GlucoFlex
Glucosamine Sulfate
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| Ingredients : | |
| Glucosamine Sulfate KCl(Pure Pharmaceutical Grade): 500 mg |
| Dosage: | 1 capsules 3 times daily as needed or as directed by your health professional. |
Glucosamine is an aminosugar found throughout the body. It is synthesized by the glucosamine synthetase, combining glucose and the aminoacid glutamine.
Glucosamine is an essential componant of many macromolecules (glycoprotein, glycosaminoglycan, proteoglycan). These macromolecules play vital roles: in the interstitium, they form the basis for the matrix (collagen and proteoglycan); in the mucus membrane, they are found in the basal membrane, the glycocalyx and the mucus itself; in the joints, they form the tendons, ligaments, cartilage and synovial fluid.
The aminosugars being synthesized by the body, the demand sometimes exceeds the supply in the event of strains, wounds and various aggressions. In many diseases, a lack of glycoproteins or other substances based on aminosugars has been found. Osteoarthritis and inflammatory bowel disease are but some of those diseases.
An hypothesis has been made that supplementation of glucosamine sulfate might stimulate the synthesis of the missing glycoproteins. Since the early 80's, research is confirming this hypothesis with the improvement of the symptoms of patients treated with glucosamine sulfate. Studies have compared glucosamine sulfate with ibuprofen and indomethacin in osteoarthritis. The anti-inflammatory drugs relieved the symptoms faster but had a negative long term effect on the cartilage and the evolution of the disease. Glucosamine sulfate brought relief after only two weeks of treatment. After eight weeks, the relief lasted even after the cessation of treatment.
Glucosamine sulfate is a prodrug quickly absorbed (90%), metabolised by the liver, strongly linked to plasmatic proteins and well distributed to action sites where it is used for the synthesis of glycoproteins, glycosaminoglycans and proteoglycans. Only 28% is excreted in the urine. Since glucosamine sulfate is not metabolised as a sugar, it should not interfere with diabetis.
Action mecanism:
Glucosamine sulfate stimulates the synthesis of glycolysed substances by bypassing the enzyme glucosamine synthetase.Dosage and side effects:
The suggested dosage is 50mg/kg in divided doses with meals. The side effects are minor and similar to placebo. There has been cases of diarrhea and rash.Indication:
Glucosamine sulfate is indicated in joint problems such as osteoarthritis and arthrosis. It has also been studied in the inflammatory bowel disease (Crohn's disease, ulcerative colitis) with good results. In theory, glucosamine sulfate can help anywhere glycoprotein synthesis may be at fault: mucus membrane, interstitium matrix, etc.The onset of action of the glucosamine sulfate is from 2 to 8 weeks since it operates by stimulating the endogenous synthesis of the missing macromolecules.
References
REFERENCE 2 OF 28
ltern Med Rev 1998 Feb;3(1):27-39
The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease.
Kelly GS
Successful treatment of osteoarthritis must effectively control pain, and should slow down or reverse progression of the disease. Biochemical and pharmacological data combined with animal and human studies demonstrate glucosamine sulfate is capable of satisfying these criteria. Glucosamine sulfate's primary biological role in halting or reversing joint degeneration appears to be directly due to its ability to act as an essential substrate for, and to stimulate the biosynthesis of, the glycosaminoglycans and the hyaluronic acid backbone needed for the formation of proteoglycans found in the structural matrix of joints. Chondroitin sulfates, whether they are absorbed intact or broken into their constituent components, similarly provide additional substrates for the formation of a healthy joint matrix. Evidence also supports the oral administration of chondroitin sulfates for joint disease, both as an agent to slowly reduce symptoms and to reduce the need for non-steroidal anti-inflammatory drugs. The combined use of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease has become an extremely popular supplementation protocol in arthritic conditions of the joints. Although glucosamine sulfate and chondroitin sulfates are often administered together, there is no information available to demonstrate the combination produces better results than glucosamine sulfate alone.
REFERENCE 2 OF 28
Russell AL
Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift.
In: Med Hypotheses (1998 Oct Oct) 51(4):347-9
Glucosamine, after a latent period, is rapidly developing a position in the treatment of osteoarthritis, as well as a potential therapeutic place in wound healing and gastrointestinal disorders. Although recognized for a great many years, the association of gastrointestinal disorders and arthritis has been looked on as an unexplained oddity. Could this be indicative of a common etiology in the rate-limiting production of glucosamine? Could diverse presentations and pathology be due to a common-stem biochemical defect?
Institutional address: Brampton Pain Clinic Bramalea Ontario Canada.
REFERENCE 3 OF 28
Setnikar I, Giacchetti C, Zanolo G
Pharmacokinetics of glucosamine in the dog and in man.
In: Arzneimittelforschung (1986 Apr Apr) 36(4):729-35
The pharmacokinetics, organ distribution, metabolism and excretion of glucosamine were studied in the dog giving uniformly labelled [14C]-glucosamine (sulfate), i.v. or orally, in single doses. Immediately after i.v. administration, the radioactivity in plasma is due to glucosamine, and freely diffuses into organs and tissues. This radioactivity disappears quickly from plasma (initial t1/2 = 13 min, terminal t1/2 = 118 min). After 30-60 min the radioactivity in plasma is no longer due to glucosamine, but is incorporated into alpha- and beta-globulins. The protein-incorporated radioactivity is found already 20-30 min after i.v. administration, reaches a peak after 8 h and then slowly disappears, with a t1/2 = 2.9 days. Of the administered radioactivity, more than 34% is excreted in the urine, mainly as glucosamine, and 1.7% is excreted in the feces. Radioactivity is excreted also as [14C]-CO2 in the expired air. The radioactivity, after i.v. administration, diffuses rapidly from blood into the body. Some organs show an active uptake of radioactivity, e.g. the liver and the kidney. Other tissues, such as the articular cartilage, also have an active uptake. In most other organs the radioactivity found can be explained by passive diffusion processes from plasma. After oral administration of a single dose of [14C]-glucosamine the radioactivity is quickly and almost completely absorbed from the gastrointestinal tract. The pattern of disappearance, metabolic transformation, tissue distribution and excretion of the radioactivity are consistent with those found after i.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
REFERENCE 4 OF 28
Setnikar I, Palumbo R, Canali S, Zanolo G
Pharmacokinetics of glucosamine in man.
In: Arzneimittelforschung (1993 Oct Oct) 43(10):1109-13
The pharmacokinetics of glucosamine sulfate (CAS 29031-19-4) was investigated in 6 healthy male volunteers (2 per administration route) using 14C uniformly labelled 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, with an initial t1/2 of 0.28 h. 1-2 h after administration the radioactivity due to glucosamine disappears almost completely and is replaced by a radioactivity originating from plasma proteins, in which glucosamine or its metabolites are incorporated. This radioactivity reaches a peak after 8-10 h and then declines with a t1/2 of 70 h. About 28% of the administered radioactivity is recovered in the urine of the 120 h following the administration and less than 1% is recovered in the feces. After i.m. administration similar pharmacokinetic patterns are observed. After oral administration a proportion close to 90% of glucosamine sulfate is absorbed. Free glucosamine is 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Institutional address: Rotta Research Laboratorium S.p.A. Monza Italy.
REFERENCE 5 OF 28
Setnikar I, Giachetti C, Zanolo G
Absorption, distribution and excretion of radioactivity after a single intravenous or oral administration of [14C] glucosamine to the rat.
In: Pharmatherapeutica (1984) 3(8):538-50
Blood levels, tissue distribution and excretion patterns of radioactivity were studied in the rat after administration of [14C] glucosamine sulphate by the intravenous or oral route. After intravenous administration, plasma radioactivity declined in the first 30 min, then increased, reaching a peak at the 2nd hour, and disappeared, with a half-disappearance time of 28 hours. The radioactivity diffused rapidly in the tissues. Higher levels than in plasma were reached in the liver and kidneys. There was early incorporation of radioactivity in the skeletal tissues (cartilage and bone). About 50% of the administered radioactivity was excreted with the expired CO2 and about 35% with the urine. Faecal excretion was small (2% of the administered dose). After oral administration, radioactivity was quickly found in plasma, where it reached a peak at 4 hours. It then declined slowly, with biphasic kinetics. The tissue distribution, including uptake in the skeleton, repeated the pattern found after intravenous administration. There was only small faecal excretion, showing an almost complete bioavailability of glucosamine given orally, and the large excretion with the CO2 (82%) showed that glucosamine is to a large extent broken down to smaller fragments. Autoradiographic studies confirmed the tissue distribution pattern and showed in more detail the tissue localization of radioactivity.
REFERENCE 6 OF 28
Clin Ther 1996 Nov-Dec;18(6):1184-90
Pilot study of oral polymeric N-acetyl-D-glucosamine as a potential
treatment for patients with osteoarthritis.
Talent JM, Gracy RW
Glucosamine and its derivatives, such as glucosamine sulfate and N-acetyl-D-glucosamine (NAG), have been shown to be effective in the treatment of patients with osteoarthritis. Unfortunately, the half-life of glucosamine in the blood is relatively short; therefore, a sustained-release form of the compound would be highly desirable. The purpose of this pilot study was to determine whether the polymeric form of NAG (POLY-Nag) could provide a longer-lasting oral source of NAG. Ten healthy subjects each ingested 1 g/d of either NAG or POLY-Nag for 3 days. After a 4-day washout period, each subject was crossed over to receive the other compound for 3 days. Serum samples were collected and analyzed using high-performance liquid chromatography. Results show that orally ingested NAG and POLY-Nag are absorbed, resulting in increased serum levels of NAG, and POLY-Nag appears to be at least as effective as NAG. Serum levels of NAG had decreased by 48 hours after cessation of ingestion of NAG or POLY-Nag but were still above baseline levels. Increases in serum glucosamine levels indicate that NAG and POLY-Nag are converted to glucosamine in vivo. In conclusion, POLY-Nag may provide a source of serum glucosamine for treatment of patients with osteoarthritis. Longer and more rigorous pharmaco-kinetic and clinical studies need to be done.
Institutional address: Dept of Biochemistry and Molecular Biology, Univ. of North Texas Health Science Center, Fort Worth, TX
REFERENCE 7 OF 28
Setnikar I, Pacini MA, Revel L
Antiarthritic effects of glucosamine sulfate studied in animal models.
In: Arzneimittelforschung (1991 May May) 41(5):542-5
The antireactive activity of glucosamine sulfate (GS) (CAS 29031-19-4) was tested in the rat in experimental models of subacute inflammation (sponge granuloma and croton oil granuloma), on subacute mechanical arthritis (kaolin arthritis) and in immunological-reactive arthritis and generalized inflammation (adjuvant arthritis). On these models GS was found effective in oral daily doses of 50-800 mg/kg. The potency of GS in comparison of that of indometacin used in the same tests as reference substance was found 50-300 times lower. Since, however, the toxicity of indometacin in chronic toxicity experiments is 1000-4000 times larger, the therapeutic margin with regard to prolonged treatments of inflammatory disorders results 10-30 times more favourable for GS than for indometacin. GS can therefore be considered as a drug of choice for prolonged oral treatment of rheumatic disorders.
Institutional address: Rotta Research Laboratorium S.p.A. Monza Italy.
REFERENCE 8 OF 28
Med Hypotheses 1998 Jul;51(1):11-5
Vascular heparan sulfates may limit the ability of leukocytes to penetrate the endothelial barrier--implications for use of glucosamine in inflammatory disorders.
McCarty MF
Oral glucosamine has anti-inflammatory activity in rodents, and anecdotal evidence suggests that it may be clinically useful in inflammatory bowel disorders. A possible explanation is that supplemental glucosamine increases production of heparan sulfate (HS) proteoglycans by the vascular endothelium, thereby improving the endothelium's barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of HS. Heparin can inhibit neutrophil activation, adhesion, and chemotaxis, and--like glucosamine--has been reported effective for managing inflammatory bowel syndromes. Cytokine-mediated loss of endothelial HS may be a key factor in the coordinated inflammatory response. These considerations suggest that glucosamine may have clinical utility in a range of inflammatory disorders, and should be assessed with regard to its impact on cancer metastasis and peripheral ischemic disease. In inflammatory bowel disease, fish oil, ginkgolides, and enteric-coated 5-aminosalicylic acid may safely complement the efficacy of glucosamine.
Institutional address: Nutrition 21, San Diego, CA 92109, USA.
REFERENCE 9 OF 28
Am J Gastroenterol 1983 Jan;78(1):19-22
Decreased incorporation of 14C-glucosamine relative to 3H-N-acetyl glucosamine in the intestinal mucosa of patients with inflammatory bowel disease.
Burton AF, Anderson FH
The synthesis of glycoproteins was investigated in intestinal mucosa from patients with inflammatory bowel disease (IBD) and from those with various other conditions. The incorporation into acid-insoluble macromolecules of the amino sugar glucosamine, the first and committed metabolite in the biosynthetic sequence, and its immediate derivative, N-acetyl glucosamine was determined. Tissue was incubated with 1-2 nmol 14C-glucosamine and 3H-N-acetyl glucosamine and the simultaneous incorporation of both isotopes was measured. Bowel tissue from areas microscopically uninvolved in active disease process was examined. Values for the incorporation of both substrates into acid-soluble constituents were similar for both IBD and non-IBD groups, as was also the incorporation of 3H into acid-insoluble constituents. The incorporation of 14C, however, when expressed relative to that of 3H in each individual patient, i.e., 14C/3H, was distinctly different in IBD cases. In 26 non-IBD samples this ratio ranged from 0.04-0.26 with a mean of 0.097 +/- 0.009. In nine cases of Crohn's disease values ranged from 0.013-0.06 with a mean of 0.039 +/- 0.011 (p less than 0.01); in nine cases of ulcerative colitis values were 0.007-0.06 with a mean of 0.031 +/- 0.006 (p less than 0.01). It is concluded that the step involving the N-acetylation of the amino sugar is relatively deficient in patients with IBD and this could reduce the synthesis of the glycoprotein cover which protects the mucosa from damage by bowel contents.
REFERENCE 10 OF 28
Gut 1998 Apr;42(4):485-92
Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease.
Sido B, Hack V, Hochlehnert A, Lipps H, Herfarth C, Droge W
BACKGROUND: Reactive oxygen species contribute to tissue injury in inflammatory bowel disease (IBD). The tripeptide glutathione (GSH) is the most important intracellular antioxidant. AIMS: To investigate constituent amino acid plasma levels and the GSH redox status in different compartments in IBD with emphasis on intestinal GSH synthesis in Crohn's disease. METHODS: Precursor amino acid levels were analysed in plasma and intestinal mucosa. Reduced (rGSH) and oxidised glutathione (GSSG) were determined enzymatically in peripheral blood mononuclear cells (PBMC), red blood cells (RBC), muscle, and in non-inflamed and inflamed ileum mucosa. Mucosal enzyme activity of gamma-glutamylcysteine synthetase (gamma GCS) and gamma-glutamyl transferase (gamma GT) was analysed. Blood of healthy subjects and normal mucosa from a bowel segment resected for tumor growth were used as controls. RESULTS: Abnormally low plasma cysteine and cystine levels were associated with inflammation in IBD (p < 10(-4)). Decreased rGSH levels were demonstrated in non-inflamed mucosa (p < 0.01) and inflamed mucosa (p = 10(-6)) in patients with IBD, while GSSG increased with inflammation (p = 0.007) compared with controls. Enzyme activity of gamma GCS was reduced in non-inflamed mucosa (p < 0.01) and, along with gamma GT, in inflamed mucosa (p < 10(-4)). The GSH content was unchanged in PBMC, RBC, and muscle. CONCLUSIONS: Decreased activity of key enzymes involved in GSH synthesis accompanied by a decreased availability of cyst(e)ine for GSH synthesis contribute to mucosal GSH deficiency in IBD. As the impaired mucosal antioxidative capacity may further promote oxidative damage, GSH deficiency might be a target for therapeutic intervention in IBD.
Institutional Address: Department of Surgery, University of Heidelberg, Germany.
REFERENCE 11 OF 28
Panasyuk A, Frati E, Ribault D, Mitrovic D
Effect of reactive oxygen species on the biosynthesis and structure of newly synthesized proteoglycans.
In: Free Radic Biol Med (1994 Feb Feb) 16(2):157-67
The effect of reactive oxygen species (ROS) generated by a xanthine oxidase hypoxanthine system (mainly H2O2) on proteoglycan (PG) metabolism and structure was investigated in vitro, using cell monolayers of cultured rabbit articular chondrocytes and purified resident and newly synthesized proteoglycans. It was shown that ROS generated in this system frequently stimulate (at low concentrations), and consistently inhibit (at higher concentrations), the incorporation of 35SO4 and 3H-glucosamine into PG molecules synthesized by cultured chondrocytes. The inhibition of isotopes' incorporation at higher enzyme concentrations was suppressed completely by heating xanthine oxidase and allopurinol with superoxide dismutase (SOD) and catalase. ROS at high concentration also inhibited 3H-uridine incorporation but had no effect on 35SO4 and 3H-uridine uptake by the cells. They also alter hyaluronan (HA) and PG monomers by fragmenting the core protein moiety and destroying the hyaluronic acid binding region. Altered PG monomers do not interact with HA to form complexes, but fragmented HA still retain a significant PG monomer-binding capacity. PG-HA complexes are easily and irreversibly destroyed by ROS. These results suggest that ROS may at low fluxes stimulate PG-synthesis under physiological conditions and alter cartilage metabolism and structure in conditions where they are overproduced, such as in rheumatoid arthritis, and in hemochromatosis and other iron storage diseases.
Institutional address: U349 INSERM Paris France.
REFERENCE 12 OF 28
Schenck P, Schneider S, Miehlke R, Prehm P
Synthesis and degradation of hyaluronate by synovia from patients with rheumatoid arthritis.
In: J Rheumatol (1995 Mar Mar) 22(3):400-5
OBJECTIVE. Hyaluronate degradation was analyzed in cultures of healthy tissue and tissue obtained from patients with rheumatoid arthritis. METHODS. Arthritic and healthy synovial tissues were incubated in culture with [3H]glucosamine. Labelled hyaluronate was extracted and its size determined by gel filtration. The production of low molecular weight hyaluronate was analyzed by pulse-chase experiments. Radical production was measured by a cytochrome C reduction assay. RESULTS. Healthy tissues and some arthritic tissues that did not contain significant amounts of granulocytes produced high molecular weight hyaluronate. In contrast, arthritic tissue infiltrated with granulocytes released low molecular weight hyaluronate. Pulse-chase experiments suggested that hyaluronate was degraded in these arthritic tissues. Exogenous hyaluronate was degraded only by intact tissue, but not by cells in culture obtained from synovial membranes of synovial fluids. Hyaluronate degradation was accompanied by massive oxygen radical production. Radical scavengers protected hyaluronate from degradation in synovial tissue. Some protection was achieved by superoxide and catalase or by methionine and complete protection by the iron chelators diethyltriaminepentacetic acid or deferoxamine mesylate. CONCLUSION. Degradation of hyaluronate in arthritic synovial tissue may be inhibited in tissue culture by radical scavengers.
Institutional address: Institut fur Physiologische Chemie und Pathobiochemie Munster Germany.
REFERENCE 13 OF 28
Fink MP
Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis.
In: Crit Care Med (1991 May) 19(5):627-41
BACKGROUND AND METHODS: The mucosa of the GI tract serves as an important barrier limiting the systemic absorption of luminal microbes and microbial products. Two methods commonly used to assess the integrity of the GI mucosal barrier are assessment of the extent of microbial translocation and measurement of mucosal permeability to hydrophilic probes. RESULTS: Studies using these methods have provided convincing evidence that the barrier function of the intestinal mucosa is deranged in numerous animal models of shock, trauma, and sepsis. CONCLUSIONS: Although the mechanisms underlying mucosal injury under these circumstances remain incompletely understood, current evidence suggests that mucosal damage in shock, trauma, and sepsis is likely due to various combinations of intracellular hypoxia due to ischemia, tissue injury caused by reactive oxygen metabolites, the deleterious effects of various lipid mediators (e.g., platelet-activating factor) and/or cytokines (e.g., tumor necrosis factor), and deficient utilization or supply of key nutritional substrates (e.g., glutamine).
Institutional address: Department of Surgery University of Massachusetts Medical Center Worcester 01605.
REFERENCE 14 OF 28
Roberts GP, Jenner L
Glycoproteins and glycosaminoglycans synthesized by human keratinocytes in culture. Their role in cell-substratum adhesion.
In: Biochem J (1983 May 15) 212(2):355-63
Glycoproteins and proteoglycans synthesized by human keratinocytes in medium containing D-[1-14C]glucosamine were extracted and analysed by polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate. Extraction of the labelled keratinocytes with 0.5% Triton X-100 removed most of the glycoconjugates and left the cytoskeleton and nuclear residue adherent to the substratum. In addition to the cytoskeletal proteins, there was a relatively simple profile of glycoproteins and glycosaminoglycans associated with this adherent cytoskeleton. These consisted of eight glycoproteins in the mol.wt. range 99000-232000, five proteins in the keratin region (mol.wt. 42000-61000), hyaluronic acid and a sulphated glycosaminoglycan. Surface labelling of the keratinocytes with galactose oxidase (with or without neuraminidase)/KB3H4 revealed that many of the glycoproteins were exposed on the cell surface. The importance of the glycoproteins and proteoglycans in attaching the keratinocytes to the substratum was examined by studying their expression after incubation in medium containing tunicamycin and their degradation after digestion with trypsin and hyaluronidase. These studies, together with an examination of the glycoconjugates released by sequential extraction with 0.5% Triton X-100 followed by 0.2% sodium dodecyl sulphate, revealed that the glycoprotein of mol.wt. 232000 has an important role in mediating the attachment of keratinocytes to the substratum.
REFERENCE 15 OF 28
McCarty MF
Glucosamine may retard atherogenesis by promoting endothelial production of heparan sulfate proteoglycans.
In: Med Hypotheses (1997 Mar Mar) 48(3):245-51
Heparan sulfate proteoglycans produced by vascular endothelium may function physiologically to restrain the migration, multiplication, and phenotypic transition of vascular smooth-muscle cells, and to maintain an anticoagulant luminal surface by bonding and activating antithrombin III. Thus, ample production of heparan sulfate proteoglycans may act to prevent atherosclerosis and its thrombotic complications. The ability of exogenous heparin to stimulate synthesis of heparan sulfate proteoglycans by vascular endothelium may be largely responsible for the positive outcomes of most controlled evaluations of low-dose heparin as a long-term therapy for coronary disease. Glucosamine, a biosynthetic precursor of mucopolysaccharides, can substantially enhance mucopolysaccharide production when added to cultured fibroblasts or chondrocytes; the clinical utility of oral glucosamine in osteoarthritis may reflect increased synthesis of cartilage proteoglycans. It is reasonable to speculate that exogenous glucosamine will likewise enhance heparan sulfate proteoglycans production by vascular endothelial cells, and, when administered orally in regimens comparable to those effective in osteoarthritis, will thereby act to retard atherogenesis.
Institutional address: Nutrition 21 San Diego CA 92109 USA.
REFERENCE 16 OF 28
[Gonarthrosis--current aspects of therapy with glucosamine sulfate (dona200-S)] Gonarthrosis--Aktuelle Aspekte der Therapie mit Glucosaminsulfat (dona200-S).
In: Fortschr Med Suppl (1998) 183:1-12 (Published in German)
For many years glucosamine sulfate has been successfully used in the therapy of osteoarthritis. Today's importance of the treatment with glucosamine sulfate is even increasing. Glucosamine sulfate meets all standards of an efficient and well tolerated drug. This is proven by experimental as well as clinical studies, in which glucosamine sulfate was tested in accordance with the current state of scientific research. The results show that glucosamine sulfate will lead to long-lasting pain reduction and functional improvement by means of increasing anabolical mechanisms, reducing the activity of proteolytic enzymes and by its antiinflammatory effect. Since this therapeutical effect is not due to an inhibition of the prostaglandin synthesis, treatment is not accompanied by the known unwanted side effects. Glucosamine sulfate is very well tolerated by patients of all ages under short-term as well as long-term treatment.
REFERENCE 17 OF 28
Setnikar I
Antireactive properties of "chondroprotective" drugs.
In: Int J Tissue React (1992) 14(5):253-61
The medicinal therapy of osteoarthritis is based on the use of analgesics, NSAIDs and corticosteroids to relieve pain and inflammation. In addition, "chondroprotective" agents (CPA) are used to stop the evolution of the disease. In this review the biochemical and pharmacological activities of some of the most widely used CPAs are described. All of these show more or less marked antiinflammatory activities, which for some of them are the result of an inhibition of cyclo-oxygenase and of prostaglandin biosynthesis, in which case they should be more properly classified as mild NSAIDs. Only two of the CPAs reviewed, diacerein and D-glucosamine sulfate, elicit antiinflammatory and antireactive effects without significant inhibition of the prostaglandin biosynthesis. These agents have also remarkable chondroprotective effects, and only these two agents should be classified as true CPAs. In particular glucosamine sulfate, which naturally occurs in the human body and is almost devoid of toxicity, is suitable for long-term therapeutic use. This, with its chondrometabolic, antireactive and antiarthritic properties, represents the pharmacological rationale for the use of glucosamine sulfate as a disease-modifying agent in osteoarthritis.
Institutional address: Rotta Research Laboratorium S.p.A. Monza Italy.
REFERENCE 18 OF 28
Rovati LC
Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs.
In: Int J Tissue React (1992) 14(5):243-51
Putative disease-modifying drugs are usually clinically used in osteoarthritis with two main aims: not only stopping or reducing the cartilage degenerative process after a long-term treatment, but also controlling the symptoms of the disease within a few days or weeks, thus avoiding or diminishing the use of symptomatic medications. Due to the difficulties of implementing the first aim, the latter aim was more often investigated, even if most often with inadequate study design and insufficient numbers of patients. We have recently carried out 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). Long-term trials are in progress and several aspects are to be considered in their design: they must be double-blind, placebo-controlled, randomized, continued for a period of years and (most importantly) with the careful use of imaging and biochemical techniques capable of generating objective evaluation criteria.
Institutional address: Department of Clinical Pharmacology Rotta Research Laboratorium S.p.A. Monza Italy.
REFERENCE 19 OF 28
McCarty MF
The neglect of glucosamine as a treatment for osteoarthritis--a personal perspective.
In: Med Hypotheses (1994 May May) 42(5):323-7
Osteoarthritis results from progressive catabolic loss of cartilage proteoglycans, owing to an imbalance between synthesis and degradation. Standard drug therapy is only of palliative benefit and may exacerbate loss of cartilage. Glucosamine is an intermediate in mucopolysaccharide synthesis, and its availability in cartilage tissue culture can be rate-limiting for proteoglycan production. A number of double-blind studies dating from the early 1980s demonstrate that oral glucosamine decreases pain and improves mobility in osteoarthritis, without side effects. Nevertheless, medical researchers and physicians in the US have totally ignored this rational and safe therapeutic strategy. By mechanisms that are still unclear, the natural methyl donor S-adenosylmethionine also promotes production of cartilage proteoglycans, and is therapeutically beneficial in osteoarthritis in well-tolerated oral doses. These and other safe nutritional measures supporting proteoglycan synthesis, may offer a practical means of preventing or postponing the onset of osteoarthritis in older people or athletes.
REFERENCE 20 OF 28
McCarty MF
Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis.
In: Med Hypotheses (1998 Jun Jun) 50(6):507-10
Anecdotal reports of rapid symptomatic response to high-dose glucosamine in osteoarthritis are not credibly explained by the traditional view that glucosamine promotes synthesis of cartilage proteoglycans. An alternative or additional possibility is that glucosamine stimulates synovial production of hyaluronic acid (HA), which is primarily responsible for the lubricating and shock-absorbing properties of synovial fluid. Many clinical and veterinary studies have shown that intra-articular injections of high-molecular-weight HA produce rapid pain relief and improved mobility in osteoarthritis. HA has anti-inflammatory and analgesic properties, and promotes anabolic behavior in chondrocytes. The concentration and molecular weight of synovial fluid HA are decreased in osteoarthritis; by reversing this abnormality, high-dose glucosamine may provide rapid symptomatic benefit, and in the longer term aid the repair of damaged cartilage.
Institutional address: Nutrition 21 San Diego CA 92109 USA.
REFERENCE 21 OF 28
Lopes Vaz A
Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients.
In: Curr Med Res Opin (1982) 8(3):145-9
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 an glucosamine and the difference between the two groups turned significantly in favour 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.
REFERENCE 22 OF 28
Arzneimittelforschung 1998 May;48(5):469-74
Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis.
Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I
A double-blind therapeutic investigation was performed on 178 Chinese patients suffering from osteoarthritis of the knee randomized into two groups, one treated for 4 weeks with glucosamine sulfate (GS, CAS 29031-19-4, Viartril-S) at the daily dose of 1,500 mg and the other with ibuprofen (IBU, CAS 15687-27-1) at the daily dose of 1,200 mg. Knee pain at rest, at movement and at pressure, knee swelling, improvement and therapeutic utility as well as adverse events and drop-outs were recorded after 2 and 4 weeks of treatment. The variables were recorded also after 2 weeks of treatment discontinuation in order to appreciate the remnant therapeutic effect. Both GS and IBU significantly reduced the symptoms of osteoarthritis with the trend of GS to be more effective. After 2 weeks of drug discontinuation there was a remnant therapeutic effect in both groups, with the trend to be more pronounced in the GS group. GS was significantly better tolerated than IBU, as shown by the adverse drug reactions (6% in the patients of the GS group and 16% in the IBU group--p = 0.02) and by the drug-related drop-outs (0% of the patients in the GS group and 10% in the IBU group--p = 0.0017). The better tolerability of GS is explained by its mode of action, because GS specifically curbs the pathogenic mechanisms of osteoarthritis and does not inhibit the cyclo-oxygenases as the non-steroidal anti-inflammatory drugs (NSAIDs) do, with the consequent anti-inflammatory analgesic activities but also with the several adverse reactions due to this not targeted effect. The present study confirms that GS is a selective drug for osteoarthritis, as effective on the symptoms of the disease as NSAIDs but significantly better tolerated. For these properties GS seems particularly indicated in the long-term treatments needed in osteoarthritis.
Institutional address: Peking Union Medical College Hospital, The People's Republic of China.
REFERENCE 23 OF 28
Tapadinhas MJ, Rivera IC, Bignamini AA
Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal.
In: Pharmatherapeutica (1982) 3(3):157-68
An open study was carried out by 252 doctors throughout Portugal to assess the effectiveness and tolerability of oral glucosamine sulphate in the treatment of arthrosis. Patients received 1.5 g daily in 3 divided doses over a mean period of 50 +/- 14 days. The results from 1208 patients 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. The onset of possible side-effects was significantly related to pre-existing gastro-intestinal disorders and related treatments, and to concomitant diuretic treatment.
REFERENCE 24 OF 28
Gottlieb MS
Conservative management of spinal osteoarthritis with glucosamine sulfate and chiropractic treatment.
In: J Manipulative Physiol Ther (1997 Jul-Aug Jul-Aug) 20(6):400-14
OBJECTIVE: To evaluate the rationale behind the most commonly used treatments of osteoarthritis, including nonsteroidal anti-inflammatory drugs (NSAIDs), and to assess more effective conservative treatment options. SUMMARY OF BACKGROUND DATA: This review includes a description of the pathophysiology and prevalence of osteoarthritis, joint physiology and NSAID treatment of osteoarthritis, as well as side effects on joints, the gastrointestinal tract, kidneys and livers. Several studies of conservative treatment, consisting of supplementation of glucosamine sulfate (which occurs naturally in the human body), exercise, and the use of chiropractic treatment for maintaining joint function and preventing further destruction, are reviewed. DATA SOURCES: A computerized search of Medline using the key indexing terms osteoarthritis, degenerative joint disease, nonsteroidal anti-inflammatory drugs, glucosamine sulfate, chiropractic and manipulation. RESULTS: Numerous studies wee obtained under each subheading and reviewed by category. Human and animal-model studies are described. CONCLUSION: The rationales for using NSAIDs in the treatment of osteoarthritis is controversial and openly contested. Given the detrimental effects of NSAIDs on joints and other organs, their use should be discouraged and their classification as a first choice conservative treatment should be abolished. A truly effective and conservative approach to the treatment of osteoarthritis should include chiropractic manipulation, essential nutrient supplementation, exogenous administration of glucosamine sulfate and rehabilitative stretches and exercises to maintain joint function. Because there is no correlation between pain levels and the extent of degeneration detected by radiographic or physical examination, conservative treatment should be initiated and sustained based on functional, objective findings and not strictly on how the patient feels. The use of NSAIDs should be limited to the treatment of gross inflammation and analgesics should only be used in the short-term when absolutely necessary for pain palliation. The present conservative approach could lead not only to a better quality of life but also to the saving of health care dollars by reducing the iatrogenic morbidity and mortality associated with NSAID use.
REFERENCE 25 OF 28
Stanescu V, Chaminade F, Muriel MP
Age-related changes in small proteoglycans of low buoyant density of human articular cartilage.
In: Connect Tissue Res (1988) 17(4):239-52
Proteoglycans extracted from articular cartilage of large joints of humans aged 4, 11, 70 and 75, were fractionated on associative density gradients. The top fraction (A3) was purified by ion-exchange chromatography and subsequent gel filtration on Sepharose CL 4B in 4 M GuCl, 0.5% Triton x 100. Proteoglycans from young cartilages yielded a narrow rapid migrating band on gel electrophoresis, had a Kav of 0.43 and 0.44 on Sepharose CL 4B, a glucosamine/galactosamine ratio of 0.11 and 0.12 and a glycoprotein core rich in aspartic acid and leucine with a Mr of about 47,000. Proteoglycans from old cartilages gave a wider and slower migrating band on gel electrophoresis, had a wide peak with a Kav of 0.38 and 0.40 on Sepharose CL 4B, a glucosamine/galactosamine ratio of 5.1 and 3.2, a glycoprotein core rich in glutamic acid and glycine, and with a Mr of about 170,000-180,000. Analysis using monoclonal antibodies detected epitopes of keratarn sulfate and of hyaluronic acid binding region in the fractions from old but not in those from young cartilages. Small proteoglycans not derived from the large monomers are the major component of low-buoyant-density fractions of proteoglycans from young cartilages. Fragments of large monomers containing keratan sulfate and hyaluronic acid binding region are the major component of similar fractions from old cartilage.
Institutional address: Unite de Recherches de Genetique Medicale (INSERM U.12) Hopital des Enfants-Malades Paris France
REFERENCE 26 OF 28
Dahl IM, Husby G
Hyaluronic acid production in vitro by synovial lining cells from normal and rheumatoid joints.
In: Ann Rheum Dis (1985 Oct Oct) 44(10):647-57
Organ cultures and primary cell cultures were established from synovial tissue collected from patients with rheumatoid arthritis. Hyaluronic acid measured by the incorporation of [3H]glucosamine into the polysaccharide was found to be synthesised in the cultures immediately after transfer from in-vivo to in-vitro conditions. This was in contrast to the primary cultures established from cells isolated from normal joints. The latter cells did not synthesise any detectable hyaluronate. 90-100% of the cells in primary culture were found to be esterase positive, indicating their macrophage nature. The molecular weight of the hyaluronate produced by the pathological cells was low (approximately 50 000) compared with the molecular weight of hyaluronate found in joint fluid from normal or rheumatoid joints. Cell lines of fibroblasts established from rheumatoid joints and studied after four or seven passages also produced hyaluronate of low molecular weight. It is known that similar cell lines from normal joints produce a high molecular weight polymer.
REFERENCE 27 OF 28
Steinberg JJ, Tsukamoto S, Sledge CB
Breakdown of cartilage proteoglycan in a tissue culture model of rheumatoid arthritis.
In: Biochim Biophys Acta (1983 May 4) 757(1):47-58
Proteoglycan breakdown was studied in a coculture model which mimics the confrontation between synovium and cartilage that occurs in rheumatoid arthritis. Bovine nasal-septum cartilage discs radioactively labeled (35SO2-4 with or without [3H]glucosamine) and 'chased' in non-radioactive medium were cultured in contact with minced rheumatoid synovial membranes for intervals up to 8 days. Synovium-stimulated (2-3-fold) cartilage breakdown was unaffected by ascorbate supplementation. Labeled products (small molecules plus proteoglycan complexes) in culture media were characterized by chromatographic, sedimentation and enzymic digestion methods. Breakdown was dominated by the release of a range of proteoglycan products, fully disaggregated and incapable of reaggregation with added hyaluronate. Because constituent glycosaminoglycans were of uniform size, proteoglycan polydispersity was attributed to differences in core protein length. Hydrocortisone inhibited degradation and partially prevented the shift of proteoglycans to lower average molecular weight. An additional breakdown pattern occasionally noted during the initial 48 h of coculture was characterized by release of a subpopulation of low charge-density proteoglycan bearing shortened glycosaminoglycan chains, consistent with glycosidase action. We conclude that rheumatoid synovia exhibit two distinct cartilage degradative potencies in vitro that may be important in vivo: (a) A variable hyaluronidase-like activity at early culture times, and (b) a dominant proteolytic activity generating an array of disaggregated proteoglycan products that differ largely on the basis of their core lengths. The response to hydrocortisone is consistent with inhibition of proteolysis through the stabilization of cellular membranes.
REFERENCE 28 OF 28
Ryu J, Treadwell BV, Mankin HJ
Biochemical and metabolic abnormalities in normal and osteoarthritic human articular cartilage.
In: Arthritis Rheum (1984 Jan Jan) 27(1):49-57
Incorporation of radioactive precursors into macromolecules was studied with human normal and osteoarthritic articular cartilage organ culture. Analysis of the salt extracted matrix components separated by cesium chloride buoyant density gradient centrifugation showed an increase in the specific activities of all gradient fractions prepared from the osteoarthritic cartilage. Further analysis of these fractions showed the osteoarthritic cartilage contained 5 times as much sulfate incorporated into proteoglycans, and an even greater amount of 3H-glucosamine incorporated into material sedimenting to the middle of the gradient. Greater than half of this radioactive middle fraction appears to be hyaluronate, as judged by the position it elutes from a DEAE column and its susceptibility to hyaluronidase digestion. This study supports earlier findings showing increased rates of macromolecular synthesis in osteoarthritis, and in addition, an even greater synthetic rate for hyaluronic acid is demonstrated.
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