Aventis Pharma Deutschland GmbH

Bone degenerative diseases, including osteoporosis, impair the fine balance between osteoclast bone resorption and osteoblast bone formation. Single-agent therapy for anabolic and anticatabolic effects is attractive as a drug target to ameliorate such conditions. Inhibition of nuclear factor (NF)-κB reduces the osteoclast bone resorption. The role of NF-κB inhibitors on osteoblasts and bone formation, however, is minimal and not well investigated. Using an established NF-κB inhibitor named S1627, we demonstrated that inhibition of NF-κB increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model. To determine the effect of NF-κB on a model of osteoporosis, we injected two doses of inhibitor (25 and 50 mg/kg·d) twice a day in sham-operated or ovariectomized 12-wk-old mice and killed them after 4 wk. The anabolic effect of S1627 on trabecular bone was determined by micro focal computed tomography and histomorphometry. Bone mineral density of inhibitor-treated ovariectomized animals was significantly increased compared with sham-operated mice. Osteoblast-related indices like osteoblast surface, mineral apposition rate, and bone formation rate were increased in S1627-treated animals in a dose-dependent manner. NF-κB inhibition by S1627 increased the trabecular bone volume in ovariectomized mice. Furthermore, S1627 could inhibit the osteoclast number, and osteoclast surface to bone surface. In vitro osteoclastogenesis and bone resorbing activity were dose-dependently reduced by NF-κB inhibitor S1627. Taken collectively, our results suggest that NF-κB inhibitors are effective in treating bone-related diseases due to their dual anabolic and antiresorptive activities.

OBJECTIVE—To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects.RESEARCH DESIGN AND METHODS—Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10–20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2–3 days before again receiving inhaled insulin 1 h after the last cigarette.RESULTS—Before smoking cessation, maximum insulin concentration (Cmax) and area under the curve (AUC) for insulin concentration time (AUC-Insulin0–360) with inhaled insulin were higher, and time to Cmax (tmax) shorter, in smokers than nonsmokers (Cmax 26.8 vs. 9.7 μU/ml; AUC-Insulin0–360 2,583 vs. 1,645 μU · ml−1 · min−1; tmax 20 vs. 53 min, respectively; all P < 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUC-Insulin0–360 2,324 vs. 2,269 μU · ml−1 · min−1; P = NS). After smoking cessation, AUC-Insulin0–360 decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. Cmax decreased and tmax increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics.CONCLUSIONS—Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether.

Measurement of endothelial function in patients with atherosclerosis and lipid disorders is an important tool for the risk evaluation of a cardiovascular event, such as acute myocardial infarction and stroke. The feasibility of measuring endothelial function non-invasively in animal models has been limited so far. Therefore, we compared the assessment of endothelial function by in vivo transcutaneous vascular ultrasound (TVU) with the classical method of ex vivo organ bath, using the carotid artery of hypercholesterolaemic and normocholesterolaemic rabbits. The assessments of endothelial function by both techniques were performed on the same segments of the carotid artery. Vascular ultrasound detected impaired endothelium-dependent vasorelaxation induced by acetylcholine in the common carotid artery of hypercholesterolaemic rabbits. These results strongly correlated with measurements of endothelial function of isolated carotid artery rings. Furthermore, atherogenic diet caused significant fatty streak formation in the aorta, as well as significant increase of C-reactive protein and cholesterol levels. Endothelial function, an early marker of cardiovascular risk, could be non-invasively assessed and graded by TVU measurements. It correlated highly with vasoreactivity of isolated vessels in an organ bath ( r2=0.68). We conclude that vascular ultrasound in hypercholesterolaemic rabbits is a valid method for evaluating endothelial function associated with atherosclerosis.