-IBIS-1.7.6-
rx
supplement
glucosamine sulfate
Nutrition

definition

glucosamine sulfate:
ª chemistry:
• Glucosamine is a chemically defined, small molecule (molecular weight 179.17) with a pKa of 6.91. It is an amino-monosaccharide and one of the basic constituents of the disaccharidic units of articular cartilage glycosaminoglycans.

ª metabolism:
• Glucosamine’s favorable chemico-physical properties enable a rapid distribution of the compound throughout the body and its selective incorporation in the articular cartilage after systemic (parenteral or oral) administration, as shown using [C]-glucosamine in animal pharmacokinetic studies. (Setnikar I, et al. Arzneim Forsch 1993;43:1109-1113.)

ª function:
• Glucosamine is a key compound of the ground substance that makes up connective tissue. It is this ground substance – called proteoglycans – that determines the strength and resiliency of connective tissue. Glucosamine is the preferred substrate and stimulant for proteoglycan synthesis and. at the same time, inhibits proteoglycan degradation.
• Glucosamine exogenously given is a preferred substrate for the biosynthesis of these glycosaminoglycans.
• Glucosamine sulfate is not only a substrate, but can stimulate the synthesis of glycosaminoglycans and even proteoglycans (including therefore the proteic moiety).
• Glucosamine protects the cartilage from the metabolic impairment provoked by some non-steroidal antiinflammatory drugs (NSAIDs), as well as the chondrocytes from the lesive action of high-dose corticosteroids.
• Glucosamine sulfate showed mild antiinflammatory activities by a mechanism of action other than the inhibition of the biosynthesis of prostaglandins.

ª requirements:
• RDA: No RDA has been established.

ª therapeutics:
Osteoarthritis (OA): to decrease the severity of the symptoms, mainly represented by pain and limitation of motion, and to control the evolution of the disease. Studies show glucosamine sulfate may be more effective than placebo and may be as effective as NSAIDs in relieving the pain and inflammation of osteoarthritis. D'Ambrosio E, et al. Pharmatherapeutica 1981;2(8):504-508; Pujalte JM, et al. Curr Med Res Opin 1980;7(2):110-114; Crolle G, D’Este E. Curr Med Res Opin 1980;7:104-109; Vaz AL. Curr Med Res Opin 1982;8(3):145-149.) D’Ambrosio et al. divided thirty patients with chronic degenerative articular disorders into two groups: Group one received glucosamine sulfate therapy by injection for seven days, followed by oral glucosamine for two weeks, while group two received injections of piperazine/chlorbutanol for seven days, followed by two weeks of oral placebo. (Pharmatherapeutica 1981;2(8):504-508.) The researchers observed marked symptomatic improvement in the patients who received glucosamine sulfate compared to those who received placebo and concluded that glucosamine sulfate should be a "first choice for the basic and long-term treatment of primary or secondary osteoarthosic disorders". In other studies, Pujalte et al (Curr Med Res Opin 1980) reported similar results, as did Crolle and D’Este, who go on to recommend that glucosamine sulfate be considered as basic therapy for primary or secondary osteoarthrosis for relieving symptoms and restoring articular function. Vaz also reported positive results in a double-blind trial which compared the effectiveness of glucosamine sulfate with that of ibuprofen. (Curr Med Res Opin 1982;8(3):145-149.) Although early response was faster with ibuprofen, the improvements with glucosamine sulfate were more consistent and progressive, leading to significantly lower pain scores by the end of the eight week study period. In none of the above investigations were complaints or significant adverse reactions noted.
Low back pain
Injuries to cartilage

ª mode of action:
• Classified as a chondroprotective agent. glucosamine sulfate may help to relieve symptoms of osteoarthritis and may help stop the progression of the disease as well. (Setnikar I. Int J Tissue React 1992;14(50:253-261.)
• Osteoarthritis is the result of a degenerative process of the articular cartilages due to abnormalities in the biosynthesis of proteoglycans by the chondrocytes. The amino-monosaccharide Glucosamine Sulfate is the preferred substrate for this biosynthesis and stimulates the chondrocytes to produce proteoglycans with a normal polymeric structure. Glucosamine Sulfate also inhibits some cartilage-destroying enzymes such as collagenase and phospholipase A2, and the generation of cell-damaging superoxide radicals. Glucosamine sulfate therefore stops the pathogenic mechanism of osteoarthritis, relieves its symptoms, and retards the progression of the disease. The drugs which selectively stop the pathogenesis of osteoarthritis and retards the progression of the disease are classified as "Slow Acting Drugs for Osteoarthritis".
(Lequesne M, et al. J Rheumatol. 1994;21(41) 65-73.)

ª therapeutic dose:
• 500 mg three times daily, orally-administered.
• Obese individuals may need to increse dosages by 20 mg per kg body weight daily. (Murray M. p. 342; 1996.)
• In studies, injectable. parenteral and orally-administered glucosamine sulfate appear to have been well-tolerated.

ª forms:
Glucosamine is primarily available commercially in three forms:
• glucosamine sulfate
Glucosamine sulfate is the preferred form due to its very high absorption, ease of utilization, immediacy of incorporation into connective tissue matrix and history of clinical studies. The sulfur component in this form seems to be essential to efficacy. Sulfur is an essential nutrient for joint tissue, where it functions in the stabilization of the connective tissue matrix of cartilage, tendons, and ligaments.
• glucosamine hydrochloride
This form of glucosamine lacks the sulfur component, which appears to be critical to the beneficial effects desired.
• N-acetyl-glucosamine (NAG)
Researchers have concluded that "glucosamine is a more efficient precursor of macromolecular hexosamine (glycosaminoglycans) than N-acetylglucosamine. It is possible that N-acetylglucosamine does not penetrate the cell membranes and, as a result, is not available for incorporation into glycoproteins and mucopolysaccharides."
(Vidal Y, et al. Pharmacol Res Comm 1978;10,557-569.)

ª side effects:
• Rarely mild and transient gastrointestinal effects, including stomach upset, heartburn, diarrhea, nausea and indigestion. These symptoms are often reduced by taking the glucosamine sulfate with a meal.
• One study noted that he onset of possible side-effects was significantly related to pre-existing gastrointestinal disorders and related treatments, and to concomitant diuretic treatment.
(Tapadinhas MJ, et al. Pharmatherapeutica 1982;3:157-168.)

ª toxicity:
• No toxicity noted in sources used. No allergic reactions have been reported.

ª antagonists:
• Individuals taking diuretics may need to take higher doses (20 mg per kg body weight daily). (Murray M. p. 342; 1996.)
• Possibly NSAIDs, due to contrary mode of action.

ª contraindications:
• Patients hypersensitive to glucosamine sulfate.

ª interactions:
• No drug interaction has been reported so far.

• Individulas taking diuretics may need to take higher doses (20 mg per kg body weight daily). (Murray, M. p. 342; 1996.)

footnotes

Almada AL, Harvey PW, Platt KJ. Effect of chronic oral glucosamine sulfate upon fasting insulin resistance index (FIRI) in nondiabetic individuals. Experimental Biology 2000; San Diego, CA; March 18, 2000.
Abstract: Previous animal studies have demonstrated that glucosamine sulfate can induce insulin resistance. In the present trial, 6 nondiabetic subjects received 500 mg tid of glucosamine sulfate (GS-500 brand) for 12 weeks. Fasting insulin levels showed an "increasing trend" in the glucosamine group when compared with controls after 12 weeks. However, these results were not statistically significant (P=0.25). Fasting glucose levels were unaffected. The researchers suggest that additional, more rigorous studies are needed to assess glucosamine's effects on insulin resistance.

Crolle G, D’Este E. Glucosamine sulfate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin 1980;7:104-109.

D’Ambrosio E, Casa B, Bompasi R, et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1981;2:504-508.
Abstract: Two groups of in-patients with chronic degenerative articular disorders received daily for 7 days either 400 mg glucosamine sulphate or a piperazine/chlorbutanol combination by intravenous or intramuscular injection. During the 2 following weeks, the patients receiving glucosamine had oral glucosamine capsules (6 x 250 mg daily); the other group had placebo. During both initial parenteral treatments, each symptom significantly improved, but to a faster and greater extent in the group treated with glucosamine. During the maintenance period, a further improvement was recorded in the patients treated with glucosamine, whereas in those on placebo the symptom scores increased almost to the pre-treatment level. This was considered the major difference between basic therapy, such as with glucosamine, and purely symptomatic treatment. Clinical and biological tolerance were excellent with both treatments, and no definitely drug-related complaints were recorded.

Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double-blind investigation. Clin Ther 1980;3(4):260-272.

Lequesne M, et al. J Rheumatol. 1994;21(41) 65-73.

Muller-Fassbender H, Bach G, Haase W, Rovati, Setnikar I. Glucosamine Sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis and Cartilage 2;1994.
Abstract: Glucosamine sulfate was found to be more effective than placebo in controlling the symptoms of osteoarthritis (0A) in a randomized, double-blind, parallel-group study of 200 hospitalized patients with active OA of the knee, symptoms for at least 3 months and a Lequesne’s index of at least 7 points. The study compared glucosamine sulfate 500 mg three times daily vs ibuprofen 400 mg three times daily, orally for 4 weeks. The improvement tended to be sooner under ibuprofen (48% responders vs 28% after the 1st treatment week), but there was no difference from the 2nd week onward, with a success rate of 52% in the ibuprofen group and of 48% in the glucosamine group (P=0.67) at the end of treatment. On the other hand, 35% of patients on ibuprofen reported adverse events , mainly of gastrointestinal origin, vs. 6% adverse events with glucosamine. The number of adverse event related drop-outs was different between the two groups. Glucosamine sulfate was therefore as effective as ibuprofen on symptoms of knee OA and confirmed glucosamine sulfate as a safe symptomatic Slow Acting Drug for OA. Thus the study concluded that glucosamine sulfate is able to stimulate proteoglycan synthesis by chondrocytes and has mild anti-inflammatory properties.

Murray M. Encyclopedia of Nutritional Supplements. Prima Publishing: Rocklin, CA; 1996.

Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7:110-114.
Abstract: The efficacy and tolerance of oral glucosamine sulphate were tested against placebo in a prospective double-blind trial in 20 out-patients with established osteoarthrosis. Two capsules of either glucosamine sulphate (250 mg) or placebo were administered 3-times daily over a period of 6 to 8 weeks. Articular pain, joint tenderness and restricted movement were semi-quantitatively scored 1 to 4 every 3 days, and individually averaged over the treatment period (overall composite score). Possible side-reactions were similarly scored upon positive questioning of the patients. Hematology, erythrocyte sedimentation rate, urine analysis and X-rays were recorded before and after treatment. Significant alleviation of symptoms was associated with the use of the active drug at the prescribed dose. Similarly, patients given glucosamine sulphate experienced earlier alleviation of symptoms compared with those who had placebo. The use of glucosamine sulphate also resulted in a significantly larger proportion of patients who experienced lessening or disappearance of symptoms within the trial period. No adverse reactions were reported by the patients treated with glucosamine, and no variation in laboratory tests was recorded.

Reichelt A, Forster KK, Fischer M, et al. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. ArzneimForschung 1994;44:75-80.
Abstract: When orally given, glucosamine sulfate (Dona, CAS 29031-19-4) is more effective than placebo and at least as effective as non-steroidal anti-inflammatory drugs in relieving osteoarthritis symptoms. 155 out-patients with knee osteoarthritis (Lequesne’s criteria), radiological stage between I and III, Lequesne’s severity index of at least 4 points and symptoms for at least 6 months, were treated with i.m. glucosamine sulfate (or placebo) 400 mg twice a week for 6 weeks. Clinic visits were performed at enrollment, after a 2-week baseline, at weekly intervals during treatment and 2 weeks after drug discontinuation. Responders to treatment were considered those patients with a reduction of at least 3 points in the Lequesne index, together with a positive overall judgment by the investigator. The Lequesne index was slightly over 10 points in average in both groups at the beginning of treatment. A significant decrease in the index was observed for glucosamine compared to placebo (3.3 vs. 2.0 points in average, respectively; p < 0.05, Student’s t-test). The responder rate in the evaluable patients was 55% with glucosamine (n = 73) and only 33% (n = 69) with placebo (p = 0.012, Fisher’s Exact Test). According to the intention-to-treat approach, considering also drop-outs, these proportions were 51% vs. 30% (p = 0.(5).

Rovati LC. Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs. Int J Tissue React 1992;14:243-251.
Abstract: This study incorporated three double-blind, controlled, parallel groups, randomized, 4-6 week trials of glucosamine sulphate versus placebo or the NSAID ibuprofen on a total of 606 gonarthrosic out-patients. Movement limitation and pain were scored according to the Lequesne index, and the efficacy goals were strictly pre-determined. Access to other medications was not allowed. Glucosamine was significantly more effective than placebo, while no difference was detected in comparison with the NSAID(p<0.025 and p=0.77, respectively: Fisher's two-tailed exact test). On the other hand, glucosamine was as well tolerated as placebo, while the percentage of patients suffering adverse drug reactions was higher in the ibuprofen group (37% vs 7%;p<0.001).

Setnikar I. Antireactive properties of chondroprotective drugs. Int J Tissue React 1992;14(50:253-261.

Setnikar I, Palumbo R, Canali S, Zanolo G. Pharmacokinetics of glucosamine in man. Arzneim Forsch 1993;43:1109-1113.
Abstract: The pharmacokinetics of glucosamine sulfate (CAS 29031-19-4) was investigated in 6 healthy male volunteers (2 per administration route) using 14C uniformly labeled glucosamine sulfate and administering it in single dose by intravenous (i.v.), intramuscular (i.m.) or oral route. The results show that after i.v. administration the radioactivity due to glucosamine appears in plasma and is rapidly eliminated. After i.m. administration similar pharmacokinetic patterns were observed. After oral administration a proportion close to 90% of glucosamine sulfate is absorbed. Free glucosamine was not detectable in plasma. The radioactivity incorporated in the plasma proteins follows pharmacokinetic patterns which are similar to those after i.v. or i.m. administration, but its concentration in plasma is about 5 times smaller than that after parenteral administration. The AUC after oral administration is 26% of that after i.v., or i.m. administration. The smaller plasma levels of radioactivity after oral administration are probably due to a first pass effect in the liver which metabolizes a notable proportion of glucosamine into smaller molecules and ultimately to CO2, water and urea. The results confirm that glucosamine sulfate is a prodrug for glucosamine that is well absorbed after oral administration and that, after i.v, i.m. or oral administration, diffuses into several tissues, including bones and articular cartilages.

Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-168.
Abstract: In an open study, 1208 patients with arthrosis, under the care of 252 doctors, received 1.5 g daily of glucosamine sulfate in 3 divided doses over a mean period of 30-14 days. The results from were analyzed and showed that the symptoms of pain at rest, on standing and on exercise and limited active and passive movements improved steadily through the treatment period. The improvement obtained lasted for a period of 6 to 12 weeks after the end of treatment. Objective therapeutic efficacy was rated by the doctors as "good" in 59% of patients, and "sufficient" in a further 36%. These results were significantly better than those obtained with previous treatments (except for injectable glucosamine) in the same patients. Sex, age, localization of arthrosis, concomitant illnesses or concomitant treatments did not influence the frequency of responders to treatment. Oral glucosamine was fully tolerated by 86% of patients, a significantly larger proportion than that reported with other previous treatments and approached only by injectable glucosamine.

Vajaradul Y. Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthrosis. Clin Ther 1981;3:336-343.
Abstract: Fifty-four outpatients with gonarthrosis participated in a double-blind clinical test with the aim of evaluating the efficacy and tolerance of intra-articular glucosamine in comparison with a 0.9% NaCI placebo. Each patient had one intra-articular injection per week for five consecutive weeks. Pain, active and passive mobility of the joint, swelling, and generalized and local intolerance symptoms were recorded before beginning the treatment, and four weeks after the last injection. Glucosamine reduced pain to a significantly greater extent than did placebo, and resulted in significantly more pain-free patients. The angle of joint flexion substantially increased after glucosamine treatment. Active mobility increased with both treatments, with a more favorable trend after glucosamine administration. Knee swelling did not decrease significantly after glucosamine, whereas it worsened (although not significantly) after placebo. There were no local or general intolerance symptoms during and after treatment. Glucosamine administration was able to accelerate the recovery of arthrosic patients, with no resulting side effects, and to partially restore articular function. In addition, the clinical recovery did not fade after treatment ended, but lasted for the following month, at least. The authors concluded that glucosamine therapy deserves "a selected place in the management of osteoarthrosis".

Vaz AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149.
Abstract: A double-blind trial was carried out in 40 out-patients with unilateral osteoarthrosis of the knee to compare the efficacy and tolerance of oral treatment with 1.5 g glucosamine sulphate or 1.2 g ibuprofen daily over a period of 8 weeks. Pain scores decreased faster during the first 2 weeks in the ibuprofen than in the glucosamine treatment group. Although the rate of decrease was slower, the reduction in pain scores was continued throughout the trial period in patients on glucosamine and the difference between the two groups turned significantly in favor of glucosamine at Week 8. No significant differences were observed in swelling or any of the other parameters monitored. Tolerance was satisfactory with both treatments, with only minor complaints being reported by 2 patients on glucosamine compared with 5 patients on ibuprofen.

Vidal Y, Plana RR, et al. Articular cartilage pharmacology, I, In vitro studies on glucosamine and non-steroidal anti-inflammatory drugs. Pharmacol Res Comm 1978;10,557-569.

Zupanets IA, Drogovoz SM, Bezdetko NV, et al. [The influence of glucosamine on the antiexudative effect of nonsteroidal anti-inflammatory agents]. Farmakol Toksikol 1991;54:61-63. [Article in Russian]
Abstract: The study of the antiexudative activities of voltaren, indomethacin and piroxicam in combination with glucosamine on the model of carrageenan inflammation showed that the combination makes it possible to decrease the effective doses of nonsteroidal anti-inflammatory drugs by 2-2.7 times with the preservation of the pronounced antiexudative activity. A diverse influence of aminosugar on the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs depending on the sequence and routes of administration is connected with their membrane mechanisms and metabolic features of amino sugar.