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Glucosamine



Glucosamine
IUPAC name (3R,4R,5S,6R)- 3-Amino-6- (hydroxymethyl)oxane-2,4,5-triol
Other names 2-Amino-2-deoxy-D-glucose chitosamine
Identifiers
CAS number 3416-24-8
PubChem 439213
MeSH Glucosamine
SMILES C([C@@H]1[C@H]([C@@H]
([C@H](C(O1)O)N)O)O)O
Properties
Molecular formula C6H13NO5
Molar mass 179.17 g/mol
Melting point

150 °C, 423 K, 302 °F

Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is found as a major component of the exoskeletons of crustaceans and other arthropods, in fungi and many higher organisms and is one of the most abundant monosaccharides.[1] It is produced commercially by the hydrolysis of crustacean exoskeletons. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies.

Additional recommended knowledge

Contents

Biochemistry

Glucosamine was first identified in 1876 by Dr. Georg Ledderhose, but the stereochemistry was not fully defined until 1939 by the work of Walter Haworth.[1] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[2] Specifically, glucosamine-6-phosphate is synthesized from fructose-6-phosphate and glutamine[3] as the first step of the hexosamine biosynthesis pathway.[4] The end-product of this pathway is UDP-N-acetylglucosamine (UDP-GlcNAc), which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.

As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production. However, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease, remains unclear.[5]

Health effects

Oral glucosamine is commonly used for the treatment of osteoarthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness[6][7], despite the positive results evidenced in several prospective controlled clinical trials.

Use

A typical dosage of glucosamine salt is 1,500 mg per day. Glucosamine contains an amino group that is positively charged at physiological pH. The anion included in the salt may vary. Commonly sold forms of glucosamine are glucosamine sulphate and glucosamine hydrochloride. The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present and whether additional salts are included in the manufacturer's calculation.[8] Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane.

Glucosamine is a popular alternative medicine used by consumers for the treatment of osteoarthritis. Glucosamine is also extensively used in veterinary medicine as an unregulated but widely accepted supplement.[9]

Safety

Clinical studies have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish may wish to avoid it. However, since glucosamine is derived from the shells of these animals while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy.[10] Alternative sources using fungal fermentation of corn are available. Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[5] but several investigations have found no evidence that this occurs.[11][12][13]. A review conducted by Anderson et al in 2005 summarizes the effects of glucosamine on glucose metabolism in in vitro studies, the effects of oral administration of large doses of glucosamine in animals and the effects of glucosamine supplementation with normal recommended dosages in humans, concluding that glucosamine does not cause glucose intolerance and has no documented effects on glucose metabolism[14]. Other studies conducted in lean or obese subjects concluded that oral glucosamine at standard doses does not cause or significantly worsen insulin resistance or endothelial dysfunction[15].[16][17]

The U.S. National Institutes of Health is currently conducting a study of supplemental glucosamine in obese patients, since this population may be particularly sensitive to any effects of glucosamine on insulin resistance.[18]

In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans. Since glucosamine is classified as a dietary supplement in this country, safety and formulation are solely the responsibility of the manufacturer; evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition.[19]

In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulphate. In this case, evidence of safety and efficacy is required for the medical use of glucosamine and several guidelines have recommended its use as an effective and safe therapy for osteoarthritis. Actually, the Task Force of the European League Against Rheumatism (EULAR) committee recently granted glucosamine sulfate a level of toxicity of 5 in a 0-100 scale[20], and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis also confirm its excellent safety profile[21].

Bioavailability and pharmacokinetics

Two recent studies confirm that glucosamine is bioavailable both systemically and at the site of action (the joint) after oral administration of crystalline glucosamine sulphate in osteoarthritis patients. Steady state glucosamine concentrations in plasma and synovial fluid were correlated and in line with those effective in selected in vitro studies[22].[23]

Mechanisms of Action

The benefit of glucosamine sulfate in patients with osteoarthritis is likely the result of a number of effects including its anti-inflammatory activity[24][25], the stimulation of the synthesis of proteoglycans[26], and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes[27][28][29][30]

Clinical studies

There have been multiple clinical trials of glucosamine as a medical therapy for osteoarthritis, but results have been conflicting. The evidence both for and against glucosamine's efficacy has led to debate among physicians about whether to recommend glucosamine treatment to their patients.[31]

Multiple clinical trials in the 1980s and 1990s, all sponsored by the European patent-holder, Rottapharm, demonstrated a benefit for glucosamine. However, these studies were of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding.[32][33] Rottapharm then sponsored two large (at least 100 patients per group), three-year-long, placebo-controlled clinical trials of the Rottapharm brand of glucosamine sulfate. These studies both demonstrated a clear benefit for glucosamine treatment.[34][35] There was not only an improvement in symptoms but also an improvement in joint space narrowing on radiographs. This suggested that glucosamine, unlike pain relievers such as NSAIDs, can actually help prevent the destruction of cartilage that is the hallmark of osteoarthritis. On the other hand, several subsequent studies, independent of Rottapharm, but smaller and shorter, did not detect any benefit of glucosamine.[36][37]

Due to these controversial results, some reviews and meta-analyses have evaluated the efficacy of glucosamine. Richy and col performed a meta-analysis of randomized clinical trials in 2003 and found efficacy for glucosamine on VAS and WOMAC pain, Lequesne index and VAS mobility and good tolerability[38].

Recently, a review by Bruyere et al. about glucosamine and chondroitin sulfate for the treatment of knee and hip osteoarthritis concludes that both products act as valuable symptomatic therapies for osteoarthritis disease with some potential structure-modifying effects[39].

This situation led the National Institutes of Health to fund a large, multicenter clinical trial studying reported pain in osteoarthritis of the knee, comparing groups treated with chondroitin sulfate, glucosamine, and the combination, as well as both placebo and celecoxib.[40] The results of this 6-month trial found that patients taking glucosamine HCl, chondroitin sulfate, or a combination of the two had no statistically significant improvement in their symptoms compared to patients taking a placebo.[41] The group of patients who took celecoxib did have a statistically significant improvement in their symptoms. These results suggest that glucosamine and chondroitin did not effectively relieve pain in the overall group of osteoarthritis patients, but it should be interpreted with caution because most patients presented only mild pain (thus a narrow margin to appraise pain improvement) and because of an unusual response to placebo in the trial (60%). However, exploratory analysis of a subgroup of patients suggested that the supplements taken together (glucosamine and chondroitin sulfate) may be significantly more effective than placebo (79.2% versus 54%; p = 0.002) and a 10% higher than the positive control, in patients with pain classified as moderate to severe (see testing hypotheses suggested by the data).

In an accompanying editorial, Dr. Marc Hochberg also noted that "It is disappointing that the GAIT investigators did not use glucosamine sulfate ... since the results would then have provided important information that might have explained in part the heterogeneity in the studies reviewed by Towheed and colleagues"[42][43] But this concern is not shared by pharmacologists at the PDR who state, "The counter anion of the glucosamine salt (i.e. chloride or sulfate) is unlikely to play any role in the action or pharmacokinetics of glucosamine".[44] Thus the question of glucosamine's efficacy will not be resolved without further updates or trials.

In this respect, a 6-month double-blind, multicenter trial has been recently performed to assess the efficacy of glucosamine sulfate 1500 mg once daily compared to placebo and acetaminophen in patients with osteoarthritis of the knee (GUIDE study). The results showed that glucosamine sulfate improved the Lequesne algofunctional index significantly compared to placebo and the positive control. Secondary analyses, including the OARSI responder indices, were also significantly favorable for glucosamine sulfate[45].

A subsequent meta-analysis of randomized controlled trials, including the NIH trial by Clegg, concluded that hydrochloride is not effective and that there was too much heterogeneity among trials of glucosamine sulfate to draw a conclusion.[46]. In response to these conclusions, Dr. J-Y Reginster in an accompanying editorial suggests that the authors failed to apply the principles of a sound systematic review to the meta-analysis, but instead put together different efficacy outcomes and trial designs by mixing 4-week studies with 3-year trials, intramuscular/intraarticular administrations with oral ones, and low-quality small studies reported in the early 1980s with high-quality studies reported in 2007[47].

However, currently OARSI (OsteoArthritis Research Society International) is recommending glucosamine as the second most effective treatment for moderate cases of osteoarthritis. Likewise, recent European League Against Rheumatism practice guidelines for knee osteoarthritis grants to glucosamine sulfate the highest level of evidence, 1A, and strength of the recommendation, A.

References

  1. ^ a b Horton, Derek; Wander, J.D. (1980). The Carbohydrates Vol IB. New York: Academic Press, 727-728. ISBN 042-556351-5. 
  2. ^ Roseman S. "Reflections on glycobiology," J Biol Chem, 2001 November 9; 276(45):41527-42. PMID 11553646. Full Text Online
  3. ^ Ghosh S, Blumenthal HJ, Davidson E, Roseman S. "Glucosamine metabolism. V. Enzymatic synthesis of glucosamine 6-phosphate", J Biol Chem, 1960 May; . PMID 13827775. PDF online.
  4. ^ International Union of Biochemistry and Molecular Biology
  5. ^ a b Buse MG. "Hexosamines, insulin resistance, and the complications of diabetes: current status," Am J Physiol Endocrinol Metab, 2006 Jan; 290(1):E1-E8. PMID 16339923.
  6. ^ Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF, Plaas AH. "Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses," Arthritis Rheum, 2005 Jan; 52(1):181-91. PMID 15641100.
  7. ^ Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE. "Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness," Ann Rheum Dis. 2006 Feb; 65(2):222-6. PMID 16079170.
  8. ^ PDR Health
  9. ^ Nolen RS. "Facing crackdown, dietary supplement companies promise changes," JAVMA News. 2002 August 15.
  10. ^ Gray H, Hutcheson P, Slavin R. "Is glucosamine safe in patients with seafood allergy?" J Allergy Clin Immunol, 2004; 114(2):459-60. PMID 15341031.
  11. ^ Scroggie DA, Albright A, Harris MD. "The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial," Arch Intern Med, 2003 July 14; 163(13):1587-90. PMID 12860582.
  12. ^ Tannis A.J, Barban J, Conquer J.A. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004; 12 (6): 506-511.
  13. ^ Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, Caputo M, Mc Clain D, Del Prato S, Giaccari A, Muggeo M, Bonora E, Bonadonna RC. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes. 2000 49; 926-935.
  14. ^ Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food and Chemical Toxicology. 2005; 43 (2): 187- 201
  15. ^ Muniyappa R, Kame RJ, Hall G, Grandon SK, Bronstein JA, Ver M.R, Hortin GL, Quon MJ. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes. 2006; 55 (11): 3142-50.
  16. ^ Powels M, Jacobs JR, Span PN, Lutterman JA, Smits P, Tack CJ. Short – term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab. 2001; 86:2099-2103.
  17. ^ Biggee B, Blinn CM, Nuite M, Sibert JE, Mc Alindon TE. Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis. 2007, 66 (2): 260-262.
  18. ^ Clinicaltrials.gov
  19. ^ FDA
  20. ^ Jordan KM, Arden NK. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis, 2003; 62:1145–1155
  21. ^ Zhang W, Moskowitz RW. OARSI recommendations for the management of hip and knee osteoarthritis, Part I: Critical appraisal of existing treatment guidelines and systematic review of current research evidence activity. Osteoarthritis and Cartilage, 2007; 15: 981- 999
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  23. ^ Persiani S, Rotini R, Trisolino G, Rovati LC, Locatelli M, Paganini D, Antonioli D, Roda A. Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose1 OsteoArthritis and Cartilage (2007) 15, 764-772
  24. ^ Largo R, et al. Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2003 Apr;11(4):290-8.
  25. ^ Chan PS, et al. Short-term gene expression changes in cartilage explants stimulated with interleukin beta plus glucosamine and chondroitin sulfate. J Rheumatol. 2006 Jul;33(7):1329-40.
  26. ^ Bassleer C, et al. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage. 1998 Nov;6(6):427-34.
  27. ^ Dodge GR, et al. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthritis Cart. 2003 Jun;11(6):424-32.
  28. ^ Chan PS, et al. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res. 2005; 66 (11):1870-6.
  29. ^ Uitterlinden EJ, et al. Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage. 2006 Mar;14(3):250-7.
  30. ^ Chu SC, et al. Glucosamine sulfate suppresses the expressions of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis. Clin Chim Acta 2006 Oct;372(1-2):167-72.
  31. ^ Manson and Rahman, 2004
  32. ^ Adams ME. "Hype about glucosamine," Lancet, 1999 July 31;354(9176):353-4. PMID 10437858.
  33. ^ McAlindon TE, LaValley MP, Gulin JP, Felson DT. "Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-analysis," JAMA, 2000; 283:1469-1475. PMID 10732937.
  34. ^ Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C. "Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial," Lancet, 2001 January 27; 357(9252):251-6. PMID 11214126.
  35. ^ Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. "Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study," Arch Intern Med, 2002 October 14;162(18):2113-23. PMID 12374520.
  36. ^ Hughes R, Carr A. "A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee," Rheumatology (Oxford), 2002 Mar; 41(3):279-84. Full text online.
  37. ^ Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, Pope J, Hong P, Grant E, Esdaile JM, "Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis," Arthritis Rheum. 2004 October 15; 51(5):738-45. PMID 15478160.
  38. ^ Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster J-Y.Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis. A comprehensive meta-analysis. Archives of Internal Medicine 2003; 163: 1514-1522
  39. ^ Bruyere O., Reginster J.Y. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging, 2007; 24 (7): 573-580
  40. ^ Clinicaltrials.gov
  41. ^ Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis," New Engl J Med, 2006 February 23; 354(8):795-808. PMID 16495392.
  42. ^ PMID 15846645
  43. ^ Hochberg MC. "Nutritional supplements for knee osteoarthritis--still no resolution," N Engl J Med, 2006 February 23; 354(8):858-60. PMID 16495399.
  44. ^ PDR Health
  45. ^ Herrero-Beaumont G et al. Glucosamine Sulfate in the Treatment of Knee Osteoarthritis Symptoms. A Randomized, Double-Blind, Placebo-Controlled Study Using Acetaminophen as a Side Comparator. Arthritis & rheumatism, 2007; 56 (2): 555–567
  46. ^ Vlad SC, Lavalley MP, McAlindon TE, Felson DT (2007). "Glucosamine for pain in osteoarthritis: Why do trial results differ?" 56 (7): 2267-2277. doi:10.1002/art.22728. PMID 17599746.
  47. ^ Reginster J.Y. The efficacy of glucosamine sulfate in osteoarthritis: financial and nonfinancial conflict of interest. Arthritis & Rheumatism, 2007; 56 (7): 2105-2110


 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Glucosamine". A list of authors is available in Wikipedia.
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