
Calcium fructoborate (CFB) is a nature-identical plant mineral complex (a “borocarbohydrate”) originally found in certain fruits, vegetables, nuts and legumes, and currently produced by a previously described patented process (9). CFB is a non-animal, generally recognized as safe (GRAS), non-genetically modified organism (GMO), water-soluble material that has been reported to be fast-acting and effective at low doses for relief of joint discomfort (10-14). Our previous research showed that calcium fructoborate significantly improved knee comfort 9, 14, 15) and flexibility through a self-reported Western Ontario and McMaster Universities Index (WOMAC) score (16, 17) and McGill Pain Questionnaire (MPQ) index (18-21) during a 2-week supplementation11. This research supported that CFB may provide “fast-acting” relief for joint discomfort if used twice daily at a 108mg dose (11). However, because discomfort associated with many knee problems generally persists longer than the previously-studied two-week time-frame, (e.g., in progressive conditions related to osteoarthritis), further investigation was required to measure the longer-term (sub-chronic) effects of CFB on subjects with knee discomfort. In the present study, we examined the effects of once per day (QD) CFB at 216 mg/dose versus twice per day (BID) CFB at 108 mg/dose versus a placebo during ninety days of supplementation. This paper reveals the results of our investigation.

 

Materials and Methods

Consent

This study was conducted according to the Declaration of Helsinki guidelines. All procedures involving human subjects were approved by the Institutional Review Board (Comité de Ética en Investigación Biomédica para el Desarrollo de Fármacos, S.A. de C.V., Av. Sebastian Bach No. 5257, Col. La Estancia, C.P. 45030, Zapopan, JAL, Mexico) (IRB: FCE-NCI-16-06-KNN).
After Institutional Review Board protocol approval, subjects were recruited through advertisement in local papers. Three hundred and sixty male and female subjects were prescreened, according to the inclusion and exclusion criteria. All applicants signed an informed consent form. NutraClinical Inc. (San Diego, CA, USA) performed supplement distribution, sample and data collection according to a protocol designed by BioResearch Lab, VDF FutureCeuticals, Inc. (Irvine, CA, USA).

Materials

CFB was provided and standardized by VDF FutureCeuticals, Inc., Momence, IL, USA. Silica oxide and fructose were from (Sigma Chem. Co. St. Louis, MO, USA). Capsules were from Capsuline (Pompano Beach, FL, USA), Nalgene® amber bottles were from Thermo-Fisher Scientific (Waltham, MA, USA).

Inclusion and Exclusion Criteria

Inclusion criteria

Subjects who reported knee discomfort for more than 4 weeks prior to enrollment in the study, and who had an initial McGill Score: >50 – <65 (Average 55.4, SD± 4.05, P=0.64) were included in the study.
Age range: >35 – <65 years; the average age for the subjects included in the study was 52.8 years of age (SD ± 8.19).
Other than reported knee discomfort, subjects were generally healthy with no visible evidence of having respiratory or other infections. Subjects were non-diabetic and free of known allergies to dietary products.
No supplements of any kind were permitted within two weeks prior to and during the study period. Participants were advised to abstain from taking vitamin D, testosterone supplements, and steroid-containing prescription or non-prescription medications for 30 days prior to the study period.
Subjects were not included based on the following criteria: Age: <30 or >65 years, BMI: <21 or >30; pregnant, nursing, or planning to get pregnant; currently enrolled in another study; subjects with cardiovascular diseases; any knee injury, taking medications for pain or non-steroidal anti-inflammatory drugs (NSAIDs), dietary or nutritional supplements, or vitamin D two weeks prior to the start of this trial.

Study description

One hundred and fifty-six subjects who satisfied the inclusion criteria were included in the study, with twelve (12) subjects accounted for each group to replace dropouts in order to complete 120 subjects. Subjects were divided into two groups (78 females and 78 males) and by using simple randomization consisting of 78 tokens containing either a number “1”, “2” or “3”. The researchers matched the tokens to a list containing all the participant names and recorded the codes assigned for every supplementation. In order to maintain a double-blind status, neither the researchers nor the subjects were aware of the contents of the capsules. After the study was completed, all the bottles were collected from the subjects (for compliance) and the data was analyzed.
Baseline assessment on Day 1 included a medical history and physical examination for all subjects. Participants underwent blood collections at baseline and on days 7, 14, 30, 60 and 90. Subjects fasted for at least 12 hours prior to blood collection.
Each participant received two bottles containing white capsules and blue/white capsules along with instructions to take the white capsules in the morning and the blue/white capsules in the afternoon, thirty minutes before meals (breakfast or lunch) and preferably with water. Following a “2-capsule per day” dosage for all groups ensured a comparable perception of all participants being supplemented. Placebo capsules contained 50 mg of silica/80mg fructose for both, white and blue/white capsules. CFB-G1 capsules contained 108mg/capsule of CFB for both white and blue/white capsules. CFB-G2 capsules contained 216mg of CFB in the white capsules and 50mg silica/80mg fructose in the blue/white capsules. On day 1, all subjects received their test products and were instructed to take first white capsule dose immediately after blood collection. McGill and WOMAC Questionnaires were administered at baseline and at 7, 14, 30, 60 and 90 days.

Follow up visits

Each subject received the full number of capsules required for the duration of the study. Subjects received daily telephone calls to assure compliance. As instructed, subjects brought their test bottles to each follow-up visit. During each visit, researchers counted and recorded the remaining number of capsules in the test bottles to ensure compliance.

Rescue medication and concomitant medication

Subjects were allowed to take acetaminophen only in cases where pain exceeded a value of 6 out of 10 on a provided hospital-type pain scale (simple circle drawings of faces depicting increasing levels of pain). Subjects were provided with Acetaminophen 500mg/tablet and asked to take a maximum of 1000mg per day in cases where the pain exceeds tolerability. Participants were instructed to not take this medication within 48 hours of a visit. All the events were recorded in the Rescue Medication Form for every day of the treatment. Subjects were asked to record every Rescue Medication event in the subject’s diary. Subjects were asked to take their diaries to each study visit. A summary on subjects taking the Rescue Medication was generated and included in the final study report. Other concomitant medications were recorded in the Concomitant Medication Log Sheet for every day of the treatment.

Blood Collection

Blood was collected at baseline prior to supplementation and again at days 7, 14, 30, 60 and 90. Samples were always collected under fasting conditions. Two 9 mL blood samples were drawn from an antecubital vein in anticoagulant-free (dry tubes) (BD Vacutainer Franklin Lakes, NJ, USA) in each participant. Immediately after collection, blood samples were allowed to clot. Serum samples were collected upon clot formation after centrifugation. Serum was aliquoted, snap frozen and kept at -70°C until use.

Blood chemistry

Blood chemistry was performed on blood samples after every visit. Serum samples collected from each subject at Day 1, Day 60 and Day 90 underwent analysis to monitor any changes during the trial. Analyses included serum glucose, blood urea, nitrogen, creatine, total bilirubin, alkaline phosphatase, total proteins, albumin, globulin, uric acid, calcium, phosphorus, iron, sodium, potassium, chlorine, CO2, triglyceride, total cholesterol, HDL and LDL. The assays for asparate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and gamma-glutamyl transpeptidase (GGTP) were also performed.

McGill Pain Questionnaire

The McGill Pain Questionnaire (MPQ) is a multidimensional pain questionnaire used to quantify the quality and intensity of pain. This scale contains four subscales consisting of 78 words that participants use to indicate feelings of pain. Participants choose seven words from categories of pain description, pain components, evaluation of pain, and a miscellaneous descriptor category. Each chosen word has an associated numerical value, and total scores range from 0 (no pain) to 78 (severe pain). The McGill Pain Questionnaire was administered at baseline, (and used as part of the inclusion/exclusion criteria), and at 7, 14, 30, 60 and 90 days post-supplementation.

Western Ontario and McMaster Universities Arthritis Index

The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a questionnaire used to assess the physical function of joints. WOMAC consists of 24 items divided into 3 subscales, including pain (5 items; scores range from 0 to 20), stiffness (2 items; scores range from 0 to 8), and functional limitations (17 items; scores range from 0 to 68). Total scores range from 0 (best) to 96 (worst). The WOMAC index was administered at baseline for all subjects included in the study, and again at 7, 14, 30, 60 and 90 days post-supplementation.

Data analysis

Statistical Methods

All statistical analyses were performed using Graphpad Prism version 6.0. A value < 0.05 was taken to indicate statistical significance. Statistical differences in the tested groups were calculated by One-Way ANOVA or using a two-sided, two-sample t-test. To address the a priori hypothesis that the supplements would improve mean described discomfort in study subjects with self-reported knee joint pain (and as further confirmed by the intake criteria), the primary analysis tested the effect of treatment on the mean 7-day and 14-day changes from baseline in WOMAC score and McGill score. Subsequent data analysis was also performed for days 30, 60 and 90. A repeated measures analysis of variance (ANOVA) was used to estimate within-group changes in mean WOMAC and MPQ scores over the duration of the study.

 

Results

Demographic characteristics of the study population are presented in Table 1. Baseline MPQ values were 55.39 (SD ± 4.05) and WOMAC average values were 46.19 (SD ± 19.2). After randomization, One-way analysis of variance (ANOVA) was performed. The age difference between all three groups was not significant (P=0.47). Since the CFB-G2 group failed the normality test for BMI (P=0.03). Kolmogolov-Smirnoff normality test was performed for both parameters; age and BMI. There were no significant differences at baseline between groups in either MPQ (P=0.64) or WOMAC (P=0.21).
As previously stated, supplements of any kind were not permitted within two weeks prior to and during the study period. Participants were advised to abstain from taking vitamin D, testosterone supplements, and prescription or over-the-counter drugs containing steroids for 30 days prior to the study period. In the placebo group, twenty female and twenty male subjects finished the study, as well as in CF-G1. In CF-G2; twenty-one females and twenty males completed the study.

 

WOMAC scores are presented in figure 1. When compared to placebo, CFB-G1 showed a significant decrease on day 14 score (95% CI -0.06674 to 17.42) (P=0.02), day 30 (95% CI 3.630-20.77) (P=0.003), day 60 (95% CI 7.254 to 22.85) (P<0.0001) and day 90 (95% CI 17.62 to 32.13) (P<0.0001). This decrease was also observed for CFB-G2 on day 14 (95% CI -0.2749 to 17.10) (P=0.02), day 30 (95% CI 5.654 to 22.69) (P=0.0003), day 60 (95% CI 8.31 to 23.87) (P<0.0001) and day 90 (95% CI 22.03 to 36.45) (P<0.0001). A similar pattern was also observed for MPQ scores. When compared to placebo, the average MPQ score decreased on the CFB-G1 group on day 7 (95% CI 1.516 to 8.334) (P=0.002), day 14 (95% CI 2.936 to 11.86) (P=0.001), day 30 (95% CI 7.341 to 16.31) (P<0.0001), day 60 (95% CI 10.32 to 19.88) (P<0.0001) and day 90 (95% CI 13.39 to 22.46) (P<0.0001). This was also observed for the CFB-G2 group on day 7 (95% CI 0.004905 to 6.780) (P=0.02), day 14 (95% CI 0.5187 to 9.392) (P=0.01), day 30 (95% CI 6.746 to 15.66) (P<0.0001), day 60 (95% CI 9.624 to 19.13) (P<0.0001) and day 90 (95% CI 10.94 to 19.95) (P<0.0001) (Figure 2). When compared to each other, no significant differences were detected between groups CFB-G1 and CFB-G2.

Figure 1
WOMAC Scores by groups from day 0 [D0] to day 90 [D90]. WOMAC scores were significantly reduced after day 14 and continued to be reduced until D90. No significant differences were observed between CFB-G1 and CFB-G2. Data are presented as score values (mean ± SEM). [*] symbol represents statistical significance between Placebo and CFB-G1 and CFB-G2, p<0.05

Abbreviations: CFB, calcium fructoborate; WOMAC, Western Ontario and McMAster Universities Arthritis Index; SEM, standard error of the mean.

Figure 2
MPQ Scores by groups from day 0 [D0] to day 90 [D90]. MPQ scores were significantly reduced at day 7 and continued to be reduced until D90. No significant differences were observed between CFB-G1 and CFB-G2. Data are presented as score values (mean ± SEM). [*] symbol represents statistical significance between Placebo and CFB-G1 and CFB-G2, p<0.05

Abbreviations: CFB, calcium fructoborate; MPQ, McGill Pain Questionnsire; SEM, standard error of the mean.

 

Blood chemistry analysis at day 0, day 60 and day 90 did not indicate any statistically significant changes of key electrolytes, enzymes, lipids and glucose blood levels. All subjects completed this trial without any indications of unusual side effects.

 

Discussion

Chronic knee discomfort is a condition that affects the quality of life and impacts mobility. To overcome knee pain, some patients resort to prescription and over-the-counter medications, including opioids or other analgesics to mask pain or steroids to reduce inflammation associated with arthritis (22-24). However, since long-term use of prescription and non-prescription drugs can cause serious side effects (25, 26), the use of dietary supplements has been considered as an alternative in the improvement of knee discomfort while reducing the need for NSAIDs.
Previous research supports the use of supplements containing calcium fructoborate (CFB) for fast-acting joint support (10-12). CFB provides knee discomfort relief in as little as 7 days 11 as measured by WOMAC score and McGill index. This study demonstrates the efficacy of CFB for continuous and increasing relief of knee discomfort over a 90-day period. Data herein is in agreement with and extends the results from our previous research on this supplement (10-12). During our previous research, a twice per day CFB dose was provided at 110mg. In this study, we compared the efficacy of a twice-daily (BID) 108mg dose versus a once-daily (QD) 216mg CFB dose. Our results indicated that both supplementations effectively reduced knee discomfort to a similar extent in WOMAC and McGill scores as compared to placebo. Moreover, no significant differences were observed between both supplemented groups (QD and BID). These results suggest that once-daily dosing may be just as effective as BID and may assure high likelihood of subject compliance. In previous research, calcium fructoborate has not only shown short- and long-term effects on reducing knee discomfort, but also seems to reduce pro-inflammatory and pro-atherogenic markers (27). The effects of CFB on circulating miRNA and on serum biomarkers of inflammation, cartilage and synovium activity are yet to be studied. A future study would help clarify such effects and may help to identify potential mechanisms of action (MOA).

 

Acknowledgements: We express our gratitude to John Hunter (FutureCeuticals Inc.) for his comments and suggestions in the preparation of this article. We would like to thank Lynn H. for her help in editing the manuscript.

Disclosure Statement: The present study was funded by Futureceuticals, Inc. (Momence IL, USA). All authors declare that they have no conflicts of interest. No competing financial interests exist.

Ethical standards: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

 

References

1. Nguyen U-SDT, Zhang Y, Zhu Y, et al. Increasing Prevalence of Knee Pain and Symptomatic Knee Osteoarthritis. Annals of internal medicine. 2011; 155: 725-732.
2. Jinks C, Jordan K, Croft P. Measuring the population impact of knee pain and disability with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain. 2002; 100: 55-64.
3. Neugebauer V, Han J, Adwanikar H, Fu Y, Ji G. Techniques for assessing knee joint pain in arthritis. Molecular Pain. 2007; 3: 8.
4. Marks R. Obesity profiles with knee osteoarthritis: correlation with pain, disability, disease progression. Obesity (Silver Spring). 2007; 15: 1867-1874.
5. Wang Y, Prentice LF, Vitetta L, Wluka AE, Cicuttini FM. The effect of nutritional supplements on osteoarthritis. Alternative medicine review. 2004; 9: 275-296.
6. Gregory PJ, Sperry M, Wilson AF. Dietary supplements for osteoarthritis. Am Fam Physician. 2008; 77.
7. Grover AK, Samson SE. Benefits of antioxidant supplements for knee osteoarthritis: rationale and reality. Nutr J. 2016; 15: 1.
8. French TMC, Daniel O. The utility of neutraceuticals in the treatment of osteoarthritis. Current Rheumatology Reports. 2007; 9: 25-30.
9. Miljkovic D, Scorei RI, Cimpoiasu VM, Scorei ID. Calcium fructoborate: plant-based dietary boron for human nutrition. J Diet Suppl. 2009; 6: 211-226.
10. Reyes-Izquierdo T, Phelan, M.J., Keller, R., Shu, C., Argumedo, R., Pietrzkowski, Z. . Short-term efficacy of a combination of glucosamine and chondroitin sulfate compared toa combination of glucosamine, chondroitin sulfate and calcium fructoborate (CFB) on improvement of knee discomfort conditions in healthy subjects. A comparative, double-blind, placebo controlled acute clinical study. J Aging Res Clin Practice. 2014; 3: 223-228.
11. Pietrzkowski Z, Phelan MJ, Keller R, Shu C, Argumedo R, Reyes-Izquierdo T. Short-term efficacy of calcium fructoborate on subjects with knee discomfort: a comparative, double-blind, placebo-controlled clinical study. Clin Interv Aging. 2014; 9: 895.
12. Reyes-Izquierdo T, Nemzer B, Gonzalez AE, et al. Short-term intake of calcium fructoborate improves WOMAC and McGill scores and beneficially modulates biomarkers associated with knee osteoarthritis: a pilot clinical double-blinded placebo-controlled study. Am J Biomed Sci. 2012; 4: 111-122.
13. Scorei ID, Scorei RI. Calcium fructoborate helps control inflammation associated with diminished bone health. Biol Trace Elem Res. 2013; 155: 315-321.
14. Scorei R, Mitrut P, Petrisor I, Scorei I. A double-blind, placebo-controlled pilot study to evaluate the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers for middle-aged people with primary osteoarthritis. Biol Trace Elem Res. 2011; 144: 253-263.
15. Scorei RIR, P. Calcium fructoborate–potential anti-inflammatory agent. Biol Trace Elem Res. 2011; 143: 1223-1238.
16. Bellamy N. Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis index. Semin Arthritis Rheum. 1989; 18: 14-17.
17. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988; 15: 1833-1840.
18. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975; 1: 277-299.
19. Melzack R. Re: Discriminative capacity of the McGill Pain Questionnaire. Pain. 1985; 23: 201-203.
20. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987; 30: 191-197.
21. Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005; 103: 199-202.
22. James Williams H, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis & Rheumatology. 1993; 36: 1196-1206.
23. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis?: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004; 63: 901-907.
24. Towheed T, Maxwell L, Judd M, Catton M, Hochberg MC, Wells GA. Acetaminophen for osteoarthritis. The Cochrane Library. 2006.
25. Chen Y, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. 2008.
26. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA. 1999; 282: 1929-1933.
27. Rogoveanu OC, Mogosanu GD, Bejenaru C, et al. Effects of Calcium Fructoborate on Levels of C-Reactive Protein, Total Cholesterol, Low-Density Lipoprotein, Triglycerides, IL-1beta, IL-6, and MCP-1: a Double-blind, Placebo-controlled Clinical Study. Biol Trace Elem Res. 2015; 163: 124-131.

SHORT-TERM EFFICACY OF A COMBINATION OF GLUCOSAMINE AND CHONDROITIN SULFATE COMPARED TO A COMBINATION OF GLUCOSAMINE, CHONDROITIN SULFATE AND CALCIUM FRUCTOBORATE (CFB) ON IMPROVEMENT OF KNEE DISCOMFORT CONDITIONS IN HEALTHY SUBJECTS.

A COMPARATIVE, DOUBLE-BLIND, PLACEBO CONTROLLED ACUTE CLINICAL STUDY

 

 

 

T. Reyes-Izquierdo1, M.J. Phelan2, R. Keller3, C. Shu1, R. Argumedo1, Z. Pietrzkowski1

 

1. FutureCeuticals Inc., Applied BioClinical Laboratory, 16259 Laguna Canyon Rd, Irvine, CA, USA 92618; 2. Department of Statistics, School of Information and Computer Science. 2026 Donald Bren Hall, University of California at Irvine, Irvine, CA, 92697; 3. NutraClinical Inc., 16259 Laguna Canyon Rd, Irvine, CA USA92618

Corresponding Author: Tania Reyes-Izquierdo, Ph.D. 16259 Laguna Canyon Rd, Irvine CA, 92618 USA, Phone +1 949 502 4496, Fax +1 949 502 4987, Email: tania@abclinicaldiscovery.com

 


Corrigendum

 

Disclosure Statement: The present study was funded by VDF FutureCeuticals, Inc (Momence IL, USA). At the time of submission, T. Reyes-Izquierdo, R. Argumedo, amd Z. Pietrzkowski were employed by VDF FutureCeuticals, Inc.

Abstract: The following text replaces the Abstract in its entirety:

Abstract: Purpose: To compare and evaluate the effects of treatment with a blend of glucosamine, chondroitin sulfate and calcium fructoborate as compared to a placebo, on joint discomfort. Methods: Individuals with self-reported knee discomfort were randomized and blinded to treatment with a combo containing glucosamine and chondroitin sulfate or glucosamine, chondroitin sulfate and calcium fructoborate. Both groups were compared to placebo. Symptoms of discomfort and joint function were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the McGill Pain Questionnaire (MPQ) before treatment and after 7 and 14 days of treatment. Results: For these three arms, ninety-six individuals were selected and were randomly assigned into groups of 32, each containing an equal number of males and females. Treatment with glucosamine combined with chondroitin sulfate and CFB resulted in a statistically significant 24% reduction of mean WOMAC score and a 25% reduction of mean McGill index at day 14 over baseline (p-value = 0.0006 and p-value < 0.0001, respectively). Conclusions: Results showed that short-term use of CFB in combination with chondroitin sulfate and glucosamine was effective in reducing knee discomfort and improving the physical mobility of the joints.

Materials & Methods: Study Description

The following text provides additional information to supplement the Material and Methods: Study Description section:
The study was comprised of four arms that included one placebo group and three treatment groups, as follows:
(1) Calcium Fructoborate (“CFB”)
(2) Glucosamine and Chondroitin (“GC”) and CFB
(3) GC
(4) Placebo
This study tested two hypotheses: (1) that CFB would be effective for short term treatment of joint pain and (2) that a combination of CFB and GC would be effective for short term treatment of joint pain. Results relating to CFB alone were reported in Pietrzkowski et al., “Short-term efficacy of calcium fructoborate on subjects with knee discomfort: a comparative, double-blind, placebo-controlled clinical study.” Clinical interventions in aging 9 (2014): 895. Results relating to a combination of CFB and GC are reported herein.

Materials & Methods: Experimental Groups

The following text provides additional information to supplement the Material & Methods: Experimental Groups section:
Subjects in the placebo group and CFB (alone) group were instructed to take one capsule twice per day. Subjects in the GC and CFB group (i.e., TR1) and the GC (alone) (i.e., TR2) group were instructed to take two capsules twice per day.

Results
The WOMAC p-value was correctly reported as 0.0006 in Table 3. However, the Results section of the article contained a typographical error, incorrectly referring to the same WOMAC p-value as “0.006.”

 


Abstract

Purpose: To compare and evaluate the effects of treatment with a blend of glucosamine and chondroitin sulfate, or a blend of glucosamine, chondroitin sulfate and calcium fructoborate as compared to a placebo, on joint discomfort. Methods: Individuals with self-reported knee discomfort were randomized and blinded to treatment with a combo containing glucosamine and chondroitin sulfate or glucosamine, chondroitin sulfate and calcium fructoborate. Both groups were compared to placebo. Symptoms of discomfort and joint function were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the McGill Pain Questionnaire (MPQ) before treatment and after 7 and 14 days of treatment. Results: Ninety individuals were selected for this study and were randomly assigned in groups of 30 containing 15 male and 15 female participants to each of three treatment conditions. Treatment with glucosamine combined with chondroitin sulfate and CFB resulted in a statistically significant 24% reduction of mean WOMAC score and a 25% reduction of mean McGill index at day 14 over baseline (p-value = 0.0006 and p-value < 0.0001, respectively). Treatment with placebo or with glucosamine and chondroitin material did not result in significant improvement of the conditions. Conclusions: Results showed that short-term treatment with glucosamine and chondroitin could be efficacious only if used in combination with CFB.

 

Key words: Calcium fructoborate, glucosamine, chondroitin sulfate, WOMAC, McGill, joint discomfort.


 

Introduction

Chronic knee discomfort is a common phenomenon among population of older age (1). Many circumstances can cause or contribute to it (2). Individuals experiencing knee discomfort often report long-term distress, swelling, or sensitivity in one or both knees. Conventional management of knee discomfort mainly focuses on relief of symptoms using analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) (3, 4). Some dietary supplements have reported to show some potency to reduce symptoms associated with joint discomfort (5-10).

Chondroitin sulfate is an important structural component of cartilage. Chemically, it is a sulfated glycosaminoglycan composed of N-acetyl-galactosamine and glucuronic acid (11). Over the years, this material has been used as a dietary supplement to treat symptoms of joint discomfort. This material is bioavailable at the level 15-24% of orally administered dose (12-15). It has been suggested that ingested chondroitin sulfate may show anti-inflammatory activity, inhibit proteolytic activity, stimulate the synthesis of proteoglycans and hyaluronic acid and reduce catabolic activity of chondrocytes (16). This material has been used to reduce deficiency and degradation of endogenous chondroitin sulfate in the body, to modulate IL-1β and Nf-kB in chondrocytes, activities that have been suggested may improve OA conditions if chondroitin is used over an extended time. (15, 17-19) However, clinical potency of chondroitin sulfate remains a subject of open discussion due to mixed efficacy results (15, 20-22). Recent studies have addressed the efficacy of treatment with chondroitin and have concluded that some positive results may be observed after long-term supplementation (23-25).

Another dietary glycan that has been suggested to have beneficial effects on joint discomfort is glucosamine sulfate. Glucosamine sulfate is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine sulfate (“glucosamine”) has been marketed to relieve symptoms of osteoarthritis, which involves the age-dependent erosion of articular cartilage (25, 26).

Glucosamine is marketed to support the structure and function of joints in people suffering from joint discomfort. Commonly sold forms of glucosamine are glucosamine sulfate, glucosamine hydrochloride, and N-Acetyl Glucosamine. Although there is no evidence to suggest that glucosamine sulfate offers advantages over medications estrace is a form of estrogen – the female hormone necessary for many processes in the body. generic estrace is used to treat symptoms of  glucosamine hydrochloride, the latest does not need to be stabilized with salt and offers a more concentrated form of glucosamine. Given these facts, the product of choice for consumers should be Glucosamine hydrochloride (27). The use of glucosamine for management of OA conditions has been studied and reported in a manner similar to chondroitin sulfate; however, clinical potency of treatment of OA conditions with glucosamine remains unclear; despite previously performed clinical studies (28) A mixture of these dietary supplements (glucosamine and chondroitin) has been used to help delay or reverse the loss of cartilage (29, 30).

Calcium fructoborate (CFB) is a natural borate complex first described by Miljkovic (31) CFB has been tested in clinical studies to verify its potency to reduce joint discomfort symptoms and certain inflammatory markers (32, 33). Previous studies have shown that treatment with CFB resulted in statistically significant reduction of blood C-Reactive Protein (CRP) levels in subjects with angina pectoris (34, 35) and in subjects with increased risk of cardiovascular conditions (36). CFB is a patented, nature-identical compound produced according to a proprietary process described by Miljkovic (US Patent #5,962,049) (31). Chemical structure and identity of CFB has been previously described (32). Based upon these previous observations, we have designed this short term pilot clinical trial wherein CFB has been combined with glucosamine and chondroitin sulfate in order to observe possible effects on knee discomfort.

 

Materials and Methods

Materials

CFB was provided by VDF FutureCeuticals, Inc., (Momence, IL, USA). Glucosamine hydrochloride, chondroitin sulfate, silica oxide and fructose were from Sigma-Aldrich (St Louis, MO, USA),

Inclusion criteria for study subjects: Age range: >35 and<65 years; BMI: >21 and <30; no visible evidence of having a cold or other infections; non-diabetic; free of allergies; McGill Score >35 but less than 60.

Exclusion criteria

Age range: <35 and >65 years; BMI: <21 or >30 (kg/ m2); diabetes; subjects who were pregnant, nursing, or planning to get pregnant; subjects currently enrolled in another study; subjects with cardiovascular diseases; subjects taking medications for pain or NSAIDs, subjects taking supplements or vitamin D within two weeks of this trial.

Consent

This study was conducted according to the guidelines put forth in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board at Vita Clinical S.A. (Avenida Circunvalacion Norte #135, Guadalajara, JAL, Mexico 44270) (IRB Number: ABC-NCI-13-08-FRXB). All study subjects were generally healthy and had not used any type of medication or supplement for a period of 15 days prior to the start of the study. Study was performed by NutraClinical Inc. (San Diego, USA) according to the study protocol designed by VDF FutureCeuticals, Inc./ Applied Bioclinical Lab (Irvine, CA, USA).

Study description

After protocol had been approved by the Institutional Review Board, male and female subjects between 35-65 years of age were prescreened according to the inclusion and exclusion criteria. Subjects were recruited through advertisement in local papers. Distribution of the treatments and data collection was performed by NCI (NutraClinical Inc. 16259 Laguna Canyon Rd., Irvine, CA 92618). A total of 96 subjects were selected to participate in the study. All admitted participants had McGill scores between 35 and 60 (per inclusion criteria) and all had given written consent. Participants were randomly assigned into three (3) groups of 32 subjects. Each group contained an equal number of males and females. Each group was subjected to one of three treatment conditions. On Day 1 (baseline) medical history and physical examinations were performed on all subjects. Blood collections were performed on days 1 (baseline), 7 and 14 and always under fasting conditions (12h). On day 1, all subjects received their test products and were instructed to take the first dose immediately after blood collection. All bottles containing the tested materials and all capsules were similar in appearance. McGill and WOMAC Questionnaires were administered at baseline and at 7 and 14 days.

Experimental Groups

Placebo contained 80mg of fructose and 15mg of silica oxide per capsule. Subjects in the placebo group were instructed to take one (1) capsule twice per day before meals. Treatment 1 (TR1) capsules contained a mixture of 375 mg glucosamine, 100 mg chondroitin sulfate and 55 mg CFB. Treatment 2 (TR2) capsules contained a mixture of only 375mg of Glucosamine and 100mg of Chondroitin sulfate. Subjects in TR1 and TR2 experimental groups were advised to take two capsules twice per day before meals. All subjects were instructed to take the capsules before breakfast and lunch and minimum fifteen minutes prior to eating.

Western Ontario and McMaster Universities Arthritis Index. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a widely used questionnaire used to calculate physical function of joints (37). The WOMAC consists of 24 items divided into 3 subscales: pain (5 questions; scores range from 0 to 20), stiffness (2 items; scores range from 0 to 8), and functional limitations (17 items; scores range from 0 to 68). Total scores range from 0 (best) to 96 (worst). The WOMAC index was administered on day 1, day 7 and day 14 of treatment.

McGill Pain Questionnaire. The McGill Pain Questionnaire (MPQ) is a multidimensional pain questionnaire used to quantify the quality and intensity of pain (38, 39). The questionnaire was designed to provide quantitative measures of clinical pain that can be treated statistically. The scale contains 4 subscales consisting of 78 words that participants use to describe feelings of pain. On the first category, subjects have to select a word that “describes” the pain (like “quivering”, “pounding”). The second category includes the pain components (“tiring”, “suffocating”). The third category is the evaluation of the pain (from “no pain” to “excruciating”). The last part includes a miscellaneous description (“spreading”, “torturing”, “miserable”). After completing the questionnaire, users will have selected seven words that best describe their pain. Each chosen word has an associated numerical value, giving a total score ranging from 0 (no pain) to 78 (severe pain). The McGill pain questionnaire was administered on day 1 (pre-treatment) and after 7 and 14 days of treatment.

Blood Collection

Blood was collected at baseline prior to treatment. For each participant, two 9 mL blood samples were drawn from an antecubital vein in anticoagulant-free (dry tubes) (BD Vacutainer Franklin Lakes, NJ, USA). Blood again was drawn at Day 7 and Day 14 of the treatment, and always under fasted conditions.

Statistical Methods

In order to address the a priori hypothesis that treatment would improve mean reported discomfort in study subjects with self-reported discomfort in knee joint, the primary analysis tested the effect of treatment on the mean 7-day and 14-day change from baseline in WOMAC score (Western Ontario and McMaster Universities Arthritis Index) and McGill score (pain index of McGill University). A repeated measures analysis of variance (ANOVA) (40) was used to estimate treatment effects on within-subject changes in mean WOMAC and McGill scores over the 7- and 14-day period. Specifically, each score was regressed on an indicator of treatment group, post-treatment day, and the treatment-day interaction. In this case, a test of the coefficients for the treatment-day interaction equaling zero is equivalent to a test of the treatment effect at day 7 and day 14. Both the WOMAC and McGill scores were analyzed using this approach.

 

Results

Age and BMI characteristics of the study population are presented in Table 1. The average age of the 92 study participants was 49.2 years. The groups were comparable with respect to BMI (26.6 kg/m2 for all 92 women’s health. body- building, hypnotherapy, herbals, male enhancement. study subjects). Fifty percent of subjects in each treatment group were male. Two participants on the control group and 2 on TR1 did not follow compliance and were dropped from the study. A total of 92 participants remained on study through visits 1, 2 and 3. Numerical summaries of WOMAC and MPQ scores are listed in Table 2. At baseline, range of WOMAC values was 41.6-53.5 and range of McGill score values was 49.2-51.5. It is noticeable that the average value of WOMAC in TR2 was lower comparing to control and TR1 at baseline. However, MPQ score average values were in the same range in all experimental groups. The analysis of treatment effects was based on mean within subject change from baseline.

 

Table 1 Characteristics of study subjects as presented by an average values (mean+/-SEM) at Day 1 (baseline)

Table 1: Characteristics of study subjects as presented by an average values (mean+/-SEM) at Day 1 (baseline)

Abbreviations: BMI, body mass index; WOMAC, Western Ontario and McMaster Universities Arthritis index; McGill, McGill Pain Questionnaire; SE, Standard Error of the Mean

 

Table 2 Numerical Summaries of WOMAC and MPQ score by Treatment and Day. Reporting AVE ± SD. WOMAC and MPQ values were determined at baseline and on day 7 and 14

Table 2: Numerical Summaries of WOMAC and MPQ score by Treatment and Day. Reporting AVE ± SD. WOMAC and MPQ values were determined at baseline and on day 7 and 14

Abbreviations: WOMAC, Western Ontario and McMaster Universities Arthritis Index; MPQ, McGill Pain Questionnaire; AVE, average; SD, standard deviation. *Significant difference from baseline P-value=0.006. **Significant difference from baseline P-value >0.00001

 

Table 3 shows the estimated effects of active treatment versus placebo at 7 and 14 days follow up. In each case the mean within-subject change from baseline for active compounds is compared to the mean within-subject change for the placebo. A negative estimate indicates that treatment was involved in greater reductions in reported discomfort. The within-subject change in mean WOMAC score over 14 days was estimated to be 9.67 points lower on TR1 (glucosamine, chondroitin sulfate plus CFB) when compared to control (Estimate effect = -9.67, P-Value = 0.006). The within-subject change in mean McGill score over 14 days was estimated to be 8.28 points greater on TR1 when compared to control (Estimated effect = -8.28, P-Value < 0.00001). TR2 (glucosamine and chondroitin, alone) appeared to have an effect on WOMAC scores at day 7, but it is in the wrong direction. This is interpreted to be an artifact associated with the lower mean WOMAC score in group TR2 at baseline. The apparent effect vanished at day 14, and no effect of TR2 is reported on McGill scores throughout the follow-up period. Generally, for both the WOMAC and McGill score, TR1 was more effective than TR 2 at reducing knee discomfort over the two week period.

Blood chemistry analysis performed at Days 1, 7 and Day 14 did not indicate any significant changes in blood levels of key electrolytes, enzymes, lipids and glucose. All subjects completed this trial without any indications of unusual effects.

 

Table 3 Treatment Effects over 7 and 14 Days for WOMAC and MPQ Scores

Table 3: Treatment Effects over 7 and 14 Days for WOMAC and MPQ Scores

 

Discussion

Chronic knee discomfort is a condition that significantly affects the quality of life due to its impact on physical movements. Conventional treatment for joint discomfort involves the use of NSAIDs and dietary supplements such as glucosamine and chondroitin supplements. Since NSAIDs are associated with potential side effects(3, 4, 41, 42); the rationale behind the use of dietary supplements is to improve chronic joint discomfort while reducing the need for NSAIDS. Chondroitin sulfate and glucosamine supplements have been commonly used as dietary supplements to reduce and/or slow down cartilage damage in subjects with joint discomfort (43-47).

Calcium fructoborate (CFB) is a natural plant mineral borate complex produced by a patented process first described by Miljkovic (Miljkovic et al., US Patent #5,962,049) (31). Of the existing boron and borate supplements available, CFB might be the most researched and might offer the most potential for human health (31, 48). CFB, a potential anti-inflammatory agent (35, 49, 50) with the ability to modulate key markers associated with inflammation-related conditions, such as osteoarthritis (32, 50, 51), has been recently reported to subjectively improve feelings of flexibility, comfort, and quality of life in a period of only 14 days (33). For this study, we chose a combination of CFB, along with glucosamine hydrochloride and chondroitin sulfate to assess any synergistic effect. The objective of this study was to investigate any possible short-term benefits in decreasing discomfort and improving physical mobility in participants during a short period of time (only 14 days). We also observed the effects of using a combination of chondroitin sulfate and glucosamine alone. Even though the recruited participants had not been previously diagnosed, the criterion of selection was based on the McGill Pain Questionnaire, which is not only used to evaluate and monitor pain, but also to determine the effectiveness of any intervention. Discomfort and physical function of the joints were recorded for baseline, Day 7 and Day 14 of the study period. The data tables from the study show that at the start of the study all participants had similar discomfort and physical function scores (Table 2). Results presented in Table 3 showed that TR1 (a combination of CFB, chondroitin and glucosamine) significantly reduced mean WOMAC and McGill scores when compared to placebo. In contrast, TR2 using only chondroitin sulfate and glucosamine had no effect under these experimental conditions. Although our study showed that the combination of all 3 nutrients can result in significant rather rapid improvement in knee discomfort and improved mobility, further investigation is justified and can yield additional insight into these materials.

 

Conclusions

Data from our study clearly indicate that short-term use of CFB in combination with chondroitin sulfate and glucosamine was effective in reducing knee discomfort and improving the physical mobility of the joints. Future investigations conducted with a larger cohort of subjects and for a longer duration; may provide better understanding of the short and long term effects of supplementation. The present study could be repeated as a crossover; in order to observe any effects of the combination therapy in subjects.

 

Acknowledgements: We express our gratitude to John Hunter and Brad Evers (FutureCeuticals Inc.) for their comments and suggestions in the preparation of this article. We would like to thank Mahalakshmi Babu for her help in editing the manuscript.

Disclosure Statement: The present study was funded by Futureceuticals, Inc. (Momence IL, USA). All authors declare that they have no conflicts of interest. No competing financial interests exist.

 

References

1. Porcheret M, Jordan K, Jinks C, Society PCicwtPCR. Primary care treatment of knee pain—a survey in older adults. Rheumatology. 2007;46(11):1694-700.

2. Frese T, Peyton L, Mahlmeister J, Sandholzer H. Knee Pain as the Reason for Encounter in General Practice. ISRN Family Medicine. 2013;2013:6.

3. Crofford L. Use of NSAIDs in treating patients with arthritis. Arthritis Research & Therapy. 2013;15(Suppl 3):S2.

4. Östör A, Watson PA. Topical NSAIDS provide effective pain relief for patients with hand or knee osteoarthritis with similar efficacy, and fewer side effects, than oral NSAIDS. Evidence Based Medicine. 2012.

5. Wang Y, Prentice LF, Vitetta L, Wluka AE, Cicuttini FM. The effect of nutritional supplements on osteoarthritis. Altern Med Rev. 2004;9(3):275-96. Epub 2004/09/25.

6. Ameye LG, Chee WS. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Arthritis Res Ther. 2006;8(4):R127. Epub 2006/07/25.

7. Vandeweerd JM, Coisnon C, Clegg P, Cambier C, Pierson A, Hontoir F, et al. Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis. Journal of Veterinary Internal Medicine. 2012;26(3):448-56.

8. Akhtar N, Haqqi TM. Current nutraceuticals in the management of osteoarthritis: a review. Therapeutic advances in musculoskeletal disease. 2012;4(3):181-207.

9. Lopez HL. Nutritional interventions to prevent and treat osteoarthritis. Part II: focus on micronutrients and supportive nutraceuticals. PM&R. 2012;4(5):S155-S68.

10. Ragle RL, Sawitzke AD. Nutraceuticals in the Management of Osteoarthritis. Drugs & aging. 2012;29(9):717-31.

11. Davidson EA, Meyer K. Chondroitin, a new mucopolysaccharide. The Journal of biological chemistry. 1954;211(2):605-11. Epub 1954/12/01.

12. Bana G, Jamard B, Verrouil E, Mazieres B. Chondroitin sulfate in the management of hip and knee osteoarthritis: an overview. Adv Pharmacol. 2006;53:507-22. Epub 2007/01/24.

13. Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs & aging. 2007;24(7):573-80. Epub 2007/07/31.

14. Bucsi L, Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 1998;6 Suppl A:31-6. Epub 1998/09/23.

15. Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. The New England journal of medicine. 2006;354(8):795- 808. Epub 2006/02/24.

16. Kubo M, Ando K, Mimura T, Matsusue Y, Mori K. Chondroitin sulfate for the treatment of hip and knee osteoarthritis: current status and future trends. Life sciences. 2009;85(13-14):477-83. Epub 2009/08/22.

17. Hart L. Are glucosamine and/or chondroitin sulfate effective for knee osteoarthritis? Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine. 2006;16(6):528-9. Epub 2006/11/23.

18. Uebelhart D, Malaise M, Marcolongo R, de Vathaire F, Piperno M, Mailleux E, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2004;12(4):269-76. Epub 2004/03/17.

19. Mazieres B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. The Journal of rheumatology. 2001;28(1):173-81. Epub 2001/02/24.

20. Ragle RL, Sawitzke AD. Nutraceuticals in the management of osteoarthritis : a critical review. Drugs & aging. 2012;29(9):717-31. Epub 2012/09/29.

21. Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Annals of the rheumatic diseases. 2010;69(8):1459- 64. Epub 2010/06/08.

22. Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO, 3rd, Harris CL, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis and rheumatism. 2008;58(10):3183-91. Epub 2008/09/30.

23. Attia M, Scott A, Carpentier G, Lian O, Van Kuppevelt T, Gossard C, et al. Greater glycosaminoglycan content in human patellar tendon biopsies is associated with more pain and a lower VISA score. British journal of sports medicine. 2013. Epub 2013/10/09.

24. Ishimaru D, Sugiura N, Akiyama H, Watanabe H, Matsumoto K. Alterations in the chondroitin sulfate chain in human osteoarthritic cartilage of the knee. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2013. Epub 2013/11/28.

25. Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Annals of the rheumatic diseases. 2014. Epub 2014/01/08.

26. Henrotin Y, Lambert C. Chondroitin and glucosamine in the management of osteoarthritis: an update. Current rheumatology reports. 2013;15(10):361. Epub 2013/08/21.

27. Aghazadeh-Habashi A, Jamali F. The glucosamine controversy; a pharmacokinetic issue. Journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2011;14(2):264-73. Epub 2011/07/08.

28. Bertozzi CR, Freeze HH, Varki A, Esko JD. Glycans in Biotechnology and the Pharmaceutical Industry. In: AC Varki, Richard D.; Esko, Jeffrey D., editor. Essentials of Glycobiology. 2nd edition ed. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009.

29. Homandberg GA, Guo D, Ray LM, Ding L. Mixtures of glucosamine and chondroitin sulfate reverse fibronectin fragment mediated damage to cartilage more effectively than either agent alone. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2006;14(8):793-806.

30. Sherman AL, Ojeda-Correal G, Mena J. Use of glucosamine and chondroitin in persons with osteoarthritis. PM & R : the journal of injury, function, and rehabilitation. 2012;4(5 Suppl):S110-6. Epub 2012/06/01.

31. Miljkovic D, Scorei RI, Cimpoiasu VM, Scorei ID. Calcium fructoborate: plant-based dietary boron for human nutrition. Journal of dietary supplements. 2009;6(3):211-26. Epub 2009/01/01.

32. Reyes-Izquierdo T, Nemzer B, Gonzalez AE, Zhou Q, Argumedo R, Shu C, et al. Short-term Intake of Calcium Fructoborate Improves WOMAC and McGill Scores and Beneficially Modulates Biomarkers Associated with Knee Osteoarthritis: A Pilot Clinical Double-blinded Placebo-controlled Study. American Journal of Biomedical Sciences. 2012;4(2): p111-22.

33. Pietrzkowski Z, Phelan MJ, Keller R, Shu C, Argumedo R, Reyes-Izquierdo
T. Short-term efficacy of calcium fructoborate (CFB) on subjects with knee discomfort. A comparative, double blind, placebo-controlled clinical study. Clinical Interventions in Aging. 2014;9:895-9.

34. Scorei R. Is boron a prebiotic element? A mini-review of the essentiality of boron for the appearance of life on earth. Origins of life and evolution of the biosphere : the journal of the International Society for the Study of the Origin of Life. 2012;42(1):3-17. Epub 2012/04/25.

35. Scorei ID, Scorei RI. Calcium fructoborate helps control inflammation associated with diminished bone health. Biological trace element research. 2013;155(3):315-21. Epub 2013/08/29.

36. Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013;29(1):178-83. Epub 2012/11/17.

37. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. The Journal of rheumatology. 1988;15(12):1833-40. Epub 1988/12/01.

38. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975;1(3):277-99. Epub 1975/09/01.

39. Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005;103(1):199-202. Epub 2005/06/29.

40. Diggle PJH, P.; Liang, K.Y.; Zeger, S.L. . Analysis of Longitudinal Data. 2nd Edition ed. New York, NY, USA.: Oxford University Press; 2009.

41. Chung L, Chakravarty EF, Kearns P, Wang C, Bush TM. Bleeding complications in patients on celecoxib and warfarin. Journal of clinical pharmacy and therapeutics. 2005;30(5):471-7. Epub 2005/09/17.

42. Bush TM, Shlotzhauer TL, Imai K. Nonsteroidal anti-inflammatory drugs. Proposed guidelines for monitoring toxicity. The Western journal of medicine. 1991;155(1):39-42. Epub 1991/07/01.

43. Felson DT. Glucosamine and chondroitin sulfate in knee osteoarthritis: where now? Nature clinical practice Rheumatology. 2006;2(7):356-7. Epub 2006/08/26.

44. Baime MJ. Glucosamine and chondroitin sulfate did not improve pain in osteoarthritis of the knee. ACP journal club. 2006;145(1):17. Epub 2006/07/04.

45. Vassiliou VS. Glucosamine and chondroitin sulfate for knee osteoarthritis. The New England journal of medicine. 2006;354(20):2184-5; author reply -5. Epub 2006/05/20.

46. Pelletier JP. Glucosamine and chondroitin sulfate for knee osteoarthritis. The New England journal of medicine. 2006;354(20):2184-5; author reply -5. Epub 2006/05/20.

47. Ernst E. Glucosamine and chondroitin sulfate for knee osteoarthritis. The New England journal of medicine. 2006;354(20):2184-5; author reply -5. Epub 2006/05/19.

48. Wagner CC, Ferraresi Curotto V, Pis Diez R, Baran EJ. Experimental and theoretical studies of calcium fructoborate. Biological trace element research. 2008;122(1):64-72. Epub 2008/01/30.

49. Scorei RIC, C.; Ion, R.; Cimpean, A.; Galateanu, B.; Mitran, V.; Iordachescu, D. In vitro effects of calcium fructoborate upon production of inflammatory mediators by LPS-stimulated RAW 264.7 macrophages. Biological trace element research. 2010;135(1-3):334-44. Epub 2009/08/12.

50. Scorei R, Mitrut P, Petrisor I, Scorei I. A double-blind, placebo-controlled pilot study to evaluate the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers for middle-aged people with primary osteoarthritis. Biological trace element research. 2011;144(1-3):253-63. Epub 2011/05/25.

51. Scorei IR. Calcium fructoborate: plant-based dietary boron as potential medicine for cancer therapy. Front Biosci (Schol Ed). 2011;3:205-15. Epub 2011/01/05.

CONSUMPTION OF MANGOSTEEN FRUIT PULP POWDER (MX3) PROVIDES BENEFICIAL EFFECT ON KNEE DISCOMFORT NOT ASSOCIATED WITH INJURY. A DOUBLE BLIND, PLACEBO-CONTROLLED PILOT CLINICAL STUDY

 

R. Rodriguez1, Z. Pietrzkowski2, R. Keller1, T. Reyes-Izquierdo2

 

1. NutraClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA 92618, USA; 2. Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA 92618, USA; 3. DMI Medical Supply Co., Inc., Door #3 Victor San Bldg., JP Laurel Ave., cor. Cabaguio Ave., Davao City, 8000, Philippines

Corresponding Author: Robert Keller, 16259 Laguna Canyon Road, Irvine, CA http://abilifygeneric-online.com/catalog/Depression/Lexapro.htm 92618, USA, Phone +1 619 675-4103, Fax +1 619 684-3152, Email: robert@ nutraclinicalinc.com

 


Abstract

Aim: To evaluate the effect of purple Mangosteen fruit pulp powder (MX3) on subjects with knee joint discomfort and reduced joint function. Methods: Subjects with self-reported knee discomfort were randomized and blinded for treatment with either a twice daily dose of 500mg daily dose of MX3 (Group 1), a single daily dose of 500mg MX3 (Group 2) or a once a day daily dose of placebo(Group 3) during a 28 day period. Symptoms of discomfort were evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the McGill Pain Questionnaire (MPQ) before the treatment and after 10 and 28 days of treatment. Blood samples were also collected for blood chemistry purposes. Results: Thirty six individuals were recruited for this study. Group 1 contained 2 male and 10 female subjects, average age 55 (SD ±5.2), BMI 27.8 (SD ±3.44). Group 2 contained 4 male and 8 female subjects age 59 (SD ±5.1), with a BMI of 28.6 (SD ± 3.7). Group 3 had 1 male and 11 female participants age 55 (SD ± 9.1) BMI 28.5 (SD ± 3.3). All participants completed the study. Data reported on day 28 for the McGill index showed a reduction of 56% on group 1, 46% on group 2 compared to a 9% in the placebo group (p=0.0004). WOMAC showed a 39% reduction on group 1, a 34% in group 2 and a 16% in placebo (p=0.04). CRP analysis in blood did not show any significant differences. Conclusions: Short-term use of MX3 did not show significant improvement at day 10 when compared to placebo. However, results indicate that long term use of MX3 might reduce knee joint discomfort, as indicated by WOMAC and McGill. Further clinical studies will confirm if a long term treatment with MX3 can improve knee joint function and reduce discomfort on subjects showing symptoms of osteoarthritis.

 

Key words: Mangosteen fruit powder, Garcinia mangostana, WOMAC, McGill, joint discomfort.


 

Introduction

Mangosteen (Garcinia mangostana Linn) is a tropical fruit that has been used as a traditional indigenous medicinal material across Southeast Asia (Thailand, Malaysia, Taiwan, Philippines, Indonesia, and Sri Lanka) for treatment of a wide range of ailments including trauma, diarrhea and skin infections, wound healing, and related gastrointestinal complaints . Mangosteen is known to contain a wide range of naturally-occurring polysaccharide and xanthone compounds within the fruit, leaves, heartwood, and especially the pericarp (rind/peel/hull) with widespread biological activities, including anti-inflammatory (1-4), antioxidant (5, 6), anti-proliferative (7-10), immune-stimulatory (11), and antibacterial/antiviral effects (10, 12-14). More recently a group of secondary metabolites known as xanthones have been isolated from the pericarp of the mangosteen Garcinia mangostana and are attributed the medicinal and health beneficial properties of the fruit (15). Various health-promoting activities of xanthones in the pericarp of Garcinia mangostana have been observed in vitro. However, controlled trials to observe the efficacy of these xanthones in human subjects, as well as the effect on several ailments, is very limited. MX3 was developed and is traded by the Living Tropic Fruiticeuticals, Inc. (LTFI), a Global importer of organic products. The Philippines based company (DMI Medical Supply Co., Inc.) follows a more traditional method of manufacture. MX3 is produced by drying the mangosteen whole fruit and grinding it to a accutane fine powder (Mangosteen Fruit Pulp Powder MX3). This material has been standardized by the amount of xanthones with the proper regulations for microbial and heavy metals required to meet industrial standards. MX3 supplement was tested in subjects with self-reported knee discomfort, randomized and blinded for treatment with either a twice daily dose of 500mg daily dose of MX3 (Group 1), a single daily dose of 500mg MX3 (Group 2) or a once a day daily dose of placebo (Group 3) during a 28 day period.

Subjects were recruited for this study on the basis of a pre-existing knee joint discomfort, no shorter than 3 weeks and not related to injury. Subjects were not medically diagnosed prior to the study. The selection criterion was based on the results from the McGill Pain Questionnaire, which estimates the level of pain subjectively (16-19). Subjects were also given the Western Ontario and McMaster University assay (WOMAC) (20-23) and were selected based on their results. These questionnaires were given to the subjects at day zero (beginning of the study), day 10 and day 28.

 

Materials and Methods

Study materials

MX3 was provided by DMI Medical Supply Co., Inc., (DMI, Door #3 Victor San Bldg., JP Laurel Ave., cor. Cabaguio Ave., Davao City, 8000, Philippines). Placebo material was provided by DMI. The components of mx3 placebo capsule are the following: lactose (500mg), FD&C yellow no. 5, FD&C red no. 40 and FD&C blue no. 2.

Participant selection and treatment

This study was conducted according to the guidelines set forth in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board (Vita Clinical SA, Avenida Circunvalacion Norte #135, Guadalajara, JAL, Mexico, 44270) (Clinical study protocol #DMI-NCI-12-08-MX3, IRB No. AV130). Previous to the beginning of the protocol, all participants signed an informed consent. Thirty-six subjects with self-reported joint discomfort were recruited for this study. Subjects were recruited based on the stated mild pain on 1 of the weight-bearing questions posed on the Western Ontario and McMaster Universities (WOMAC) pain subscale and McGill pain score. Other than joint discomfort, participants were generally healthy and had no diagnosis of any respiratory tract infections, diabetes, or dietary allergies. No medications and/or supplements of any kind were permitted for two weeks prior and during the study period. Participants were advised to abstain from taking vitamin D, testosterone supplements, or steroid- containing over the counter or prescribed medications for 30 days before the study period. During the study period, participants ingested only MX3 or placebo. Subjects were supplied with capsules containing either 500 mg of MX3 or 500mg of Placebo material. Capsules and containers had the same appearance and were only differentiated by a code, to keep the subjects blind.

Subjects were divided in groups of 12 as follows: Group 1 contained 2 male and 10 female subjects, average age 55 (SD ±5.2), BMI 27.8 (SD ±3.44). Group 2 contained 4 male and 8 female subjects age 59 (SD ±5.1), with a BMI of 28.6 (SD ± 3.7). Group 3 had 1 male and 11 female participants age 55 (SD ± 9.1) BMI 28.5 (SD ± 3.3). The treatments were distributed as follows: Group one took a twice daily dose of 500mg daily dose of MX3, group 2 had a single daily dose of 500mg MX3 and group 3 had a once a day daily dose of placebo(Group 3) during a 28 day period. Subjects were advised to take the first or single dose in the morning, before the first meal, with water.

Western Ontario and McMaster Universities Arthritis Index

The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a widely used questionnaire

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used to calculate physical function of joints (23). The WOMAC consists of 24 items divided into 3 subscales; which include pain (5 items; scores range from 0 to 20), stiffness (2 items; scores range from 0 to 8), and functional limitations (17 items; scores range from 0 to 68). Total scores range from 0 (best) to 96 (worst). The WOMAC index was administered on day 1 (pre-treatment) and after 5 and 10 days of treatment.

McGill Pain Score

The McGill Pain Questionnaire (MPQ) is a multidimensional pain questionnaire used to quantify the quality and intensity of pain (16, 19). The scale contains 4 subscales consisting of 78 words that participants use to indicate feelings of pain. Seven words are chosen from categories of pain description, pain components, evaluation of pain, and a miscellaneous descriptor. Each chosen word has an associated numerical value, and total scores range from 0 (no pain) to 78 (severe pain). The McGill pain questionnaire was administered on day 1 (pre-treatment) and after 5 and 10 days of treatment.

Statistical analysis

Statistical comparison samples previous and post- treatment, within and between groups were made using Graphpad Prism 6 (Version 6.01) software. A Chi-square test was performed to determine if the data sets had a normal distribution. Normally distributed data was analysed using a paired two sample t test. P values less than 0.05 were considered statistically significant.

 

Results

Thirty-six participants were selected after being pre- screened using the WOMAC scores (23). The total WOMAC score on day zero showed a mean of 56.5 (SD 24.04) for group 1 (twice a day dose), a mean of 58.95 (SD ± 20.86) for group 2 and mean of 59.04 (SD ± 25.69) for placebo group. Ordinary one way ANOVA showed no significant in the WOMAC score before treatment (p = 0.66) or at day 10 (p=0.16). Total WOMAC score showed a reduction of 17% on group 1 (mean 47.25, SD ± 13.81, 95% CI -7.34 to 25.84), when compared to day zero (baseline). However, it was not significant (mean 47.25; 95% CI -30.53 to 7.53) (p=0.04) when compared to placebo. Group 2 showed a reduction of 13% when compared to baseline (mean 51.33 SD ± 22.86, 95% CI -11.77 to 27.02), but no significance (mean 51.33, 95% CI -34.62 to 3.45) (p=0.14) when compared to placebo. Placebo showed a reduction of 26% (mean 44, SD ± 22.53). At day 28, total WOMAC score showed a 62% reduction in group 1 (mean 21.5, SD ±12.62, 95% CI 18.41 to 51.59), when compared to baseline. It was significant when compared to placebo (mean 21.5, 95% CI 10.29 to 46.38) (p=0.04). Group 2 also showed a 49% reduction when compared to baseline (mean 30.58, SD± 17.61, 95% CU 8.979 to 47.77). When compared to placebo, group 2 was significant (mean 30.58, 95% CI 1.205 to 37.29). Data is presented as ratio (percent difference over baseline) with SE of the mean in figure 1.

 

Figure 1

 

Total WOMAC Score change over baseline at day 10 and 28 of treatment. Total WOMAC score did not show significant differences between groups before treatment (P=0.66). Ratio was calculated based on the day 0. WOMAC score did not show a significant reduction of the score on groups treated with MX3 after 10 days (reduction of 17% for group 1 and 4% for group 2) when compared with day 0. ). After 10 days of treatment, the BRC group showed a 26% significant reduction in the score (P<0.01). Values are presented as mean % ± standard error (n=20) (SD ± 12.98) for group 2 (once a day dose) and mean of 57.37 (SD ± 16.85) for placebo. There were no significant differences on day zero (baseline) among groups (p = 0.19) or at day 10 (p=0.95). At Day 10, Total McGill score showed a reduction of 4% on group 1 (mean 45.27, SD ± 12.12, 95% CI -5.94 to 12.86) (p=0.46), when compared to day zero (baseline). It was not significant (mean 45.27; 95% CI -12.85 to 11.68) (p=0.91) when compared to placebo. Group 2 showed a reduction of 13% when compared to baseline (mean 42.25 SD ± 11.07, 95% CI – 2.47 to 17.56), but no significance (mean 42.25, 95% CI – to 13.35) (p=0.14) when compared to placebo. Placebo showed a reduction of 18% (mean 43.33, SD ± 14.04) but no significance when compared to baseline (mean 43.33, 95% CI -1.474 to 29.56) (p=0.05). At day 28, total McGill score showed a 39% reduction in group 1 (mean 29.08, SD ±6.25, 95% CI 8.88 to 27.7) (p=3.66E-05), when compared to baseline. It was significant when compared to placebo (mean 29.08, 95% CI 8.59 to 29.73) (p=0.001). Group 2 also showed a 31% reduction when compared to baseline (mean 32.92, SD± 6.86, 95% CU 6.85 wellbutrin vs cymbalta to 26.89) (p=0.0006). When compared to placebo, group 2 was significant (mean 32.92, 95% CI 4.76 to 25.90) (0.0004). Data is presented as ratio (percent difference over baseline) with SE of the mean in figure 2.

Figure 2

McGill Score after 10 and 28 days of treatment. Data collected on Day 0 did not show significant differences between groups (P=0.19). The McGill score did not show significant reduction at day 10 when compared to placebo (P=0.95). and day 10 (P=0.003). Values are presented as mean % ± standard error (n=20).

 

Discussion

The McGill score on day zero showed a mean of 47.37 (SD 10.59) for group 1 (twice a day dose), a mean of 49.7.

The WOMAC and McGill scores are dependable and sensitive tools for measuring joint function, feelings of discomfort and pain, respectively. According to Gandhi et al (24) using multiple instruments for joint discomfort and function give a better diagnosis. These tools cannot be used interchangeably (25), but they can be combined. Joint discomfort and stiffness are major inhibitors of function and activity (26, 27). Current analgesic treatments can reduce discomfort and inflammation. However, chronic users of non-steroidal anti- inflammatory drugs (NSAIDs) have an increased risk of bleeding and visible damage to their small intestine (28). MX3, a product derived from mangosteen (Garcinia mangostana Linn), a tropical asian fruit traditionally used for its antioxidant (5, 6), anti-proliferative (7-10), immune-stimulatory (11), and antibacterial/antiviral effects (10, 12-14). MX3 is a natural powder which contains natural pure xhantone with antioxidant and anti-inflammatory properties. MX3 was administered as an encapsulated fine powder in two doses: either a twice daily dose of 500mg daily dose of MX3 (Group 1) or a single daily dose of 500mg MX3 (Group 2). A placebo group was included as control. Subjects were recruited based on the results from the WOMAC and McGill scores, on a self-reported knee joint discomfort for more than 3 weeks, non-related to injury and not previously medically diagnosed.

After 10 days, subjects on the group treated with 500mg MX3 twice a day for 10 days reported a 27% improvement in the WOMAC score. Subjects from group 2, treated with a single daily dose showed a 6% improvement. The McGill score improved 7% in group 1 and 13% in group 2. Overall, these groups did not show a statistical significance when compared to placebo. However, at day 28, results form group 1 total WOMAC score showed a 56% improvement when compared to baseline. Group 2 showed a 46% improvement. Results from the McGill score showed an improvement on day 28 for group 1 (47% pain reduction) or group 2 (31% pain reduction). These results suggest that in order to see a significant improvement, treatment has to be long term. Further clinical studies will confirm if a long term treatment with MX3 can improve knee joint function and reduce discomfort on subjects showing symptoms of osteoarthritis.

 

Acknowledgements: All authors declare that they have no conflicts of interest. The present study was funded by DMI Medical Supply Co., Inc. We express our gratitude to Tania Reyes-Izquierdo and Zbigniew Pietrzkowski (Applied Bio Clinical, Applied BioClinical Lab, Futureceuticals, Inc.) for their comments and suggestions in the preparation of this article.

 

References

  1. Bumrungpert A, Kalpravidh RW, Chuang CC, Overman A, Martinez K, Kennedy A, et al. Xanthones from mangosteen inhibit inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media. The Journal of nutrition. 2010;140(4):842-7. Epub 2010/02/26.

  2. Udani JK, Singh BB, Barrett ML, Singh VJ. Evaluation of Mangosteen juice blend on biomarkers of inflammation in obese subjects: a pilot, dose finding study. Nutrition journal. 2009;8:48. Epub 2009/10/22.

  3. Bumrungpert A, Kalpravidh RW, Chitchumroonchokchai C, Chuang CC, West T, Kennedy A, et al. Xanthones from mangosteen prevent lipopolysaccharide- mediated inflammation and insulin resistance in primary cultures of human adipocytes. The Journal of nutrition. 2009;139(6):1185-91. Epub 2009/05/01.

  4. Chomnawang MT, Surassmo S, Nukoolkarn VS, Gritsanapan W. Effect of Garcinia mangostana on inflammation caused by Propionibacterium acnes. Fitoterapia. 2007;78(6):401-8. Epub 2007/07/24.

  5. Weecharangsan W, Opanasopit P, Sukma M, Ngawhirunpat T, Sotanaphun U, Siripong P. Antioxidative and neuroprotective activities of extracts from the fruit hull of mangosteen (Garcinia mangostana Linn.). Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2006;15(4):281-7. Epub 2006/06/10.

  6. Jung HA, Su BN, Keller WJ, Mehta RG, Kinghorn AD. Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen). Journal of agricultural and food chemistry. 2006;54(6):2077-82. Epub 2006/03/16.

  7. Chang HF, Wu CH, Yang LL. Antitumour and free radical scavenging effects of gamma-mangostin isolated from Garcinia mangostana pericarps against hepatocellular carcinoma cell. The Journal of pharmacy and pharmacology. 2013;65(9):1419-28. Epub 2013/08/10.

  8. Chang HF, Huang WT, Chen HJ, Yang LL. Apoptotic effects of gamma- mangostin from the fruit hull of Garcinia mangostana on human malignant glioma cells. Molecules. 2010;15(12):8953-66. Epub 2010/12/09.

  9. Moongkarndi P, Kosem N, Kaslungka S, Luanratana O, Pongpan N, Neungton N. Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line. Journal of ethnopharmacology. 2004;90(1):161-6. Epub 2003/12/31.

  10. Pedraza-Chaverri J, Cardenas-Rodriguez N, Orozco-Ibarra M, Perez-Rojas JM. Medicinal properties of mangosteen (Garcinia mangostana). Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2008;46(10):3227-39.

    Of proble I replace. Do them. Sometimes: have my can 5 mg cialis a really apply it Repunzel’s place future well what is viagra used for using looking or their anything extra. I some viagra erection bottle TISSUE know shampoo, frizz. I http://pharmacyonline-incanada.com/ get rinse. Do – subtle. Try were. Blonde. This online canada pharmacy No hold between a just at canadian pharmacy review and a I a of had.

    Epub 2008/08/30.

  11. Matsumoto K, Akao Y, Kobayashi E, Ito T, Ohguchi K, Tanaka T, et al. Cytotoxic benzophenone derivatives from Garcinia species display a strong apoptosis- inducing effect against human leukemia cell lines. Biological & pharmaceutical bulletin. 2003;26(4):569-71. Epub 2003/04/04.

  12. Lannang AM, Louh GN, Biloa BM, Komguem J, Mbazoa CD, Sondengam BL, et al. Cytotoxicity of natural compounds isolated from the seeds of Garcinia afzelii. Planta medica. 2010;76(7):708-12. Epub 2009/11/26.

  13. Reutrakul V, Anantachoke N, Pohmakotr M, Jaipetch T, Yoosook C, Kasisit J, et al. Anti-HIV-1 and anti-inflammatory lupanes from the leaves, twigs, and resin of Garcinia hanburyi. Planta medica. 2010;76(4):368-71. Epub 2009/10/16.

  14. Phongpaichit S, Nikom J, Rungjindamai N, Sakayaroj J, Hutadilok-Towatana N, Rukachaisirikul V, et al. Biological activities of extracts from endophytic fungi isolated from Garcinia plants. FEMS immunology and medical microbiology. 2007;51(3):517-25. Epub 2007/09/25.

  15. Gutierrez-Orozco F, Failla ML. Biological activities and bioavailability of mangosteen xanthones: a critical review of the current evidence. Nutrients. 2013;5(8):3163-83. Epub 2013/08/16.

  16. Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005;103(1):199-202. Epub 2005/06/29.

  17. Graham C, Bond SS, Gerkovich MM, Cook MR. Use of the McGill pain questionnaire in the assessment of cancer pain: replicability and consistency. Pain. 1980;8(3):377-87. Epub 1980/06/01.

  18. Meissner JE. McGill-Melzack pain questionnaire. Nursing. 1980;10(1):50-1. Epub 1980/01/01.

  19. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975;1(3):277-99. Epub 1975/09/01.

  20. Bellamy N, Kean WF, Buchanan WW, Gerecz-Simon E, Campbell J. Double blind randomized controlled trial of sodium meclofenamate (Meclomen) and diclofenac sodium (Voltaren): post validation reapplication of the WOMAC Osteoarthritis Index. The Journal of rheumatology. 1992;19(1):153-9. Epub 1992/01/01.

  21. Bellamy N, Goldsmith CH, Buchanan WW, Campbell J, Duku E. Prior score availability: observations using the WOMAC osteoarthritis index. British journal of rheumatology. 1991;30(2):150-1. Epub 1991/04/01.

  22. Bellamy N. Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis index. Seminars in arthritis and rheumatism. 1989;18(4 Suppl 2):14- 7. Epub 1989/05/01.

  23. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. The Journal of rheumatology. 1988;15(12):1833- 40. Epub 1988/12/01.

  24. Gandhi R, Tsvetkov D, Dhottar H, Davey JR, Mahomed NN. Quantifying the pain experience in hip and knee osteoarthritis. Pain research & management : the journal of the Canadian Pain Society = journal de la societe canadienne pour le traitement de la douleur. 2010;15(4):224-8. Epub 2010/09/03.

  25. Creamer P, Lethbridge-Cejku M, Hochberg MC. Determinants of pain see if you can save severity in knee osteoarthritis: effect of demographic and psychosocial variables using 3 pain measures. The Journal of rheumatology. 1999;26(8):1785-92. Epub 1999/08/18.

  26. Creamer P, Lethbridge-Cejku M, Hochberg MC. Factors associated with functional impairment in symptomatic knee osteoarthritis. Rheumatology (Oxford, England). 2000;39(5):490-6. Epub 2000/06/15.

  27. Sharma L, Cahue S, Song J, Hayes K, Pai YC, Dunlop D. Physical functioning over three years in knee osteoarthritis: role of psychosocial, local mechanical, and neuromuscular factors. Arthritis and rheumatism. 2003;48(12):3359-70. Epub 2003/12/16.

  28. Association AG. Study Shows Long-term Use Of NSAIDs Causes Severe Intestinal Damage. [http://www.sciencedaily.com /releases/2005/01/050111 123706.htm] 2005 [cited January 16].