Brown V.A.,University of Leicester |
Patel K.R.,University of Leicester |
Viskaduraki M.,University of Leicester |
Crowell J.A.,U.S. National Cancer Institute |
And 10 more authors.
Cancer Research | Year: 2010
Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4′-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P < 0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. ©2010 AACR.
Moore K.T.,Johnson and Johnson Pharmaceutical Research and Development |
St-Fleur D.,MDS Pharma Services |
Marricco N.C.,MDS Pharma Services |
Ariyawansa J.,Johnson and Johnson Pharmaceutical Research and Development |
And 4 more authors.
Journal of Opioid Management | Year: 2010
The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS® hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady-state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation. © 2010 Journal of Opioid Management, All Rights Reserved.
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.
Damment S.,Shire Pharmaceuticals |
Secker R.,Shire Pharmaceuticals |
Shen V.,MDS Pharma Services |
Lorenzo V.,University Hospital of Tenerife |
Rodriguez M.,University of Cordoba, Spain
Nephrology Dialysis Transplantation | Year: 2011
Background. Lanthanum carbonate (FOSRENOL®, Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). In this study, we used a rat model of chronic renal failure (CRF) to examine the long-term effects of controlling serum phosphorus with lanthanum carbonate treatment on the biochemical and bone abnormalities associated with CKDmineral and bone disorder (CKDMBD).Methods. Rats were fed a normal diet (normal renal function, NRF), or a diet containing 0.75% adenine for 3 weeks to induce CRF. NRF rats continued to receive normal diet plus vehicle or normal diet supplemented with 2% (w/w) lanthanum carbonate for 22 weeks. CRF rats received a diet containing 0.1% adenine, with or without 2% (w/w) lanthanum carbonate. Blood and urine biochemistry were assessed, and bone histomorphometry was performed at study completion.Results. Treatment with 0.75% adenine induced severe CRF, as demonstrated by elevated serum creatinine. Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals. Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P < 0.05), and had little effect in NRF animals. Bone histomorphometry revealed a severe form of bone disease with fibrosis in CRF + vehicle animals; lanthanum carbonate treatment reduced the severity of the bone abnormalities observed, particularly woven bone formation and fibrosis.Conclusions. Long-term treatment with lanthanum carbonate reduced the biochemical and bone abnormalities of CKDMBD in a rat model of CRF. © 2009 The Author.
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.
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.
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.
Semba C.P.,SARcode Corporation |
Semba C.P.,Stanford University |
Swearingen D.,MDS Pharma Services |
Smith V.L.,SARcode Corporation |
And 5 more authors.
Journal of Ocular Pharmacology and Therapeutics | Year: 2011
Purpose: To investigate the safety, tolerability, and pharmacokinetics (PKs) of topical SAR 1118 Ophthalmic Solution in healthy adults. SAR 1118 is an investigational small molecule lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2) antagonist that inhibits LFA-1 binding to intercellular adhesion molecule-1 (ICAM-1; CD54) targeting T-cell-mediated inflammation. Methods: A randomized, double-masked, placebo-controlled, dose-escalation study of SAR 1118 was performed in 4 cohorts with 7 randomized subjects per cohort (2 placebo: 5 active drug subjects; 0.1%, 0.3%, 1.0%, 5.0%) in 28 healthy adults. Dosing was divided into 3 periods each separated by a 72-h treatment-free observation: once-daily (QD) x 1, twice-daily (BID) x 10, and thrice-daily (TID) x 10 days. Data obtained at the beginning and end of each period included: slit-lamp, best-corrected visual acuity (BCVA), Schirmer tear test (STT) without anesthesia, tear film break-up time (TBUT), intraocular pressure (IOP), and tear/plasma samples for PK analysis. Results: All subjects completed the study; there were no tolerability issues or missed treatments (total, 1, 428 administered doses). No serious ocular or nonocular adverse events (AEs) occurred over 1, 148 subject study days (41 days/subject) and no significant abnormalities were identified on ocular exam. There were 38 ocular AEs (N = 11 subjects) and 21 nonocular AEs (N = 11 subjects). Most AEs were mild in severity and occurred in the 0.3% and placebo groups. No changes were observed in CD3, CD4, and CD8 blood lymphocyte counts. Tear PK profiles support a QD/BID dosing schedule. Plasma levels of SAR 1118 in the 0.1% and 0.3% groups were below level of quantitation (BLQ; <0.50 ng/mL) at all time points and transiently detected within the first 5 min to ∼h following administration in the 1.0% and 5.0% groups. Conclusion: SAR 1118 Ophthalmic Solution appears safe and well-tolerated up to 5.0% TID in healthy adult subjects. PK analysis shows adequate ocular exposure with minimal systemic exposure. Copyright 2011, Mary Ann Liebert, Inc.
Brown K.S.,Daiichi Sankyo |
Armstrong I.C.,Daiichi Sankyo |
Wang A.,Daiichi Sankyo |
Walker J.R.,Daiichi Sankyo |
And 6 more authors.
Journal of Clinical Pharmacology | Year: 2010
The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open-label, randomized clinical studies. The presence of a drug interaction was concluded if the 90% confidence intervals for the geometric least squares mean ratios of AUC0-t (AUC0-48 for levothyroxine) and Cmax fell outside the no-effect limits of (80.0%, 125.0%). Concomitant administration of colesevelam had no effect on the AUC0-t or Cmax of pioglitazone but significantly decreased the AUC0-t and C max of glyburide, levothyroxine, and EE and the Cmax of repaglinide and NET. AUC0-t and Cmax of glyburide and EE, but not repaglinide or NET, were significantly decreased when the drug was given 1 hour before colesevelam. When glyburide, EE, or levothyroxine was given 4 hours before colesevelam, no drug interaction was observed. Although colesevelam has a cleaner drug interaction profile than other bile acid sequestrants, it does interfere with absorption of some drugs. A 4-hour window appears sufficient to eliminate these interactions. © 2010 the American College of Clinical Pharmacology.