Faculty Bibliography

Five meta-analyses that evaluated the safety and efficacy of chondroitin sulfate (CS) in osteoarthritis management were published in recent years in the peer-reviewed literature. All 5 analyses re-ported that CS is statistically superior to placebo in symptomatic improvement when all randomized clinical trials are included. However, the most recent meta-analysis concluded that the benefit of CS is minimal in high-quality trials and that its use should be discouraged. The latter meta-analysis also evaluated the disease-modifying activity of CS and reported a statistically significant decrease in the rate of joint-space narrowing with CS over placebo but considered its clinical importance minimal. Three of the 5 meta-analyses evaluated safety, finding no significant difference in adverse-event profiles between CS and placebo

Objective: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials. Method. Trials were similar in design, patient population and outcome measures - all included the Lequesne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized. Results: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received. 'placebo' saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequesne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequesne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95%

OBJECTIVE: First, to assess the clinical effectiveness of hylan G-F 20 in an appropriate care treatment regimen (as defined by the American College of Rheumatology (ACR) 1995 guidelines) as measured by validated disease-specific outcomes and health-related quality of life endpoints for patients with osteoarthritis (OA) of the knee. Second, to utilize the measures of effectiveness and costs in an economic evaluation (see accompanying manuscript). DESIGN: A total of 255 patients with OA of the knee were enrolled by rheumatologists or orthopedic surgeons into a prospective, randomized, open-label, 1-year, multi-centred trial, conducted in Canada. Patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). RESULTS: The AC+H group was superior to the AC group for all primary (% reduction in mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale: 38% vs 13%,P =0.0001) and secondary effectiveness outcome measures. These differences were all statistically significant and exceeded the 20% difference between groups set a priori by the investigators as the minimum clinically important difference. Health-related quality of life improvements in the AC+H group were statistically superior for the WOMAC pain, stiffness and physical function (all P< 0.0001), the SF-36 aggregate physical component (P< 0.0001) and the Health Utilities Index Mark 3 (HUI3) overall health utility score (P< 0.0001). Safety (adverse events and patient global assessments of side effects) differences favoured the AC+H group. CONCLUSION: The data presented here indicate that the provision to patients with knee OA of viscosupplementation with hylan G-F 20 within an appropriate care treatment regimen provides benefits in the knee, overall health and health related quality of life at reduced levels of co-therapy and systemic adverse reactions

OBJECTIVE: Viscosupplementation with hylan G-F 20 has recently become registered for treatment of patients with osteoarthritis (OA) of the knee in most parts of the world. The cost effectiveness and cost utility of this new therapeutic modality were determined as part of a Canadian prospective, randomized, 1-year, open-label, multicentered trial. DESIGN: A total of 255 patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Costs (1999 Canadian dollars) were collected from the societal viewpoint and included all costs related to OA of the knee and OA in all joints. Patients completed a number of outcomes questionnaires including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Health Utilities Index Mark 3 (HUI3). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). RESULTS: The AC+H group over the year had higher costs ($2125-$1415=$710, P< 0.05), more patients improved (69%-40%=29%,P =0.0001), greater increases in HUI3 (0.13-0.03=0.10, P< 0.0001) and increased quality-adjusted life years (QALYs) (0.071, P< 0.05). The incremental cost-effectiveness ratio was $2505/patient improved. The incremental cost-utility ratio was $10000/QALY gained. Sensitivity analyses and a second cost perspective gave similar results. CONCLUSION: The cost-utility ratio is below the suggested Canadian adoption threshold. The results provide strong evidence for adoption of treatment with hylan G-F 20 in the patients and settings studied in the trial

Following adrenalectomy of male rats, or adrenalectomy and ovariectomy of females, there was marked depletion of zymogen granules in acinar cells of the pancreas. Within 9 h after treatment with either triamcinolone or 17 beta-estradiol, complete restoration of these secretory vesicles was observed. This repletion was not inhibited by actinomycin-D. Supernatant fractions (100,000 g, 60 min) of rat pancreas, from both normal and surgically altered animals, contained proteins that bound [3H]-triamcinolone and [3H]-estradiol, suggesting that the action of these hormones is exerted directly on the pancreas. Binding of both steroid hormones required the presence of an additional coligand referred to as accessory factor. In addition, the binding proteins for [3H]-triamcinolone and [3H]-estradiol eluted in similar positions after Sephadex G-200 and CM Affi-gel Blue chromatography. It is uncertain, however, whether a single protein binds both steroid hormones since they had different binding isotherms. Scatchard analysis of binding of [3H]-estradiol yielded a single straight line of negative slope from which it was calculated that there were about 4.4 pmol of binding sites per mg protein, having an average apparent Kd of about 5 X 10(-8) M. Similar analysis of the data for [3H]-triamcinolone yielded a straight line of zero slope indicating nonsaturable binding of hormone at concentrations as high as 10 microM. Since both [14C]-L-leucine incorporation into protein and amylase secretion were affected markedly by the steroid-hormonal status of the animal, it is presumed that steroid-bound complexes in acinar cells of the pancreas modulate synthesis and secretion of protein