Efficacy and tolerance of a new preparation of pure glucosamine sulphate, in injectable and oral form, were investigated in 30 patients with osteoarthrosis. Two groups of m-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. Efficacy was tested by semi quantitative scoring of pain at rest and during active and passive movements, as well as limitation of articular function, before and after 7 and 21 days of treatment. Patients were positively questioned daily for possible intolerance symptoms. Haematology, circulatory data and urine analysis were tested before and after treatment. 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 firther 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. It is suggested that parenteral and/or oral treatment with pure glucosamine sulphate should be considered as basic therapy for the management of primary or secondary degenerative osteoarthrosis disorders. DOAmbrosio E, Casa B, Bompasi R, et al. Glucosamme sulphate. a controlled clinical investigation in arthrosis. Pharmatherapeutica 2.'504-508,' 1981.

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 I 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. Haematology, 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. Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curt Med Res Opin 7:110-114, 1980.

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 30-14 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 OgoodO in 59% of patients, and 0sufficientO 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 gastrointestinal disorders and related treatments, and to concomitant diuretic treatment. Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 3:157-168; 1982.

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 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. 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 8:145-149; 1982.

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. [The influence of glucosamine on the antiexudative effect of nonsteroidal anti-inflammatory agents] Zupanets IA, Drogovoz SM, Bezdetko NV, et al. Farmakol Toksikol (USSR) 54:61-3; 1991.

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 tl/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 tl/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 im. 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 previous investigations in rats and dogs showing that also in man glucosamine sulfate is a prodrag 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. Setnikar I; Palumbo R; Canall S; Zanolo G. Pharmacokinetics of glucosamine in man. Arzneim Forsch (GERMANY) 43:1109-13; 1993.

Glucosamine sulfate (Dona, CAS 29031-19-4) is a drag used in the treatment of osteoarthritis. When orally given, it is more effective than placebo and at least as effective as non-steroidal anti-inflammatory drags in relieving osteoarthritis symptoms. The aim of this multicentre, randomized, placebo-controlled, double-blind, parallel-group study was to assess the efficacy and safety of glucosamine sulfate intramuscularly given on the same parameters. 155 out-patients with knee osteoarthritis (LequesneOs criteria), radiological stage between I and III, LequesneOs 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 judgement 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 less than 0.05, Student0s 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, FisherOs Exact Test). According to the intention-to-treat approach, considering also drop-outs, these proportions were 51% vs. 30% (p: 0.(5). Reichelt A, Forster KK, Fischer M, et al. Efficacy and safety of iniramuscular glucosamine sul/ate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. ArzneimForschung 44: 75-80; 1994.

Putative disease-modifying drags 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 less than 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 less than0.001). 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 care fill use of imaging and biochemical techniques capable of generating objective evaluation criteria. Rovati LC. Clinical research in osteoarthritis: design and results of short-term and long-term trials wtth disease-modifying drugs. Int J Tissue React (SWITZERLAND) 14:243-251; 1992.

Fifty-four outpatients with gonarthrosis participated in a double-blind clinical test with the ahn 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 no 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. These features are a definite improvement over antirheumatic drugs, the major drawbacks of which are action of short duration and side effects. Glucosamine therapy therefore deserves a selected place in the management of osteoarthrosis. Yajaradul Y. Double-blind clinical evaluation of intra-articular glucosamine in out-patients with gonarthrosis. Clin Ther 3:336-343; 1981.