Glucosamine

Glucosamine
Names
IUPAC name
(3R,4R,5S)-3-Amino-6-(hydroxymethyl)oxane-2,4,5-triol
Other names
2-Amino-2-deoxy-glucose
Chitosamine
Identifiers
ATC code M01AX05
1723616
3416-24-8 Yes
ChEBI CHEBI:5417 
ChEMBL ChEMBL181132 
ChemSpider 388352 
DrugBank DB01296 Yes
EC number 222-311-2
720725
Jmol-3D images Image
KEGG D04334 
MeSH Glucosamine
PubChem 439213
UNII N08U5BOQ1K Yes
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
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
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] Glucosamine appears to be safe for use as a dietary supplement; effectiveness has not been established for any condition. In the US it is one of the most common non-vitamin, non-mineral, dietary supplements used by adults.[3]

Medical uses

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.[4] 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.[5]

Glucosamine, along with commonly used chondroitin, should not be used to treat patients who have symptomatic osteoarthritis of the knee as evidence shows that these treatments fail to provide relief for that condition.[6]

As is common with heavily promoted dietary supplements, the claimed benefits of glucosamine are based principally on laboratory studies. Clinical studies are divided, with some reporting relief from arthritic pain and stiffness, but larger well-constructed studies reporting no benefit above placebo.[7]

There is no evidence to date that consumption of glucosamine by sport participants will prevent or limit joint damage after injury.[8]

Adverse effects

One clinical study over three years showed that glucosamine in doses of 1500 mg per day is safe to use.[9] 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.[10]

Adverse effects, which are usually mild and infrequent, include stomach upset, constipation, diarrhea, headache and rash.[11] Nevertheless, there have been rare case reports of patients who have chronic liver disease and a worsening of their condition with glucosamine supplementation.[12] Interestingly, the mechanism of action is unknown. However, it is suspected that a possible hypersensitivity to the glucosamine might have occurred. In regards to adverse effects in pregnancy, only one study has investigated glucosamine in that population and found it to be safe.[13] As a precaution because of the lack of clinical studies, more information is needed before recommending glucosamine in pregnancy.

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.[14] 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.[15] Alternative, non-shellfish derived forms of glucosamine are available.[16]

Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[17] but several investigations have found no evidence that this occurs.[18][19][20] 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.[21] 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.[22][23][24]

Precautions

There have been few drug interactions with glucosamine and other medications but the most severe is its interaction with warfarin.[25] FDA and WHO medication report programs have cited multiple case reports of elevated international normalized ratio (INR) in individuals that are taking warfarin.[26] As a result, caution should be given if someone is on warfarin and is thinking about starting glucosamine.

Biochemistry

Glucosamine is naturally present in the shells of shellfish, animal bones, bone marrow, and fungi.[27] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[28] Specifically in humans, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glutamine—fructose-6-phosphate transaminase[29] as the first step of the hexosamine biosynthesis pathway.[30] 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.[17]

History

Glucosamine was first prepared in 1876 by Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid.[31][32][33] The stereochemistry was not fully determined until the 1939 work of Walter Haworth.[1][34]

Legal status

United States

In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans.[35] 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.[36] 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.[37]

Europe

In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate.[38] 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,[38] and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis indicate an acceptable safety profile.[39]

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.[40]

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.[41] 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.[42] The two class actions are still pending.

Research

Clinical trials on glucosamine and chondroitin

Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of cartilage, some have hoped that supplemental glucosamine could beneficially influence cartilage structure, and alleviate arthritis. Its use as a therapy for osteoarthritis appears safe, 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.

Possibility of bioavailability

Two studies (funded by the Rottapharm Group, Monza, Italy, who supplied the crystalline glucosamine sulfate) published in 2007 measured the concentrations of glucosamine in the synovial fluid and plasma after oral administration of glucosamine sulfate to both healthy volunteers and patients with osteoarthritis.[43][44]

In the first study, glucosamine sulfate was given to healthy volunteers at a range of doses (750, 1500 and 3000 mg) once daily. In the second study, oral glucosamine sulfate capsules (1500 mg) were given daily for two weeks to 12 patients with osteoarthritis. Glucosamine concentrations in plasma and synovial fluid increased significantly from baseline levels and the levels in the two fluids were highly correlated. The authors interpreted these levels could be biologically advantageous to articular cartilage, however the levels are still 10 - 100 fold lower than required to positively affect the cartilage (chondrocytes) to build new tissue.[45] Glucosamine sulfate uptake in synovial fluid may be as much as 20%, or could be negligible, indicating no biological significance.[46]

Veterinary medicine

Some studies have shown efficacy of glucosamine supplementation for dogs with osteoarthritis pain, particularly in combination with other nutraceuticals like chondroitin[47][48] while others have not.[49] A trial of oral combination capsules (glucosamine/chondroitin/manganese ascorbate) in dogs with osteoarthritis found no benefit on either gait analysis or subjective assessments by the veterinarian or owner.[49]

The use of glucosamine in equine medicine exists, but one meta-analysis judged extant research too flawed to be of value in guiding treatment of horses.[50]

A number of studies have measured the bioavailability of glucosamine after oral administration to horses. When given as a single oral dose (nine grams) with or without chondroitin sulfate (three grams) to ten horses, glucosamine (hydrochloride) was detected in the blood with a maximum level of 10.6 (+/- 6.9) micrograms per millilitre at two hours after dosing.[51] Another study examined both the serum and the joint synovial fluid after nasogastric (oral) or intravenous administration of 20 mg/kg glucosamine hydrochloride to eight adult horses.[52] Although joint fluid concentrations of glucosamine reached 9 - 15 micromolar following intravenous dosing, it was only 0.3 - 0.7 micromolar with nasogastric dosing. The authors calculated that these glucosamine synovial fluid levels achieved by the oral route were 500 fold lower than that required to have a positive effect on the metabolism of cartilage cells. A follow up study by the same research group compared glucosamine sulfate with glucosamine hydrochloride at the same dose (20 mg/kg) in eight horses and found a higher fluid concentration with the sulfate preparation (158 ng/mL compared to 89 ng/mL one hour post oral dose).[53] They concluded that these higher synovial fluid levels obtained with the sulfate derivative were still too low to have a relevant biological effect on articular cartilage.

A three-month trial of an oral dosage regime of a commercial preparation of glucosamine sulfate, chondroitin sulfate and methylsulfonylmethane was performed in veteran horses with no effect on gait stiffness, with exercise alone in the control group being effective.[54] The intravenous use of a combination of N-acetylglucosamine, pentosan polysulfate and sodium hyaluronate in horses with surgically-induced osteoarthritis saw improvements in xray changes to the cartilage but not histologically or in biochemical outcomes,[55] suggesting more evidence is needed for this combination and route of administration.

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" (PDF). National Center for Health Statistics. December 10, 2008. Retrieved 2009-08-16.
  4. ↑ Staff, FDA Last Updated April 11, 2013 Q&A on Dietary Supplements
  5. ↑ "Glucosamine sulfate: Effectiveness". Medline Plus. (2011)
  6. ↑ American Academy of Orthopaedic Surgeons (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Academy of Orthopaedic Surgeons), retrieved 19 May 2013, which cites
    • Jevsevar, DS; Brown, GA; Jones, DL; Matzkin, EG; Manner, PA; Mooar, P; Schousboe, JT; Stovitz, S; Sanders, JO; Bozic, KJ; Goldberg, MJ; Martin WR, 3rd; Cummins, DS; Donnelly, P; Woznica, A; Gross, L; American Academy of Orthopaedic, Surgeons (Oct 16, 2013). "The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition". The Journal of bone and joint surgery. American volume 95 (20): 1885–6. PMID 24288804.
    • Clegg, Daniel O.; Reda, Domenic J.; Harris, Crystal L.; Klein, Marguerite A.; O'Dell, James R.; Hooper, Michele M.; Bradley, John D.; Bingham, Clifton O.; Weisman, Michael H.; Jackson, Christopher G.; Lane, Nancy E.; Cush, John J.; Moreland, Larry W.; Schumacher, H. Ralph; Oddis, Chester V.; Wolfe, Frederick; Molitor, Jerry A.; Yocum, David E.; Schnitzer, Thomas J.; Furst, Daniel E.; Sawitzke, Allen D.; Shi, Helen; Brandt, Kenneth D.; Moskowitz, Roland W.; Williams, H. James (23 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.
    • Richmond, J; Hunter, D; Irrgang, J; Jones, MH; Levy, B; Marx, R; Snyder-Mackler, L; Watters WC, 3rd; Haralson RH, 3rd; Turkelson, CM; Wies, JL; Boyer, KM; Anderson, S; St Andre, J; Sluka, P; McGowan, R; American Academy of Orthopaedic, Surgeons (Sep 2009). "Treatment of osteoarthritis of the knee (nonarthroplasty)". The Journal of the American Academy of Orthopaedic Surgeons 17 (9): 591–600. PMC 3170838. PMID 19726743.
  7. ↑ Barrett, Stephen (22 July 2010). "Glucosamine and Chondroitin for Arthritis: Benefit is Unlikely". Quackwatch. Retrieved 13 July 2014.
  8. ↑ Hespel, P; Maughan, R. J.; Greenhaff, P. L. (2006). "Dietary supplements for football". Journal of sports sciences 24 (7): 749–61. doi:10.1080/02640410500482974. PMID 16766503.
  9. ↑ "Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial". The Lancet 357: 251–256. January 2011. doi:10.1016/S0140-6736(00)03610-2.
  10. ↑ Lafontaine-Lacasse M, Dore M, Picard, F; Doré; Picard (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.
  11. ↑ McFarlane, Gary J. Complementary and alternative medicines for the treatment of reheumatoid arthritis, osteoarthritis and fibromyalgia (PDF). ARC. pp. 44–46. ISBN 978-1-901815-13-9. Retrieved 29 April 2010.
  12. ↑ "Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease". World J Gastroenterol. 19: 5381–5384. Aug 28, 2013. doi:10.3748/wjg.v19.i32.5381. PMC 3752575. PMID 23983444.
  13. ↑ "Glucosamine use in pregnancy: an evaluation of pregnancy outcome.". Journal of Women's Health. 16 (3): 345–348. April 2007. doi:10.1089/jwh.2006.0149. PMID 17439379.
  14. ↑ Gray HC, Hutcheson PS, Slavin RG; Hutcheson; Slavin (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.
  15. ↑ "Kirkland Signature Extra Strength Glucosamine with MSM". Dietary Supplements Labels Database. U.S. National Library of Medicine. 3 February 2010. Archived from the original on 4 March 2010. Retrieved 23 April 2015.
  16. ↑ "Another vegetarian glucosamine launched in US". NutraIngredients-USA.com. Retrieved 27 October 2014.
  17. ↑ 17.0 17.1 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.
  18. ↑ Scroggie DA, Albright A, Harris MD; Albright; Harris (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.
  19. ↑ Tannis AJ, Barban J, Conquer JA; Barban; Conquer (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.
  20. ↑ 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.
  21. ↑ Anderson JW, Nicolosi RJ, Borzelleca JF; Nicolosi; Borzelleca (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.)
  22. ↑ 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.
  23. ↑ Pouwels MJ, Jacobs JR, Span PN, Lutterman JA, Smits P, Tack CJ; Jacobs; Span; Lutterman; Smits; Tack (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.
  24. ↑ Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE; Blinn; Nuite; Silbert; McAlindon (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.
  25. ↑ "GLUCOSAMINE HYDROCHLORIDE". http://naturaldatabase.therapeuticresearch.com/home.aspx?cs=NEWORDER&s=ND''. Therapeutic Research Faculty. Retrieved 3 November 2014.
  26. ↑ "Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database.". Pharmacotherapy 28: 540–8. April 2008. doi:10.1592/phco.28.4.540. PMID 18363538.
  27. ↑ "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.
  28. ↑ Roseman S (2001). "Reflections on glycobiology". J Biol Chem (FREE FULL TEXT) 276 (45): 41527–42. doi:10.1074/jbc.R100053200. PMID 11553646.
  29. ↑ "Glutamine—fructose-6-phosphate transaminase (isomerizing)".
  30. ↑ "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.
  31. ↑ Georg Ledderhose (1876). "Über salzsaures Glycosamin" [On glucosamine hydrochloride]. Berichte der deutschen chemischen Gesellschaft 9 (2): 1200–1201. doi:10.1002/cber.18760090251.
  32. ↑ Ledderhose G (1879). "Über Chitin und seine Spaltungs-produkte" [On chitin and its hydrolysis products]. Zeitschrift für physiologische Chemie ii: 213–227.
  33. ↑ Ledderhose G (1880). "Über Glykosamin". Zeitschrift für physiologische Chemie iv: 139–159.
  34. ↑ W. N. Haworth, W. H. G. Lake, S. Peat; Lake; Peat (1939). "The configuration of glucosamine (chitosamine)". Journal of the Chemical Society: 271–274. doi:10.1039/jr9390000271.
  35. ↑ Hubbard WK, Associate Commissioner of Policy and Planning (2012). "Letter Regarding the Relationship Between the Consumption of Glucosamine and/or Chondroitin Sulfate and a Reduced Risk of: Osteoarthritis; Osteoarthritis-related Joint Pain, Joint Tenderness, and Joint Swelling; Joint Degeneration; and Cartilage Deterioration(Docket No. 2004P-0059)". United States Department of Health and Human Services, Food and Drug Administration. Retrieved 14 May 2014.
  36. ↑ "Dietary Supplements". U.S. Food and Drug Administration. Retrieved December 10, 2009.
  37. ↑ Clinical trial number NCT00065377 for "Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People" at ClinicalTrials.gov
  38. ↑ 38.0 38.1 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.
  39. ↑ 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.
  40. ↑ "Glucosamine Settlement". www.glucosaminesettlement.com. Retrieved June 17, 2013.
  41. ↑ "21st Century Glucosamine/Chondroitin Triple Strength Class Action Lawsuit". www.topclassactions.com. Retrieved June 17, 2013.
  42. ↑ "Wal-Mart, Rite Aid Face Suit Over Glucosamine Promises". www.law360.com. Retrieved June 17, 2013.
  43. ↑ 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.
  44. ↑ Persiani S, Roda E, Rovati LC, Locatelli M, Giacovelli G, Roda A; Roda; Rovati; Locatelli; Giacovelli; Roda (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.
  45. ↑ Mroz, P. J.; Silbert, J. E. (2004). "Use of 3H-glucosamine and 35S-sulfate with cultured human chondrocytes to determine the effect of glucosamine concentration on formation of chondroitin sulfate". Arthritis & Rheumatism 50 (11): 3574–9. doi:10.1002/art.20609. PMID 15529373.
  46. ↑ Cohen MJ, Braun L (2007). Herbs & natural supplements: an evidence-based guide. Marrickville, New South Wales: Elsevier Australia. ISBN 0-7295-3796-X.
  47. ↑ Gupta, R. C.; Canerdy, T. D.; Lindley, J; Konemann, M; Minniear, J; Carroll, B. A.; Hendrick, C; Goad, J. T.; Rohde, K; Doss, R; Bagchi, M; Bagchi, D (2012). "Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: Pain evaluation by ground force plate". Journal of Animal Physiology and Animal Nutrition 96 (5): 770–7. doi:10.1111/j.1439-0396.2011.01166.x. PMID 21623931.
  48. ↑ d'Altilio, M; Peal, A; Alvey, M; Simms, C; Curtsinger, A; Gupta, R. C.; Canerdy, T. D.; Goad, J. T.; Bagchi, M; Bagchi, D (2007). "Therapeutic Efficacy and Safety of Undenatured Type II Collagen Singly or in Combination with Glucosamine and Chondroitin in Arthritic Dogs". Toxicology Mechanisms and Methods 17 (4): 189–96. doi:10.1080/15376510600910469. PMID 20020968.
  49. ↑ 49.0 49.1 ĀMoreau, M; Dupuis, J; Bonneau, N. H.; Desnoyers, M (2003). "Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis". The Veterinary record 152 (11): 323–9. PMID 12665145.
  50. ↑ 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.
  51. ↑ Du, J; White, N; Eddington, N. D. (2004). "The bioavailability and pharmacokinetics of glucosamine hydrochloride and chondroitin sulfate after oral and intravenous single dose administration in the horse". Biopharmaceutics & drug disposition 25 (3): 109–16. doi:10.1002/bdd.392. PMID 15083499.
  52. ↑ Laverty, S; Sandy, J. D.; Celeste, C; Vachon, P; Marier, J. F.; Plaas, A. H. (2005). "Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses". Arthritis and rheumatism 52 (1): 181–91. doi:10.1002/art.20762. PMID 15641100.
  53. ↑ Meulyzer, M; Vachon, P; Beaudry, F; Vinardell, T; Richard, H; Beauchamp, G; Laverty, S (2008). "Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride". Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society 16 (9): 973–9. doi:10.1016/j.joca.2008.01.006. PMID 18295513.
  54. ↑ Higler, M. H.; Brommer, H; l'Ami, J. J.; De Grauw, J. C.; Nielen, M; Van Weeren, P. R.; Laverty, S; Barneveld, A; Back, W (2013). "The effects of three-month oral supplementation with a nutraceutical and exercise on the locomotor pattern of aged horses". Equine veterinary journal 46: 611–7. doi:10.1111/evj.12182. PMID 24011144.
  55. ↑ Koenig, T. J.; Dart, A. J.; McIlwraith, C. W.; Horadagoda, N; Bell, R. J.; Perkins, N; Dart, C; Krockenberger, M; Jeffcott, L. B.; Little, C. B. (2014). "Treatment of Experimentally Induced Osteoarthritis in Horses Using an Intravenous Combination of Sodium Pentosan Polysulfate, N-Acetyl Glucosamine, and Sodium Hyaluronan". Veterinary Surgery 43 (5): 612–22. doi:10.1111/j.1532-950X.2014.12203.x. PMID 24819506.

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