Search

OBJECTIVE Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.

The use of sulfonamides of formula (I) wherein R and R1 are as defined in the description, for the preparation of medicaments for the prevention of diabetes, in particular of type-1 diabetes is herein disclosed

The invention relates to CXCR1 and/or CXCR2 inhibitors for the preparation of a medicament for use as an adjuvant in the transplant of pancreatic islets in Type 1 diabetes patients. In particular, the compounds that can be used according to the invention have the following formula (I) in which R and R' are as defined in the description

LG 30435 is a new quarternary phenothiazine derivative with H1-antihistaminic and antimuscarinic properties. The ability of LG 30435 to prevent changes in respiratory mechanics, induced by different mediators and the immunological reaction, was monitored together with biological and radioimmunological determination of circulating thromboxane-A2 (TxA2) in anaesthetized guinea-pigs. LG 30435 dose-dependently reduces the bronchoconstriction and TxA2 generation caused by different stimuli such as histamine, acetylcholine, leukotriene C4 (LTC4) and PAF-acether. In addition i.v. and aerosol administration of LG 30435 causes a dose-dependent reduction of the increase in airway resistance and TxA2 generation induced by ovalbumin challenge in actively sensitized animals. LG 30435 infused at different concentrations through the isolated guinea-pig lungs inhibits the TxB2 generation caused by different anaphylactic mediators, but not by arachidonic acid. These data, which further substantiate the bronchodilator activity of LG 30435 against a variety of stimuli and demonstrate its protective properties on lung anaphylaxis, suggest that this compound has a potential therapeutic value in the treatment of asthma.

S-(+)-2-(4-Fluorophenyl)-alpha-methyl-5-benzoxazolacetic acid (flunoxaprofen, Priaxim is a new antiinflammatory compound, which in various biological systems interferes with the generation and release of arachidonic acid metabolites of the cyclo-oxygenase pathways without affecting the formation of 5- and 12-lipoxygenase products. Flunoxaprofen reduces the concentration of thromboxane (TX)B2 (ED50 = 35.4 mg/kg p.o.) and prostaglandin (PG)E2-like activity (ED50 = 39.9 mg/kg p.o.) in the inflammatory exudate of rats 8 h after implantation of sponges soaked with carrageenan, whereas the concentration of leukotriene (LT)B4 remains in the range of that of the untreated animals (3.1 ng/ml). Flunoxaprofen inhibits cell infiltration in the exudate and this suggests that LTB4 does not initiate cell recruitment but may represent a mechanism for amplifying the inflammatory response. Using human platelets challenged with collagen, flunoxaprofen only at higher concentration (10(-4) mol/l) reduces TXB2 formation without altering generation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. This suggests a low capacity of flunoxaprofen of affecting platelet aggregation regulated by arachidonic acid metabolites. Flunoxaprofen prevents pulmonary changes due to secondary release of TXA2 in the guinea-pig. In fact this drug prevents changes due to immunological reaction and antagonizes bronchoconstriction due to exogenous administration of histamine and LTC4.(ABSTRACT TRUNCATED AT 250 WORDS)

A single intratracheal instillation of porcine pancreatic elastase (PPE, 100 U/Kg) induces in rabbits bronchial secretory cell metaplasia as well as emphysematous changes. The mucus hypersecretion and the marked reduction of ciliated cells matched by a high percentage of atypical cilia are responsible for the delayed mucociliary clearance in this model. S-Carboxymethylcysteine lysine salt (SCMC-LYS, 0.35 g/Kg b.w.), given per os daily for 10 days starting 2 days before elastase administration, significantly ameliorated the mucociliary clearance. The pharmacological treatment did not modify the degree of secretory cell metaplasia and the percentage of atypical cilia, or prevent the alveolar wall destruction. At TEM examination, the morphological aspects of secretion occurring in bronchial tree of PPE-treated animals were rarely visible in the PPE + SCMC-LYS treated group. The beneficial effect of SCMC-LYS on mucociliary clearance may be ascribed to an antisecretagogue effect of this drug through elastase inhibition and to a reduction of mucus viscosity.