Glucosamine

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Glucosamine
IUPAC name

(3R,4R,5S)-3-Amino-6-(hydroxymethyl)oxane-2,4,5-triol

Other names

2-Amino-2-deoxy-glucose
Chitosamine

Identifiers
CAS number 3416-24-8 YesY
PubChem 439213
ChemSpider 388352 N
UNII N08U5BOQ1K YesY
EC number 222-311-2
DrugBank DB01296
KEGG D04334 N
MeSH Glucosamine
ChEBI CHEBI:5417 N
ChEMBL CHEMBL181132 N
ATC code M01AX05
Beilstein Reference 1723616
Gmelin Reference 720725
Jmol-3D images {{#if:N[C@H]1C(O)OC(CO)[C@@H](O)[C@@H]1O|Image 1
Properties
Molecular formula C6H13NO5
Molar mass 179.17 g mol−1
Density 1.563 g/mL
Melting point 150 °C; 302 °F; 423 K
log P -2.175
Acidity (pKa) 12.273
Basicity (pKb) 1.724
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, as well as the cell walls of fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides.[1] It is produced commercially by the hydrolysis of crustacean exoskeletons or, less commonly by fermentation of a grain such as corn or wheat.[2] In the US it is one of the most common non-vitamin, non-mineral, dietary supplements used by adults.[3]

Biochemistry

Glucosamine is naturally present in the shells of shellfish, animal bones, bone marrow, and fungi.[4]

Glucosamine was first prepared in 1876 by Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid.[5][6][7] The stereochemistry was not fully determined until the 1939 work of Walter Haworth.[1][8] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[9] Specifically, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glucosamine-6-phosphate deaminase[10] as the first step of the hexosamine biosynthesis pathway.[11] The end-product of this pathway is Uridine diphosphate 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.[12]

Use in nutrition and medicine

Oral glucosamine is a dietary supplement and is not a pharmaceutical drug. It is illegal in the US to market any dietary supplement as a treatment for any disease or condition.[13] Glucosamine is marketed to support the structure and function of joints and the marketing is targeted to people suffering from osteoarthritis. Commonly sold forms of glucosamine are glucosamine sulfate, glucosamine hydrochloride, and N-acetylglucosamine. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Of the three commonly available forms of glucosamine, only glucosamine sulfate is given a "likely effective" rating for treating osteoarthritis.[14]

Evaluation as osteoarthritis treatment

Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, some have hoped that supplemental glucosamine could beneficially influence cartilage structure, and alleviate arthritis. Its use as a therapy for osteoarthritis appears safe,[citation needed] but there is no unequivocal evidence for its effectiveness. There have been multiple clinical trials testing glucosamine as a potential medical therapy for osteoarthritis, but the results have not supported its use.

In general, the clinical trials of the mid-1990s that furnished positive results showing glucosamine efficacy were later deemed to be of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding.[15][16] At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis.[17][18]

A Cochrane 2005 meta-analysis of glucosamine therapy for osteoarthritis found that only the Rotta brand of glucosamine appeared to be superior to placebo in the treatment of pain and functional impairment resulting from symptomatic osteoarthritis.[19] However, when the low quality and older studies were discounted and only those using the highest-quality design were considered, there was no difference from placebo treatment.[20]

In 2006, the U.S. National Institutes of Health (NIH) funded a 24 week, 12.5 million-dollar multicenter clinical trial (the GAIT trial) to study the effect of chondroitin sulfate, glucosamine hydrochloride, chondroitin/glucosamine in combination, and celecoxib as a treatment for knee-pain in two groups of patients with osteoarthritis of the knee: Patients with mild pain (n=1229), and patients with moderate to severe pain (n=354).[21] When the data from both groups were pooled and analyzed, there was no statistically significant difference between groups taking glucosamine HCl, chondroitin sulfate, glucosamine/chondroitin; and those taking a placebo. The authors of the study analyzed the moderate-to-severe pain group and found that "the difference did not reach statistical significance."[22] Another systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies. [23]

In a follow-up study in 2008, 572 patients from the GAIT trial continued their supplementation for 2 years. After 2 years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo.[24] In another 2-year follow-up study involving 662 patients from the GAIT trial, published in 2010, there was neither significant pain reduction nor improved function when comparing glucosamine and/or chondroitin to a placebo.[25]

Due to the controversy engendered by these results, additional meta-analyses have been undertaken in an attempt to evaluate them.[26] One published in 2013 in the British Medical Journal arrived at the following conclusions.
Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.[27]

Adverse effects

Clinical studies have consistently reported that glucosamine appears safe.[citation needed] However, a recent Université Laval study shows that people taking glucosamine tend to go beyond recommended guidelines, as they do not feel any positive effects from the dietary supplement. Beyond recommended dosages, researchers found in preliminary studies that glucosamine may damage pancreatic cells, possibly increasing the risk of developing diabetes.[28]

Adverse effects, which are usually mild and infrequent, include stomach upset, constipation, diarrhea, headache and rash.[29]

Since glucosamine is usually derived from the shells of shellfish while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy.[30] However, many manufacturers of glucosamine derived from shellfish include a warning that those with a seafood allergy should consult a healthcare professional before taking the product.[31][32] Alternative, non-shellfish derived forms of glucosamine are available.[33][34]

Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[12] but several investigations have found no evidence that this occurs.[35][36][37] A manufacturer-supported 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.[38] 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.[39][40][41]

Use in veterinary medicine

Use of glucosamine in veterinary medicine exists, but one study judged extant research too flawed to be of value in guiding treatment of horses.[42]

Possibility of bioavailability

Recent studies provide preliminary evidence that glucosamine may be bioavailable in the synovial fluid after oral administration of crystalline glucosamine sulfate in osteoarthritis patients, as steady state glucosamine concentrations in plasma and synovial fluid were correlated.[43][44] If eventually proven, glucosamine sulfate uptake in synovial fluid may be as much as 20%, or as little as a negligible amount, indicating no biological significance.[45]

Legal status

United States

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 the US, 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.[46] 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.[47]

Europe

In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate.[48] 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. The Task Force of the European League Against Rheumatism (EULAR) committee has granted glucosamine sulfate a level of toxicity of 5 in a 0-100 scale,[48] and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis indicate an acceptable safety profile.[49]

Class action lawsuits

In 2013, without admitting fault, manufacturer Rexall Sundown, Inc., and NBTY, Inc., agreed to pay up to $2 million to settle consumer claims related to the wording of certain claims on the packaging of glucosamine bottles sold at Costco under the Kirkland label.[50]

In August 2012, a class action lawsuit was filed in New York claiming that 21st Century Healthcare, Inc. falsely advertises that its “Glucosamine 750 Chondroitin 600 Triple Strength” dietary supplements will restore lost cartilage.[51] In April 2013, a San Diego man launched a proposed class action lawsuit in California Federal Court accusing Nutramax Laboratories, Walmart and Rite Aid of falsely advertising the effectiveness of glucosamine.[52] The two class actions are still pending.

See also

References

  1. ↑ 1.0 1.1 Pigman WW, Horton D, Wander JD (1980). The Carbohydrates. Vol IB. New York: Academic Press. pp. 727–728. ISBN 9780125563512. 
  2. ↑ "Vegan Glucosamine FAQ". Retrieved 2010-12-08. 
  3. ↑ "Complementary and Alternative Medicine Use Among Adults and Children: United States, 2007". National Center for Health Statistics. December 10, 2008. Retrieved 2009-08-16. 
  4. ↑ "Scientific Opinion of the Panel on Dietetic Products Nutrition and Allergies on a request from the European Commission on the safety of glucosamine hydrochloride from Aspergillus niger as food ingredient". The EFSA Journal 1099: 1–19. 2009. 
  5. ↑ Georg Ledderhose (1876). "Über salzsaures Glycosamin" [On glucosamine hydrochloride]. Berichte der deutschen chemischen Gesellschaft 9 (2): 1200–1201. doi:10.1002/cber.18760090251. 
  6. ↑ Ledderhose G (1878–9). "Über Chitin und seine Spaltungs-produkte" [On chitin and its hydrolysis products]. Zeitschrift für physiologische Chemie ii: 213–227. 
  7. ↑ Ledderhose G (1880). "Über Glykosamin". Zeitschrift für physiologische Chemie iv: 139–159. 
  8. ↑ W. N. Haworth, W. H. G. Lake, S. Peat (1939). "The configuration of glucosamine (chitosamine)". Journal of the Chemical Society: 271–274. doi:10.1039/jr9390000271. 
  9. ↑ Roseman S (2001). "Reflections on glycobiology". J Biol Chem (free full text) 276 (45): 41527–42. doi:10.1074/jbc.R100053200. PMID 11553646. 
  10. ↑ Ghosh S, Blumenthal HJ, Davidson E, Roseman S (1 May 1960). "Glucosamine metabolism. V. Enzymatic synthesis of glucosamine 6-phosphate". J Biol Chem 235 (5): 1265–73. PMID 13827775. 
  11. ↑ "UDP-N-acetylglucosamine Biosynthesis". Recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology on the Nomenclature and Classification of Enzymes by the Reactions they Catalyse. International Union of Biochemistry and Molecular Biology. 2002. Retrieved 2012-09-10. 
  12. ↑ 12.0 12.1 Buse MG (2006). "Hexosamines, insulin resistance, and the complications of diabetes: current status". Am. J. Physiol. Endocrinol. Metab. 290 (1): E1–E8. doi:10.1152/ajpendo.00329.2005. PMC 1343508. PMID 16339923. 
  13. ↑ Staff, FDA Last Updated April 11, 2013 Q&A on Dietary Supplements
  14. ↑ "Glucosamine sulfate: Effectiveness". Medline Plus.  (2011)
  15. ↑ Adams ME (July 1999). "Hype about glucosamine". Lancet 354 (9176): 353–4. doi:10.1016/S0140-6736(99)90040-5. PMID 10437858. 
  16. ↑ McAlindon TE, LaValley MP, Gulin JP, Felson DT (March 2000). "Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis". Journal of the American Medical Association 283 (11): 1469–75. doi:10.1001/jama.283.11.1469. PMID 10732937. 
  17. ↑ Hughes R, Carr A (March 2002). "A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee". Rheumatology (Oxford, England) 41 (3): 279–84. doi:10.1093/rheumatology/41.3.279. PMID 11934964. 
  18. ↑ Cibere J, Kopec JA, Thorne A et al. (October 2004). "Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis". Arthritis and Rheumatism 51 (5): 738–45. doi:10.1002/art.20697. PMID 15478160. 
  19. ↑ Towheed TE, Maxwell L, Anastassiades TP, et al. (2005). "Glucosamine therapy for treating osteoarthritis". Cochrane Database of Systematic Reviews (2): CD002946 (Orig. rev.). doi:10.1002/14651858.CD002946. PMID 15846645.
  20. ↑ Dahmer S, Schiller RM (August 2008). "Glucosamine". American Family Physician 78 (4): 471–6. PMID 18756654. 
  21. ↑ ClinicalTrials.gov NCT00032890 Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)
  22. ↑ Clegg DO, Reda DJ, Harris CL et al. (February 2006). "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis". New England Journal of Medicine 354 (8): 795–808. doi:10.1056/NEJMoa052771. PMID 16495392. 
  23. ↑ Vlad SC, LaValley MP, McAlindon TE and Felson DT (2007). "Glucosamine for pain in osteoarthritis; why do trial results differ?". Arthritis & Rheumatism 56 (7): 2267–77. doi:10.1002/art.22728. PMID 17599746. 
  24. ↑ Sawitzke AD; Shi, H; Finco, MF; Dunlop, DD; Bingham Co, 3rd; Harris, CL; Singer, NG; Bradley, JD et al. (October 2008). "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 58 (10): 3183–91. doi:10.1002/art.23973. PMC 2836125. PMID 18821708. 
  25. ↑ Sawitzke AD; Shi, H; Finco, MF; Dunlop, DD; Harris, CL; Singer, NG; Bradley, JD; Silver, D et al. (August 2010). "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". Arthritis and Rheumatism 69 (8): 1459–64. doi:10.1136/ard.2009.120469. PMC 3086604. PMID 20525840. 
  26. ↑ Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY (July 2003). "Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis". Archives of Internal Medicine 163 (13): 1514–22. doi:10.1001/archinte.163.13.1514. PMID 12860572. 
  27. ↑ Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Trelle S (2010). "Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis". British Medical Journal 341 (sep16 2): c4675. doi:10.1136/bmj.c4675. PMC 2941572. PMID 20847017. "Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space" 
  28. ↑ Lafontaine-Lacasse M, Dore M, Picard, F (January 2011). "Hexosamines stimulate apoptosis by altering Sirt1 action and levelsin rodent pancreatic β-cells". Journal of Endocrinology 208 (1): 41–9. doi:10.1677/JOE-10-0243. PMID 20923823. 
  29. ↑ McFarlane, Gary J. Complementary and alternative medicines for the treatment of reheumatoid arthritis, osteoarthritis and fibromyalgia. ARC. pp. 44–46. ISBN 978-1-901815-13-9. Retrieved 29 April 2010. 
  30. ↑ Gray HC, Hutcheson PS, Slavin RG (August 2004). "Is glucosamine safe in patients with seafood allergy?". The Journal of Allergy and Clinical Immunology 114 (2): 459–60. doi:10.1016/j.jaci.2004.05.050. PMID 15341031. 
  31. ↑ http://dietarysupplements.nlm.nih.gov/dietary/detail.jsp?name=Kirkland+Signature+Extra+Strength+Glucosamine+with+MSM&contain=11001019&pageD=brand
  32. ↑ http://dietarysupplements.nlm.nih.gov/dietary/detail.jsp?name=Whole+Health+Glucosamine+Sulfate+750+mg&contain=23008048&pageD=brand[]
  33. ↑ http://www.nutraingredients-usa.com/Industry/Another-vegetarian-glucosamine-launched-in-US[]
  34. ↑ http://www.cosmeticsdesign.com/Market-Trends/New-source-for-glucosamine[]
  35. ↑ Scroggie DA, Albright A, Harris MD (July 2003). "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". Archives of Internal Medicine 163 (13): 1587–90. doi:10.1001/archinte.163.13.1587. PMID 12860582. 
  36. ↑ Tannis AJ, Barban J, Conquer JA (June 2004). "Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals". Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society 12 (6): 506–11. doi:10.1016/j.joca.2004.03.001. PMID 15135147. 
  37. ↑ Monauni T, Zenti MG, Cretti A et al. (June 2000). "Effects of glucosamine infusion on insulin secretion and insulin action in humans". Diabetes 49 (6): 926–35. doi:10.2337/diabetes.49.6.926. PMID 10866044. 
  38. ↑ Anderson JW, Nicolosi RJ, Borzelleca JF (February 2005). "Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy". Food and Chemical Toxicology 43 (2): 187–201. doi:10.1016/j.fct.2004.11.006. PMID 15621331.  (Study financially supported by Cargill Incorporated, a manufacturer of glucosamine as acknowledged in the paper.)
  39. ↑ Muniyappa R, Karne RJ, Hall G et al. (November 2006). "Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects". Diabetes 55 (11): 3142–50. doi:10.2337/db06-0714. PMID 17065354. 
  40. ↑ Pouwels MJ, Jacobs JR, Span PN, Lutterman JA, Smits P, Tack CJ (May 2001). "Short-term glucosamine infusion does not affect insulin sensitivity in humans". The Journal of Clinical Endocrinology and Metabolism 86 (5): 2099–103. doi:10.1210/jc.86.5.2099. PMID 11344213. 
  41. ↑ Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE (February 2007). "Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis". Annals of the Rheumatic Diseases 66 (2): 260–2. doi:10.1136/ard.2006.058222. PMC 1798503. PMID 16818461. 
  42. ↑ Pearson, W; Lindinger, M (2009). "Low quality of evidence for glucosamine-based nutraceuticals in equine joint disease: Review of in vivo studies". Equine veterinary journal 41 (7): 706–12. doi:10.2746/042516409X424153. PMID 19927591. 
  43. ↑ Persiani S, Roda E, Rovati LC, Locatelli M, Giacovelli G, Roda A (December 2005). "Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man". Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society 13 (12): 1041–9. doi:10.1016/j.joca.2005.07.009. PMID 16168682. 
  44. ↑ Persiani S, Rotini R, Trisolino G et al. (July 2007). "Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose". Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society 15 (7): 764–72. doi:10.1016/j.joca.2007.01.019. PMID 17353133. 
  45. ↑ Cohen MJ, Braun L (2007). Herbs & natural supplements: an evidence-based guide. Marrickville, New South Wales: Elsevier Australia. ISBN 0-7295-3796-X. 
  46. ↑ "Dietary Supplements". U.S. Food and Drug Administration. Retrieved December 10, 2009. 
  47. ↑ ClinicalTrials.gov NCT00065377 Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People
  48. ↑ 48.0 48.1 Jordan KM, Arden NK, Doherty M et al. (December 2003). "EULAR Recommendations 2003: a 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)". Annals of the Rheumatic Diseases 62 (12): 1145–55. doi:10.1136/ard.2003.011742. PMC 1754382. PMID 14644851. 
  49. ↑ Zhang W, Moskowitz RW, Nuki G et al. (September 2007). "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". Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society 15 (9): 981–1000. doi:10.1016/j.joca.2007.06.014. PMID 17719803. 
  50. ↑ "Glucosamine Settlement". www.glucosaminesettlement.com. Retrieved June 17, 2013. 
  51. ↑ "21st Century Glucosamine/Chondroitin Triple Strength Class Action Lawsuit". www.topclassactions.com. Retrieved June 17, 2013. 
  52. ↑ "Wal-Mart, Rite Aid Face Suit Over Glucosamine Promises". www.law360.com. Retrieved June 17, 2013. 

External links

Types
Vitamins and
"minerals" (chemical elements)
Other common ingredients
Related articles
Non-steroidal anti-inflammatory drugs (NSAIDs) (primarily M01A and M02A, also N02BA)
Pyrazolidines
Salicylates
Acetic acid derivatives
and related substances
Oxicams
Propionic acid derivatives
(profens)
N-Arylanthranilic acids
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Items listed in bold indicate initially developed compounds of specific groups. †Withdrawn drugs. ‡Veterinary use medications.

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