Glucosamine sulfate is a drug used for the treatment of osteoarthritis (OA), based on its pharmacological and metabolic activities on the cartilage and chondrocytes, complemented by mild anti-inflammatory properties and a favorable pharmacokinetic profile. The aim of this study was to define the activity and safety of glucosamine sulfate on the symptoms of patients with OA, using a multicenter, randomized, placebo-controlled, double-blind, parallel-group study design. The study included 252 outpatients with OA of the knee (Lequesne's criteria), radiological stage between I and III, and Lequesne's severity index of at least 4 points and symptoms for at least 6 months. Patients were treated with either placebo or oral glucosamine sulfate 500 mg t.i.d. for 4 weeks, with weekly, with weekly clinic visits. Responders to treatment were defined as patients with a reduction of at least 3 points in the Lequesne's index with a positive overall assessment by the investigator. The Lequesne's index was 10.6 +/- 0.45 S.E.M. points in both groups at the start of the study. This decreased to 7.45 +/- 0.5 points in the treatment group (average 3.2) and 8.4 +/- 0.4 points in the placebo group (average 2.2) (P < 0.05, Student's t-test). The responder rate in the evaluable patients was 55% with glucosamine (N = 120) vs 38% with placebo (N = 121). These proportions were 52% vs 37% in an intention-to-treat analysis (P = 0.014 and 0.016, respectively; Fisher's Exact Test). The medications were well tolerated throughout the study, with no difference between the glucosamine and placebo treated groups. It is concluded that glucosamine sulfate may be a safe and effective symptomatic Slow Acting Drug for OA.

Human rheumatoid synovial cells in culture secrete both 72-kDa progelatinase and a complex consisting of 72-kDa progelatinase and a 24-kDa inhibitor of metalloproteinases, TIMP-2. In addition, the culture medium contains TIMP-1, the classical inhibitor of metalloproteinases, with a molecular mass of 30 kDa. TIMP-1 does not form a complex with free 72-kDa progelatinase.Free progelatinase and progelatinase complexed with TIMP-2 can be activated with the organomercury compound p-aminophenylmercury acetate. The activated complex shows less than 10% the enzyme activity of activated free gelatinase.The progelatinase -TIMP-2 complex could be shown to be an inhibitor for other metalloproteinases, such as gelatinase and collagenase secreted by human rheumatoid synovia fibroblasts, as well as for the corresponding enzymes from human neutrophils.The tissue inhibitor of metalloproteinases (TIMP-1) is a glycoprotein with a molecular mass of about 30 kDa, purified initially from culture medium conditioned by normal skin fibroblasts, and later from various human sources, including plasma, amniotic fluid and synovial fluid [l -71.The TIMP-1 gene has been localized to the x chromosome [8]. The secreted protein consists of 184 amino acids and possesses six disulfide bonds and two glycosylation sites containing N-linked oligosaccharides [5, 91.TIMP-1 specifically inhibits the extracellular-matrix-degrading metalloproteinases such as collagenase, gelatinase and stromelysin. It has no activity on mammalian membrane metalloproteinase, procollagen peptidase, or on bacterial metalloproteinases such as thermolysin [lo].Originally it was thought that TIMP-1 only binds to active enzymes and not to latent ones. However, it was reported recently, that the 72-kDa progelatinase secreted by several cell types, such as Simian-virus-40-transformed human lung fibroblasts, Harvey murine sarcoma virus-transformed human bronchial epithelial cells, human A2058 melanoma cells and normal skin fibroblasts, exists in a stable, but noncovalent 1 : 1 stoichiometric complex with a 24-kDa inhibitor of metalloproteinases called TIMP-2 [ l l , 121. In addition, a 92-kDa progelatinase -TIMP-1 complex is secreted by human lung fibroblasts [13]. This proteinase is normally produced by macrophages and polymorphonuclear leukocytes (PMNL). PMNL do not produce a tissue inhibitor of metalloproteinases, which may account for its 10-fold-higher specific activity 1131.We found human rheumatoid synovial cells to secrete not only the 72-kDa-progelatinase -TIMP-2 complex and TIMP-1, but in addition free 72-kDa progelatinase. In this communication, we show that TIMP-2, although complexed with the progelatinase, still remains an inhibitor of metalloproteinases. MATERIAL AND METHODS Cell cultureHuman rheumatoid synovium obtained by surgery was washed in Hank's solution and freed from fat and cartilage, cut into pieces (approximately 1 mm3 in size), washed with Hank's solution again, and distributed into 75-cmZ culture flasks. 8 ml Dulbecco's modified Eagle's medium containing ...

The superficial epithelial layer in the urinary bladder of adult rats was examined, in various states, using the transmission and scanning electron microscopes. A good agreement was obtained between the results of the two methods. When the urinary bladder is unexpanded, the superficial cells show marked bulges into the bladder lumen and the contacts between cells (mainly desmosomes) are displaced deep into the epithellium. The luminal surface is bizarrely bent and large parts of the membrane intrude into the cytoplasm, where they give the appearance of discoid and fusiform vesicles. Between neighboring cells, deep interdigitations are observed. In the scanning electron microscope, the surface of the epithelium appears cauliflower-like and has deep grooves, gullys and folds. When the bladder is expanded, the surface becomes smoother and the contacts between cells move to the surface. The stretched cells are angular in form (5-, 6- or 7-sided) and show great variations in surface area (150–500 μm²). The luminal cell membrane consists of an alternation of asymmetrical areas (120 Å thick and 0.2–0.4 μm in length) with normal sections which are 80 Å thick. In the scanning electron microscope, these thick areas appear as 4-, 5- or 6-sided plaques with a maximal diameter of 0.4 μm. The borders of the plaques are formed of portions of cell membrane which have a normal thickness and extrude as microcristae into the lumen. This produces a honeycomb appearance on the cell surface.

A new surgical procedure, semiarthroscopic synovectomy of the hip is described. The operation enables a radical synovectomy to be performed without the risk of necrosis of the femoral head from temporary luxation. The early results have been encouraging and the method appears to offer a low-risk alternative to conventional radical synovectomy.