In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.
Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.
BackgroundDiabetes is an important global disease, associated with significant morbidity and an increased risk of death due to chronic end-organ complications. The thiazolidinediones, used mainly as third-line agents in type 2 diabetes mellitus (T2DM), have been associated with some safety concerns, such as an increased risk of bladder cancer, an increased risk of bone fracture and heterogeneous effects on cardiovascular events.ObjectiveThis study aimed to evaluate safety data on pioglitazone for several outcomes and examine them in context with each other as well as with insulin, another third-line treatment for T2DM.MethodsThis retrospective cohort study extracted data from May 1, 2000 until June 30, 2010, from the i3 InVision Data Mart™ database. To adjust for the testing of multiple hypotheses, the Holm method was applied to endpoints representing potential harm from pioglitazone treatment, separately from those representing potential benefit from pioglitazone. The study population included patients with T2DM ≥ 45 years old who were new users of either pioglitazone or insulin. Key outcomes were incident cases of a composite of myocardial infarction (MI) or stroke requiring hospitalization; bone fracture requiring hospitalization; bladder cancer; and a composite of nine other selected cancers. Kaplan–Meier curves were generated and hazard ratios (HRs) for pioglitazone versus insulin were estimated from Cox proportional hazards models adjusted with inverse probability of treatment weights derived from propensity scores.ResultsA total of 56,536 patients (pioglitazone group 38,588; insulin group 17,948) qualified for the study. The mean follow-up was 2.2 years for pioglitazone and 1.9 years for insulin patients. Weighted survival analysis of the composite of MI and stroke, as well as the composite of nine cancers, yielded significant differences in favour of pioglitazone. For the composite of MI and stroke, the HR for pioglitazone versus insulin was 0.44 (95 % confidence interval [CI] 0.39–0.50, p < 0.0001). Modelling of the composite of nine selected cancers produced an HR of 0.78 (95 % CI 0.71–0.85, p < 0.0001). A non-statistically significant difference in favour of pioglitazone was observed in the incidence rate of bone fracture requiring hospitalization (HR 0.86, 95 % CI 0.74–1.01, p = 0.058). For bladder cancer, the overall incidence rates were relatively low and showed no significant difference between the two groups; the HR for pioglitazone versus insulin was 0.92 (95 % CI 0.63–1.33, p = 0.64).ConclusionCompared with insulin, pioglitazone was associated with a significant reduction in the risk of MI and stroke requiring hospitalization, and a significant reduction in the risk of other selected cancers. While pioglitazone treatment may be linked with a lower risk of bladder cancer and bone fracture relative to insulin, these differences were not statistically significant.
Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.
This study assessed the mucosal and systemic immune responses following repetitive adenoviral vector instillation to the parotid glands. Also, we investigated the feasibility of oral tolerance induction as a rational strategy to overcome the immunological reactions. The replication-deficient recombinant adenovirus vector AdCMVCAT was instilled into rat parotid glands. Chloramphenicol acetyltransferase (CAT) activity in the parotid was observed after a first or second AdCMVCAT infection, but not after a third vector administration. ELISA assays showed increased anti-adenovirus immunoglobulin G (IgG) and IgM in serum, and also anti-adenovirus IgA in gland extracts and saliva after virus administration. The results of in vivo neutralization experiments demonstrated that salivary IgA and IgM prevented reinfection of the parotids with adenoviral vectors. Subsequently, studies were conducted to induce tolerance to adenovirus by peroral feedings of ultraviolet (UV)-inactivated virus before gene administration to the parotid glands. Between 3 and 13 doses of virus were fed to rats. Final parotid gene expression was dependent on the number of viral feedings and the amount fed. Tolerized animals showed prolonged and heightened gene expression in the salivary glands compared to control animals and displayed gene expression even after three administrations of vector. Mononuclear cells from the spleens of these animals showed reduced proliferation following adenovirus stimulation. This same cell population was depleted of CD8+ T cells and found to produce less interferon-gamma (IFN-gamma) after virus challenge. This profile indicates the down regulation of Th1 cell-mediated responses. These results indicate that oral tolerance induction is a potentially useful adjunct to virus-based gene therapy.
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