Objective. To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis (OA) during a 6-month treatment course.Methods. Three hundred eighteen patients were enrolled in this randomized, placebo-controlled, doubleblind trial in which acetaminophen, the currently preferred medication for symptomatic treatment of OA, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily (n ‫؍‬ 106), acetaminophen 3 gm/day ( n ‫؍‬ 108), or placebo (n ‫؍‬ 104). The primary efficacy outcome measure was the change in the Lequesne index after 6 months. Secondary parameters included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and response according to the Osteoarthritis Research Society International criteria. These outcome measures were assessed using an intentto-treat analysis.Results. At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index ϳ11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo ؊1.2 [95% confidence interval ؊2.3, ؊0.8]) (P ‫؍‬ 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference ؊0.8 [95% confidence interval ؊1.9, 0.3]) (P ‫؍‬ 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P ‫؍‬ 0.004 and P ‫؍‬ 0.047, respectively, versus placebo). Safety was good, and was comparable among groups.Conclusion. The findings of this study indicate that glucosamine sulfate at the oral once-daily dosage of 1,500 mg is more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes.ClinicalTrials.gov identifier: NCT00110474.

Glucose metabolism in five healthy subjects fasted for 16 h was measured with a combination of [U-13 C]glucose and 2 H 2 O tracers. Phenylbutyric acid was also provided to sample hepatic glutamine for the presence of 13 C-isotopomers derived from the incorporation of [U-13 C]glucose products into the hepatic Krebs cycle. Glucose production (GP) was quantified by 13 C NMR analysis of the monoacetone derivative of plasma glucose following a primed infusion of [U-13 C]glucose and provided reasonable estimates (1.90 AE 0.19 mg/kg/min with a range of 1.60-2.15 mg/kg/min). The same derivative yielded measurements of plasma glucose 2 H-enrichment from 2 H 2 O by 2 H NMR from which the contribution of glycogenolytic and gluconeogenic fluxes to GP was obtained (0.87 AE 0.14 and 1.03 AE 0.10 mg/kg/min, respectively). Hepatic glutamine 13 C-isotopomers representing multiply-enriched oxaloacetate and [U-13 C]acetyl-CoA were identified as multiplets in the 13 C NMR signals of the glutamine moiety of urinary phenylacetylglutamine, demonstrating entry of the [U-13 C]glucose tracer into both oxidative and anaplerotic pathways of the hepatic Krebs cycle. These isotopomers contributed 0.1-0.2% excess enrichment to carbons 2 and 3 and $ 0.05% to carbon 4 of glutamine.

Plasma glucose 2H enrichment was quantified by 2H NMR in patients with cirrhosis (n=6) and healthy subjects (n=5) fasted for 16 h and given 2H(2)O to approximately 0.5% body water. The percent contribution of glycogenolysis and gluconeogenesis to glucose production (GP) was estimated from the relative enrichments of hydrogen 5 and hydrogen 2 of plasma glucose. Fasting plasma glucose levels were normal in both groups (87+/-7 and 87+/-24 mg/dl for healthy and cirrhotic subjects, respectively). The percent contribution of glycogen to GP was smaller in cirrhotics than controls (22+/-7% versus 46+/-4%, P<0.001), while the contribution from gluconeogenesis was larger (78+/-7% versus 54+/-4%, P<0.001). In all subjects, glucose 6R and 6S hydrogens had similar enrichments, consistent with extensive exchange of 2H between body water and the hydrogens of gluconeogenic oxaloacetate (OAA). The difference in 2H-enrichment between hydrogen 5 and hydrogen 6S was significantly larger in cirrhotics, suggesting that the fractional contribution of glycerol to the glyceraldehyde-3-phosphate (G3P)-moiety of plasma glucose was higher compared to controls (19+/-6% versus 7+/-6%, P<0.01). In all subjects, hydrogens 4 and 5 of glucose had identical enrichments while hydrogen 3 enrichments were systematically lower. This reflects incomplete exchange between the hydrogen of water and that of 1-R-dihydroxyacetone phosphate (DHAP) or incomplete exchange of DHAP and G3P pools via triose phosphate isomerase.

This l-month, randomized, double-masked, parallel-group study was conducted to compare nimesulide (100 mg twice daily) with diclofenac (50 mg three times daily) with respect to gastroduodenal tolerability and efficacy in patients with osteoarthritis. Results of gastroduodenal endoscopy in 83 patients (42 receiving nimesulide, 41 receiving diclofenac) revealed that, after 30 days, 4 patients (1 nimesulide, 3 diclofenac) had developed ulcers and 6 patients (4 nimesulide, 2 diclofenac) had developed erosions; however, differences between the treatment groups were not statistically significant. Both study drugs were well tolerated. Ten patients (5 in each group) withdrew from the study prematurely because of adverse events. Efficacy was assessed by measuring pain on visual analogue scales, using the functional index of Lequesne, and by scoring spontaneous pain, pain on passive movement, and functional impairment. Nocturnal pain was also checked. All efficacy variables showed a significant improvement during the study, and no statistically signiiicant differences were observed between the treatment groups.

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