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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, cell walls in fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides. It is produced commercially by the hydrolysis of crustacean exoskeletons or, less commonly by fermentation of a grain such as corn or wheat. In the US it is one of the most commonly used non-vitamin, non-mineral, natural products used by adults as a complementary or alternative medicine.

Biochemistry

Glucosamine was first prepared in 1876 by Dr. Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid. The stereochemistry was not fully defined until 1939 by the work of Walter Haworth. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. Specifically, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. 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.

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 prevent cartilage degeneration and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness. A Cochrane 2005 meta-analysis of glucosamine for osteoarthritis found that only "Rotta" preparations (including older studies) found beneficial effects for pain and functional impairment. It also found that when only the studies using the highest-quality design were considered, there was no effect above placebo. In addition, in vitro analysis of glucosamine has revealed that glucosamine inhibits cartilage cell characteristics. Studies reporting beneficial effects have generally used glucosamine sulfate. Chondroitin sulfate is sometimes used in conjunction, and animal studies suggest that chondroitin may increase its efficacy. Two recent randomized, double-blind controlled trials have found no effect beyond placebo in reducing pain, while one found an effect beyond placebo.

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 sulfate 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. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Glucosamine and chondroitin are "apparently poor candidates for transdermal [through the skin] absorption", but glucosamine's metabolite N-acetyl-D-glucosamine (NAG) appears to be a better candidate. The ability of NAG to permeate the skin is enhanced by ethanol and dimethyl sulfoxide (DMSO). DMSO is used to help deliver drugs in veterinary care, but is not approved for use on humans.

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.

Safety

Clinical studies have consistently reported that glucosamine appears safe.
Allergy
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. Alternative sources using fungal fermentation of corn are available.

Glucose metabolism
Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway, but several investigations have found no evidence that this occurs. 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 nodocumented effects on glucose metabolism. It should be mentioned that the authors of the above mentioned review paper (Anderson et. al.) were financially supported by Cargill, Incorporated, Eddyville, IA, a manufacturer of glucosamine as mentioned in the acknowledgments section of the paper. 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.

Regulatory control
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. The U.S. National Institutes of Healthmarker 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.

Europe
In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate. 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, and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis also confirm its excellent safety profile.

Natural sources
Glucosamine is naturally present in the shells of shellfish and animal bones and bone marrow.

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 sulfate 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.

Mechanisms of action

The possible effects of glucosamine sulfate in patients with osteoarthritis may be the result of its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans, 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.

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.

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. 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. 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.

Due to these controversial results, some reviews and meta-analyses have evaluated the efficacy of glucosamine. Richy et al. 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.

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.

This situation led the National Institutes of Healthmarker to fund a large, multicenter clinical trial (the GAIT 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. 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. 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" 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". 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.

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. 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.

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.

A 2009 small study has concluded that glucosamine reduces cartilage turnover in osteoarthritis patients in response to physical training. ==

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