Mg Water

MAGNESIUM ONLINE LIBRARY
The Magnesium Web Site

 

Healthy Water
  The Magnesium
  Online Library

The Magnesium Online Library
The Magnesium Online Library More
 

Center for Magnesium Education & Research, LLC

http://www.magnesiumeducation.com

Magnesium Symposium at Experimental Biology 2010

Program Announcement, April 24, 2010, Anaheim Convention Center

Featured Editorial from Life Extension Magazine, Sept. 2005:

How Many Americans Are Magnesium Deficient?
 

Complete Book by
Dr. Mildred S. Seelig:

Mg Deficiency in the Pathogenesis
of Disease
 

Free ebook
edited by Robert Vink and Mihai Nechifor
University of Adelaide Press
2011

Magnesium in the Central Nervous System
 

John Libbey Eurotext

Magnesium Research
Archives, 2003-Present
 

The legal battle for recognition of the importance of dietary magnesium:

Legal documents
 

Healthy Water Association

HWA Button Healthy Water Association--USA
AHWA Button Arab Healthy Water Association

 

THE MAGNESIUM
ONLINE LIBRARY

Paul Mason, Librarian
P.O. Box 1417
Patterson, CA 95363

Send Email to The Magnesium Online Library
Go to our Main Menu

 

 

Treatment of Fibromyalgia Syndrome with Super Malic®: A Randomized, Double Blind, Placebo Controlled, Crossover Pilot Study

I. JON RUSSELL, JOEL E. MICHALEK, JORGE D. FLECHAS, and GUY E. ABRAHAM

 

ABSTRACT. Objective. To study the efficacy and safety of Super Malic®, a proprietary tablet containing malic acid (200 mg) and magnesium (50 mg), in treatment of primary fibromyalgia syndrome (FM).

Methods. Twenty-four sequential patients with primary FM were randomized to a fixed dose (3 tablets bid), placebo controlled, 4-week/course, pilot trial followed by a 6-month, open label, dose escalation (up to 6 tablets bid) trial. A 2-week, medication free, washout period was required before receiving treatment, between blinded courses, and again before starting open label treatment. The 3 primary outcome variables were measures of pain and tenderness but functional and psychological measures were also assessed.

Results. No clear treatment effect attributable to Super Malic® was seen in the blinded, fixed low dose trial. With dose escalation and a longer duration of treatment in the open label trial, significant reductions in the severity of all 3 primary pain/tenderness measures were obtained without limiting risks.

Conclusions. These data suggest that Super Malic® is safe and may be beneficial in the treatment of patients with FM. Future placebo-controlled studies should utilize up to 6 tablets of Super Malic bid and continue therapy for at least 2 months. (J Rheumatol 1995;22:953-8)

Key Indexing Terms: FIBROMYALGIA MAGNESIUM MALIC ACID TREATMENT ATP

 

The development of new therapies for fibromyalgia (FM) has been substantially impaired by the lack of a proven etiology or pathogenesis for the disorder1. Clinicians typically employ various combinations of medications, exercise, rest, and psychological support. Limited benefit has been observed in controlled studies with 3 psychotropic drugs: amitriptyline2-4, cyclobenzaprine5,6, or alprazolam7 in relatively low dosage. Propionic acid nonsteroidal antinflammatory drugs, such as ibuprofen or naproxen have shown promise in combination with sedative hypnotic drugs but not as sole therapy8. While such chemical agents do exhibit some analgesic, anxiolytic, sedative, and antidepressant effects, the mechanisms responsible for their influence on FM symptoms are still uncertain.

One proposed explanation for the soft tissue pain experienced by patients with FM was that muscle energy metabolism may be compromised9-16. That possibility is not

excluded by normal skeletal muscle histologically17. It has even been suggested that abnormal blood flow may deprive muscle of sufficient oxygen18 and other nutrients. Histochemical analysis indicates that tender points in FM muscle are deficient in high energy phosphate (ATP)19. Nuclear magnetic resonance spectroscopy has suggested abnormal high energy phosphate metabolism in exercising FM muscle but that may be an artifact of poor physical conditioning21. More recently, our group has shown that red blood cells from FM are deficient in ATP relative to matched normal controls22. Muscle magnesium may also be deficient in FM23.

Malic acid, a naturally occurring, nontoxic, organic dicarboxylic acid, and magnesium are both known to be involved in the processes of generating ATP24. They play a pivotal role in mitochondrial ATP synthesis24. A rationale for the combined use of malic acid and magnesium in the treatment of FM was proposed by Abraham and Flechas24. They also reported dramatic relief from pain in FM with short term, open label administration of Super Malic®, which contains malic acid and magnesium hydroxide. The present study was designed to more rigorously test their hypothesis.

MATERIALS AND METHODS

Patients. Twenty-nine sequential patients with FM were evaluated at the screening visit (week -2) and found to meet the American College of Rheumatology (ACR) criteria25 for primary FM. After informed consent, patients were asked to discontinue all medications used to treat PM symptoms. The protocol was approved and monitored by the Institutional Review Board.

Medications. Super Malic (Optimox Corporation, Torrance, CA) contains a proprietary formulation of malic acid (200 mg) and magnesium hydroxide (50 mg)/tablet and is available without prescription in CA. The manufacturer provided an identically coated placebo that matched Super Malic with regard to appearance and taste. Acetaminophen was allowed under self- control at a dosage of 325 mg to 650 mg once/day for severe headache. No other analgesic or sedative hypnotic drugs were allowed during the initial placebo controlled trial. Patients were allowed to reintroduce prior therapies while continuing Super Malic during the final 4 months of the open label trial as indicated below.

Interventions. We describe 2 related trials: (1)a randomized, double blind, placebo controlled, 2-treatment period, crossover trial, and (2) a subsequent 6-month, open label, followup trial, in which the effects of Super Malic dosage escalation were assessed before and after resumption of prestudy medication.

Coded label trial. At entry into the initial placebo controlled trial, patients with FM were required to have been free of analgesic and sedative-hypnotic medications for the 2 weeks prior to baseline measurements. Those who successfully discontinued prestudy medications were randomized to 1 of the 2 treatment sequences: 12 patients to Super Malic followed by placebo (sequence MP), and 12 to placebo followed by Super Malic (sequence PM). They took 3 coded tablets bid for 4 weeks, followed by a 2-week washout and crossover to a 4-week treatment period with the other coded tablet at the same dosage. All clinical assessments were obtained by a single examiner UR) at the beginning and end of each 4-week trial period.

Open label trial. After completion of the placebo controlled trial, patients underwent another 2-week, medication free, washout period before beginning the open label trial. They then started therapy with 3 tablets of Super Malic bid and increased the dosage every 3-5 days until they experienced acceptable benefit or developed a symptom suspected of being a treatment related side effect.

After Month 2 of this open label trial, patients were allowed to reintroduce medications used for FM treatment before study entry. The purposes were to determine (1) whether patients would elect to resume their prior medications, and (2) whether continued treatment with Super Malic might increase the apparent effectiveness of those medications.

Outcome assessment. All 6 outcome measures used had been validated in prior studies. The 3 primary outcome measures were (I) patient self- assessment of pain on a 10 cm visual analog scale (VAS) (pain), (2) the tender point index (TPI), which is the sum of individual tenderness severities26 at each of the 18 standard ACR tender points, and (3) the tender point average (TPA), which is the mean value derived from dolorimeter readings (in kg) at each of the 18 ACR tender points

Three variables of secondary importance included (1) the Health Assessment Questionnaire (HAQ) score, (2) the Center for Epidemiologic Studies-Depression (CESD) Scale score and (3) the Hassle Scale score (Hassle)

Adverse effects. Any adverse event experienced was self-reported on the daily diary and later transferred by study staff to the case report form.

Sample size. Prospective sample size determinations were based on the results of a prior study conducted by the same team7. In that study, 15 patients receiving both ibuprofen and alprazolam experienced an average 7-point (30%) drop in TPI by the end of the blinded treatment period (Week 6). A parallel group of 14 patients receiving double placebo experienced an average 4.4-point (17.5%) drop in TPI. The standard deviations of the Week 0 to Week 6 changes in these 2 groups were 7.7 and 6.4, respectively.

Based on the results of a pilot study24, it was assumed Super Malic would be more effective than combined alprazolam and ibuprofen7. Pretreatment calculations indicated that 20 patients who completed both Super Malic and placebo interventions would provide 89% power for detecting a significant (p ≤ 0.05) 8-point (34%) difference in TPI between active and placebo interventions. The null hypothesis predicted that there would be no difference. To accommodate an estimated 20% loss to followup, the design called for a minimum of 24 patients at baseline.

Statistical analysis. SAS (SAS Institute, Cary, NC, 1993) software was used for analysis of variance and x2 tests. p Values > 0.05 and < 0.10 were considered borderline significant. Ninety-five percent confidence intervals for treatment group mean differences on continuously distributed variables were computed from least square means and the associated mean square error. All statistical tests were 2-sided at the 5% significance level.

The primary assessment of outcome for the study was based on the results from the blinded, placebo controlled trial, while the open label trial used the same measures to explore effects of Super Malic dosage titration and of its coadministration with more traditional medicinal therapies.

Analyses of placebo controlled trial followed the repeated measures analysis of variance procedure described by Ratkowsky, Evans, and Alldredge31. These analyses incorporated outcomes measured at each of 5 periods: at the end of the prestudy washout period (baseline, Week 0) at the end of the first treatment period (Week 4), at the end of the 2nd washout (Week 6), at the end of the 2nd treatment (Week 10), and at the end of the 3rd washout (Week 12). The output was in “mean response” and “mean carry over effect”/treatment period. This approach has the advantage of increased efficiency over analyses using fewer measurements, providing uncorrelated estimates of treatment and carryover effects. All analyses assume first order carryover effects, meaning that subsequent manifestations of treatment, if they existed, would not affect measurements taken more than 1 period later.

The assessment of efficacy during the open label trial individually compared responses at Months 2, 4 and 6 with the baseline values obtained following the final washout at Week 12 (redefined for the open label trial as Month 0 baseline).

Possible adverse effects from the study intervention and the influence of concomitant medications resumption during the open label trial were evaluated descriptively.

RESULTS

Of the 29 patients with FM who met study criteria at the screening visit (Week -2), 5 were excluded before the Week 0 baseline visit because they were unable to discontinue prestudy medications. Of the 24 patients with FM who were randomized, 4 were withdrawn before Week 10. Three of these decided not to continue at varying times between Week 0 and Week 4. The 4th patient dropped out after Week 6 but before Week 10.

Table 1 summarizes the baseline values for each of the demographic and outcome variables assessed among the 24 patients with FM who entered the coded trial and the 18 patients with FM who entered the open label trial. In separate analysis, demographic and clinical values from the 16 patients who completed both trials were compared with measures from the 13 subjects who dropped out at some point after the baseline (Week 0) evaluation. The dropouts did not significantly differ from the completing study patients with respect to any of the baseline variables (data not shown).

Guy Abraham Table I

The patients in this study were more severely affected than those in an earlier study performed in the same community7. The average values for pain (present study mean ± SD vs prior study: 7.3 ± 0.5 vs 6.1 ± 0.2), TPI (37.5 ± 2.0 vs 25.7 ± 1.1), and TPA (3.l ± 0.2 vs  4.1 ±0.1) were numerically worse among patients in the present trial. That was also true for the secondary variables. While the HAQ (1.4 ± 0.1 vs 1.3 ± 0.1) was only slightly higher, the CESD score (24.0 ± 2.6 vs 9.4 ± 0.6) was substantially higher. The distribution of scores on the CESD indicated that 62% of the 24 patients with FM had values greater than or equal to 18, which can be interpreted as indicating “possible clinical depression,” compared with only 5% in the previous trial7.

Baseline analyses on the blinded trial’s randomization into the 2 crossover treatment sequence groups showed that the 2 cohorts were comparable with regard to age, sex, ethnicity, and all of the baseline values from the clinical outcome measures.

No protocol violations were judged to have occurred for any randomized patient throughout the 2 trials. A few patients took allowed rescue medication (acetaminophen 325 mg, 1-2 doses in 24 hours) for headache or severe muscular pain, but most did not.

The treatment responses for each of the 3 primary and 3 secondary outcome measures in the blinded treatment trial are shown in Table 2. There were no significant carryover effects from placebo to Super Malic or vice versa. The data consistently failed to show significantly greater improvement during the Super Malic treatment period than during the placebo treatment period (see also Figure 1). Factoring in the usage of acetaminophen did not alter the results.

Guy Abraham Table II


Guy Abraham Figure 1

Eighteen of the 20 patients with FM who completed the coded trial entered the open label trial. One of those dropped out after Month 2; and another failed to take sufficient Super Malic on a vacation trip after Month 2. Thus, data from 18 patients were subjected to analysis at Month 2 and thereafter from 16 patients.

From Month 0 to Month 2 of the open label trial, the dosage of the Super Malic was raised until mean daily dosage at Month 2 was 7.2 tablets/day (range 3-10/day, with 4 taking 10/day), at Month 4 the mean dosage was 8.6 tablets/day (range 4-12/day, with 7 taking 10/day and 1 taking 12/day and at Month 6, the mean dosage was 8.8 tablets/day (range 4-14/day, with 6 taking 10/day, 1 taking 11/day, and 1 taking 14/day).

Some patients resumed prestudy medications after Month 2 as allowed in the open label trial protocol. At the Month 4 and 6 visits, 8 of the remaining 16 patients were taking such medication (e.g., by Month 4, 1 had resumed cyclobenzaprine 10 mg hs, 1 alprazolam 0.5 mg hs, 1 cortisone acetate 25 mg daily, 2 methocarbomal 780 mg hs, and 3 took ibuprofen 800-2,400 mg/day).

The mean values for the main outcome variables used in the open label trial are shown in Table 3. They reflect change with treatment for the 3 primary and 3 secondary outcome measures at Months 2 (n = 18) and 6 (n = 16). Significant improvements were observed at Month 2 in all 3 primary variables (pain, TPI, TPA) but not in any of the 3 secondary variables. Corresponding analysis of the same measures at Month 6 indicated persistence of improvement in all of the primary variables (see also Figure 1).

Guy Abraham Table III

A descriptive summary of adverse effects reported by patients is shown in Table 4. It indicates very low risk associated with the malic acid treatment. In fact, it was not clear that any adverse event was really treatment related. Of the 24 randomized patients, 13 recorded at least 1 adverse event during the 2 trials. When the code was broken on the blinded trial, it became apparent that none of the adverse events could be attributed to malic acid and/or magnesium. Gastrointestinal symptoms seemed to predominate, especially during the open label trial. Looser stools provided welcome relief from constipation in 2 cases while in 3 other patient they were easily managed by addition of bulk containing agents.

Guy Abraham Table IV

DISCUSSION

Malic acid is a naturally occurring asymmetric, organic, dicaboxylic acid molecule that exists in dextrorotatory (D) and levorotary (L) forms. It is widely distributed in the vegetable kingdom including concentrations of 4 to 8 g/l of apple juice, 90% being in L-configuration and 10 in the D-form Malic acid is available commercially in a racemic mixture with an LD of 3600 mg/kg body weight34.

Combinations of magnesium-hydroxide and malate have a wide margin of safety. Magnesium hydroxide compared favorably to the citrate, lactate and chloride form of magnesium in terms of bioavailability when administered orally35. Magnesium hydroxide at an oral dosage of 500 mg/day significantly increased muscle magnesium levels36. Super Malic was formulated to favor lymphatic absorption, mimicking parenteral administration. For a 50 kg person ingestion of 6 tablets of Super Malic would correspond to 24 mg of malate/kg body weight.

Using swimming time to exhaustion as an index of physical endurance, the optimal response in rats was observed with an oral dosage of 250 mg/kg body weight37. However mitochondrial respiration was stimulated with only 7.5 mg/kg body weight when intraperitoneal administration was used38.

All of the patients in this study met the published ACR criteria for primary FM25, 26 and exhibited the typical clinical features of that disorder. The patients were otherwise typical of FM populations with a female:male ratio of 7:1, and mean age of 49 years. The ethnic dist (62.5% Hispanic) was comparable to that of the overall San Antonio community (about 60% Hispanic). The greater severity of symptoms in this trial relative to the earlier one at this site may have resulted from a large number of tertiary referrals to IJR.

Sample size calculations for the double blind, placebo controlled, crossover study predicted that 20 patients with FM would be adequate to demonstrate a significant improvement with malic acid relative to placebo. This estimate was about one-third more conservative than the figure predicted by Abraham and Flechas24 with patients with FM given 600 mg malic acid twice daily. Therefore, the sample size chosen was considered realistic. Furthermore, the dropout rate in our study was exactly as predicted.

While the blinded, placebo controlled trial failed to show significant improvement in the 3 main outcome measures, the results from the open label trial were very encouraging. We attribute this pattern to use of a higher dosage and longer duration of treatment with Super Malic during the open label trial. Although about half of the patients in the open label trial resumed prestudy medications after Month 4, no clear benefit could be attributed to them since the overall change in symptoms from the Month 0 baseline was no greater at Month 6 than at Month 2.

None of the 3 secondary outcome measures displayed any response to coded Super Malic therapy. The borderline significant treatment effect in the HAQ appeared to result from a surprisingly strong placebo effect in the cohort first randomized to placebo and, therefore, cannot be counted as an indicator of malic acid efficacy.

The results of open label treatment with Super Malic seem to indicate that it may be beneficial on the painful FM symptoms in dosages in excess of 8 tablets/day for up to 6 months. Some tachyphylaxis cannot be excluded because concomitant medications were allowed during the last 4 months. A similar result was obtained with open label alprazolam and ibuprofen Therefore, one must wonder whether the observed improvement in both open label trials resulted in part from hopeful optimism. For whatever reason, benefit occurred while patients were receiving open label malic acid and magnesium. It is appropriate to recall that most medical care is also open label and this adjuvant therapy was associated with a minimum of risk.

Since the blinded trial results were not statistically significant, we cannot reject the null hypothesis for the 3 tablets bid dosage of Super Malic and we cannot confidently attribute the open label findings solely to the malic acid/magnesium combination. However, the benefits observed during the open label trial suggest that Super Malic may prove efficacious in a longer study in which it is administered in a higher daily dosage.

The mechanism by which malic acid and magnesium might be beneficial in patients with FM remains uncertain. Several possible roles for this combination were proposed by Abraham and Flechas24 to involve alterations in carbohydrate metabolism that would lead to increased production of ATP. Indeed, a series of recent reports detail the discovery of defects in carbohydrate metabolism among patients with FM42, 43, There is also evidence to suggest that energy generation may not be normal in FM since ATP is low in muscle tender points19 and in red cells22.

ACKNOWLEDGMENT

The authors thank Dani Presswood for editorial assistance.

REFERENCES

1. Russell IJ: Fibrositis/fibromyalgia syndrome. In: Hyde BMII, Goldstein JA, Levine PH, eds. The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome. Ottawa: The Nightingale Research Foundation, 1992:663-90.

2. Goldenberg DL, Felson DT, Dinerman H: A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum 1986;29: 1371-7.

3. Scudds RA, McCain GA, Rollman GB, Harth M: Improvements in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline. J Rheumatol 1989;19:98-103.

4. Jaeschke R, Adachi J, Guyatt G, Keller J, Wong B: Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials. J Rheumatol 1991:18:447-51.

5. Bennett RM, Gatter RA, Campbell SM, Andrews RP, Clark SR, Scarola JA: A comparison of cyclobenzaprine and placebo in the management of fibrositis. A double-blind controlled study. Arthritis Rheum 1988:31:1535-42.

6. Reynolds WJ, Moldofsky H, Saskin P. Lue PA: The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J Rheumatol 1991:18:452-4.

7. Russell IJ, Fletcher EM, Michalek JE, McBroom PC, Hester GO: Efficacy and safety of ibuprofen and alprazolam in the treatment of primary fibromyalgia/fibrositis syndrome: A double-blind placebo-controlled study. Arthritis Rheum 1991;34:552-60.

8. Yunus MB, Masi AT, Aldag JC: Short term effects of ibuprofen in primary fibromyalgia syndrome: a double blind, placebo controlled trial. J Rheumatol 1989;166:527-32.

9. Bennett RM, Clark SR, Goldberg L, et al: Aerobic fitness in patients with fibrositis. A controlled study of respiratory gas exchange and l33xenon clearance from exercising muscle. Arthritis Rheum 1989;32:454-60.

10. Mengshoel AM, Forre O, Komnaes HB: Muscle strength and aerobic capacity in primary fibromyalgia. Clin Exp Rheumatol 1990;8:475-9.

11. Henriksson KG: Muscle pain in neuromuscular disorders and primary fibromyalgia. Eur J Appl Physiol 1988;57:348-52.

12. Elert JE, Rantapaa-Dahlqvist SB, Henriksson-Larsen K, Gerdle B: Increased EMO activity during short pauses in patients with primary fibromyalgia. Scand J Rheumatol 1989;l8:321-3.

13. Elert JE, Rantapaa-Dahlqvist SB, Henriksson-Larsen K, Lorentzon R, Gentle BU: Muscle performance, electromyography and fibre type composition in fibromyalgia and work-related myalgia. Scand J Rheumatol 1992;21 :28-34.

14. Elert JE, Rantapaa-Dahlqvist SB, Henriksson-Larsen K, Gerdle B: Increased EMG activity during short pauses in patients with primary fibromyalgia. Scand J Rheumatol 1989;l8:321-3.

15. Bengtsson A, Cederblad 0, Larsson J: Carnitine levels in painful muscles of patients with fibromyalgia (letter). Clin Exp Rheumatol 1990;8:197-8.

16. Zidar J, Backman E, Bengtsson A, Henriksson KG: Quantitative EMG and muscle tension in painful muscles in fibromyalgia. Pain 1990;40:249-54.

17. Yunus MB, Kalyan-Raman UP, Masi AT, Aldag JC: Electron microscopic studies of muscle biopsy in primary fibromyalgia syndrome: A controlled and blinded study. J Rheumatol 1989;l6:97-101

18. Lund N, Bengtsson A, Thorborg P: Muscle tissue oxygen pressure in primary fibromyalgia. Scand J Rheumatol 1986

19. Bengtsson A, Henriksson KG, Larsson J: Reduced high energy phosphate levels in the painful muscles of patients with primary fibromyalgia. Arthritis Rheum 1986;29:817-21.

20. de Blecourt AC, Wolf RF, van Rijswijk MH, Kamman RL, Knipping AA, Mooyaart EL: In vivo 31P magnetic resonance spectroscopy (MRS) of tender points in patients with primary fibromyalgia syndrome. Rheumatol Int 1991;11:51-4.

21. Simms RW, Roy S, Skrinar G, et al: (31)P-NMR spectroscopy of muscle in fibromyalgia syndrome patients and sedentary controls. Arthritis Rheum 1993;37:794-800.

22. Russell IJ, Vipraio GA, Abraham GE: Red cell nucleotide abnormalities in fibromyalgia syndrome (abstr). Arthritis Rheum 1993;36:S223.

23. Clauw D, Ward K, Katz P, Rajan S: Muscle intracellular magnesium levels correlate with pain tolerance in fibromyalgia (FM) (abstr). Arthritis Rheum 1994;37:R29.

24. Abraham GE, Flechas JD: Management of fibromyalgia: Rationale for the use of magnesium and malic acid. J Nutrit Med 1992;3:49-59.

25. Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Arthritis Rheum 1990;33:160-72.

26. Russell IJ, Vipraio GA, Morgan WW, Bowden CL: Is there a metabolic basis for the fibrositis syndrome? Am J Med 1986:81:50-6.

27. Dinerman H, Goldenberg DL, Felson DT: A prospective evaluation of 118 patients with the fibromyalgia syndrome: prevalence of Raynaud’s phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal junction. J Rheumatol 1986;13:368-73.

28. Fries JF, Spitz F, Young DY: The dimensions of health outcomes: The health assessment questionnaire, disability and pain scales. J Rheumatol 1982,

29. Radloff LS: The CES-Scale: A self-report depression scale for research in the general population. Applied Physiological Measurements. Appl Physiol Meas 1977;1:385-401.

30. Dailey PA, Bishop GD, Russell IJ, Fletcher EM: Psychological stress and the fibrositis/fibromyalgia syndrome. J Rheumatol 1990;17:1380-5.

31. Ratkowsky DA, Evans MA, Alldredge JR: Cross-Over Experiments: Design. Analysis, and Application. New York: Marcel Dekker, 1993:110-5.

32. Lee HS, Wrolstad RE: Apple juice composition: Sugar, nonvolatile acid, and phenolic profiles. J Assoc Anal Chem 1988;7l:789-94.

33. Patel DM, Popp GT, Williamson S, Lund W: Malic acid. In: Handbook of Pharmaceutical Excipients. Washington: American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, London, England, 1986:176.

34. Domingo JL, Gomez JM, Llobet JM, Corbella J: Comparative effects of several chelating agents on the toxicity, distribution and excretion of aluminum. Hum Toxicol 1988;7:259-62.

35. Bohmer T, Roseth A, Holm H, Weberg-Teigen S, Wahl L: Bioavailability or oral magnesium supplementation in female students evaluated from elimination of magnesium in 24-hour urine. Magnesium Trace Elem 1990;9:272-8.

36. Sjogren A, Floren CH, Nilsson A: Oral administration of magnesium hydroxide to subjects with insulin-dependent diabetes mellitus: Effects on magnesium and potassium levels and on insulin requirements. Magnesium 1988;7: 117-22.

37. Dunaev VV, Tishkin VS, Milonova NP, Belay IM, Makarrenko AN, Garmash SN: Effect of malic acid salts on physical working capacity and its restoration after exhausting muscular work. Farmakol Toksikol 1988;51 :21-5.

38. Bobyleva-Guarriero V, Lardy HA: The role of malate in exercise-induced enhancement of mitochondrial respiration. Arch Biochem Biophys 1986:245:470-6. 1

39. Campbell SM, Clark S, Tindall EA, Forehand ME, Bennett RM: Clinical characteristics of fibrositis. I. A “blinded,” controlled study of symptoms and tender points. Arthritis Rheum 1983;26:817-24.

40. Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL: Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981:11:151-71.

41. Clark S, Campbell SM, Forehand ME, Tindall EA, Bennett R Clinical characteristics of fibrositis. II. A “blinded”: controlled study using standard psychological tests. Arthritis Rheum 1985;28:132-7.

42. Eisinger J, Ayavou T: Transketolase stimulation in fibromyalgia. J Am Coll Nutr 1990;9:56-7.

43. Eisinger J, Plantamura A, Ayavou T: Glycolysis abnormalities in fibromyalgia. J Am Coll Nutr 1994;13:144-8.


From the Rheumatology Section, Division of Clinical Immunology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas, USA.

Supported by a grant from OPTIMOX Corporation, Suite 406, 2720 Monterey Street, Torrance, Ct 90503.

I.J. Russell, MD. PhD, Associate Professor of Medicine, UTHSC, San Antonio; J.E. Michalek, PhD, Director Airforce Health Study, Armstrong Laboratory, Brooks Air Force Base, TX; J.D. Flechas, MD, MPH, private family practice, Hendersonville, NC; G.E. Abraham, MD, Medical Director, OPTIMOX Corporation, Torrance, CA, USA.

 

Address reprint requests to Dr. I.J. Russell, Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, 7X 78284-7874.

 

Submitted July 8, 1994 revision accepted November 14, 1994.


This page was first uploaded to The Magnesium Web Site on July 20, 200



http://www.mgwater.com/