Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.

UNLABELLED: Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1, EAR and LAR evaluated by area under the FEV1/time curve (AUC0-2, AUC3-10, respectively), change in baseline FEV1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 (n = 16, LS mean = 28.6, P = 0.63) but montelukast (n = 17, LS mean = 22.6, P = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ-40929837 versus placebo. REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01241422.

A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome.

OBJECTIVE: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis. DESIGN: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial. SETTING: Intensive care units of six academic medical centers in the United States. PATIENTS: Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or placebo intravenously over 20 min. Three patients in each dose group received single doses; the remaining nine patients in each group received multiple (nine) doses at 8-h intervals over 72 h. MEASUREMENTS AND MAIN RESULTS: Afelimomab appeared safe and well tolerated. Single- and multiple-dose kinetics were predictable and dose related. The elimination half-life was 44.7 h. Afelimomab treatment resulted in increased serum concentrations of TNF (includes TNF-antibody complexes) and decreased serum interleukin-6 concentrations, whereas no discernible trends were observed in placebo-treated patients. There was no significant treatment effect on 28-day mortality as was expected given the small number of patients. However, overall mortality was significantly (p = 0.001) associated with baseline interleukin-6 concentration. All patients experienced adverse events, but the vast majority were considered unrelated to the study drug and demonstrated no apparent relationship to afelimomab dose. Although 41% of patients developed human anti-murine antibodies, there were no clinical sequelae. CONCLUSIONS: Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics. A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed.

Chronic angio-oedema of the tongue associated with pernicious anaemia and Hashimoto's thyroiditis.

The cause of chronic urticaria and angio-oedema (CUA) often remains undetermined. CUA has been associated with thyroid disease and most recently with thyroid autoimmunity (i.e. elevated titres of thyroid microsomal and/or thyroglobulin antibody). There is growing speculation that in this subset of patients, CUA may represent an autoimmune phenomenon. We describe a case in which chronic angio-oedema of the tongue was the sole presenting complaint in a patient with underlying quiescent pernicious anaemia and Hashimoto's thyroiditis. Awareness of the association of Hashimoto's thyroiditis with pernicious anaemia and CUA resulted in correct diagnosis and treatment of the underlying diseases.

Regulation of cll by interleukin-10 - role of antisense IL-10.

The role of IL-10 on the in vitro growth of B cells from patients with B-chronic lymphocytic leukemia (CLL) was investigated. Previous work on a murine model of CLL demonstrated that the malignant B-l cells produce significantly higher levels of IL-10 mRNA than normal B-1 or B cells and antisense oligodeoxynucleotides specific for IL-10 mRNA inhibited their growth. In the present study, peripheral blood cells from CLL patients were found to be varied in the amount of IL-10 mRNA present. Several CLL samples underwent apoptosis in response to culturing in the presence of antisense IL-10. There was a correlation between the levels of IL-IO mRNA and the sensitivity to growth inhibition by antisense IL-10. This may indicate that, antisense IL-10 inhibits cell growth in a sub-population of CLL in which IL-10 is an autocrine cytokine.