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Roelofs A.J.,Institute of Medical science | Coxon F.P.,Institute of Medical science | Ebetino F.H.,Warner Chilcott | Lundy M.W.,MDS Pharma Services | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2010

Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647-labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14 high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Research.

Huang Y.-C.T.,Duke University | Rappold A.G.,U.S. Environmental Protection Agency | Graff D.W.,MDS Pharma Services | Ghio A.J.,U.S. Environmental Protection Agency | Devlin R.B.,U.S. Environmental Protection Agency
Inhalation Toxicology | Year: 2012

Context: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants. Objectives: Determine if simultaneous exposure to PM and NO2 results in synergistic interactions. Materials and methods: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO2, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM2.5CAPs, 89.5±10.7 g/m), or NO2+PM2.5CAPs for 2h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18h after exposure. Bronchoalveolar lavage (BAL) was performed 18h after exposure. Results: NO2 exposure alone increased cholesterol and HDL 18h after exposure, decreased high frequency component of HRV one and 18h after exposure, decreased QT variability index 1h after exposure, and increased LDH in BAL fluid. The only significant change with PM2.5CAPs was an increase in HDL 1h after exposure, likely due to the low concentrations of PM2.5CAPs in the exposure chamber. Exposure to both NO2 and PM2.5CAPs increased BAL α1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO2 or PM2.5CAPs alone, suggesting possible interactions between the two pollutants. Discussion and conclusions: NO2 exposure may produce and enhance acute cardiovascular effects of PM2.5CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants. © 2012 Informa Healthcare USA, Inc.

Hamans E.,University of Antwerp | Shih M.,MDS Pharma Services | Roue C.,Avantis Medical
Journal of Musculoskeletal Neuronal Interactions | Year: 2010

Obstructive sleep apnea (OSA) is a sleep related breathing disorder caused by partial or complete collapse of the upper airway during sleep. The disease is linked with important cardiovascular and cerebrovascular morbidity and mortality. Tongue base collapse is a major cause of upper airway occlusion in OSA and present surgical procedures to prevent this are invasive and inefficient. A novel implantable system to stabilize the tongue was evaluated in a canine model for feasibility, safety and histology. Successful implantation of the Advance System was performed in 21 canines and follow-up evaluations were performed at 30, 60, 90, 120 and 150 days. No technical or clinical adverse events were seen during the procedure. Minor clinical adverse events at some of the follow-up evaluations were treated successfully. Histologic evaluation of the implant was performed at different time points during follow-up and showed good biocompatibility, stability and osteointegration. The outcome of this study resulted in an implant for adjustable tongue advancement in humans with OSA.

Skolnick B.E.,Novo Nordisk AS | Shenouda M.,MDS Pharma Services | Khutoryansky N.M.,Novo Nordisk AS | Pusateri A.E.,Novo Nordisk AS | And 2 more authors.
Anesthesia and Analgesia | Year: 2011

Background: Clopidogrel (Plavix®) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven®) induces hemostasis in hemophilia patients with inhibitors (alloantibodies) and has been proposed as potential treatment for mitigating clopidogrel therapy-mediated bleeding. Methods: In this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrel-enhanced bleeding in an experimentally induced punch biopsy in healthy subjects. Efficacy assessments included the reversal of bleeding characteristics (bleed duration [BD], the primary end point and blood loss volume [BV] induced by punch biopsy, and thromboelastograph [TEG®] parameters) with rFVIIa or placebo after clopidogrel treatment. Results: A significant number of subjects (56%) had limited response to clopidogrel (defined as ≤30% platelet aggregation inhibition) and were discontinued from study. The remaining subjects continued and had 4 biopsies. Of 40 subjects randomized, 37 were evaluated for efficacy. Clopidogrel treatment increased BD and BV compared with the baseline biopsy. Recombinant FVIIa (10 and 20 μg/kg) significantly mitigated the clopidogrel-induced effects on BV (P = 0.007 and P = 0.001, respectively). Early trial termination limited the evaluation of effects of higher rFVIIa doses. Subgroup analyses of subjects biopsied by the same physician demonstrated significant reduction of clopidogrel-induced BD with 20 μg/kg rFVIIa (P = 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG®-R) and clot angle (TEG®-A) (P < 0.005). Conclusions: In this clinical study, rFVIIa (10 and 20 μg/kg) reversed the effect of clopidogrel on blood loss. © 2011 International Anesthesia Research Society © 2011 International Anesthesia Research Society.

Reitman M.L.,Merck And Co. | Chu X.,Merck And Co. | Cai X.,Merck And Co. | Yabut J.,Merck And Co. | And 10 more authors.
Clinical Pharmacology and Therapeutics | Year: 2011

We studied the time course for the reversal of rifampin¡̄s effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration̈ Ctime curve (AUC0-∞). The midazolamAUC 0-∞returned to baseline with a half-life of ∼8 days. Rifampin'effect on the AUCo-3h of digoxin was biphasic: the AUC o-3h increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion̈Ctransporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC50) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug̈Cdrug interaction (DDI) trial designs. © 2011 american Society for Clinical Pharmacology and Therapeutics.

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