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Hayes D.B.,MedImmune Inc. | Stafford W.F.,Boston Biomedical Research Institute
Macromolecular Bioscience | Year: 2010

The ability to obtain a sedimentation coefficient distribution as the run proceeds, and to get an early idea of the quality of a particular sample, has not been made available in real-time during the run in any of the existing software packages. It is desirable on many occasions to be able to see the number of components present in a sample at an early stage of the run. The ability to ascertain the extent of heterogeneity of sample would help enormously to reduce the amount of time that is necessary to obtain that information. Most software packages currently available require that the run be completed before analysis is carried out or at least some of the early scans analyzed off-line to determine if the run should continue. A software package called SEDVIEW has been developed by us to allow early analysis in real-time. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Clarke D.L.,Med Immune Ltd. | Carruthers A.M.,Med Immune Ltd. | Mustelin T.,MedImmune Inc. | Murray L.A.,Med Immune Ltd.
Fibrogenesis and Tissue Repair | Year: 2013

Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of fibrotic scar tissue. This is characterized by excessive accumulation of extracellular matrix (ECM) components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor (TGF)β and interleukin (IL)-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease idiopathic pulmonary fibrosis (IPF), is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling. © 2013 Clarke et al.; licensee BioMed Central Ltd.

Mahmood I.,U.S. Food and Drug Administration | Staschen C.-M.,U.S. Food and Drug Administration | Goteti K.,MedImmune Inc. | Goteti K.,Pfizer
Botanical Review | Year: 2014

The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in children ≤5 years of age. Six models (allometric model (data-dependent exponent), fixed exponent of 0.75 model, maturation model, body weight-dependent model, segmented allometric model, and age-dependent exponent model) were evaluated in this study. From the literature, the clearance values for six drugs from neonates to adults were obtained. External data were used to evaluate the predictive performance of these models in children ≤5 years of age. With the exception of a fixed exponent of 0.75, the mean predicted clearance in most of the age groups was within ≤50% prediction error. Individual clearance prediction was erratic by all models and cannot be used reliably to predict individual clearance. Maturation, body weight-dependent, and segmented allometric models to predict clearances of drugs in children ≤5 years of age are of limited practical value during drug development due to the lack of availability of data. Age-dependent exponent model can be used for the selection of first-in-children dose during drug development. © 2014, American Association of Pharmaceutical Scientists.

Kaufman J.M.,Urology Research Options | Miller M.G.,Abbott Laboratories | Fitzpatrick S.,MedImmune Inc. | McWhirter C.,Abbott Laboratories | Brennan J.J.,Abbott Laboratories
Journal of Sexual Medicine | Year: 2012

Introduction. A new formulation of testosterone gel (1.62% testosterone gel) with increased viscosity and reduced volume of application has been shown to be safe and efficacious after 182days of use in a phase 3, double-blind study in adult hypogonadal males. Aim. The objective of this study was to evaluate the efficacy and safety of the 1.62% testosterone gel after daily application to the skin in a 182-day (6-month) open-label extension of the initial 182-day double-blind study. Methods. One hundred and sixty-three subjects, aged 26 to 77years, continued on active (Continuing Active subjects) 1.62% testosterone gel for the remainder of the study (364days total). In 28 subjects who had previously received placebo (Formerly Placebo subjects), the dose was titrated to normal levels of serum total testosterone (300-1,000ng/dL). Dose adjustments for both groups were allowed at specific visits to maintain serum testosterone within a normal range. Main Outcome Measure. The main outcome measure was the percentage of subjects with serum total testosterone average concentrations (C av) within the normal range at day 364. Results. On day 364, 77.9% (95% confidence interval: 70.0, 84.6) of the Continuing Active subjects and 87.0% (66.4, 97.2) of the Formerly Placebo subjects had C av values within the eugonadal range. The 1.62% testosterone gel was safe and well tolerated in this study. Conclusion. Treatment with 1.62% testosterone gel for up to 1year (182days for the Formerly Placebo subjects, 364days for the Continuing Active subjects) was safe and efficacious, resulting in >77% of treated subjects achieving normal serum testosterone levels at final visit. © 2012 International Society for Sexual Medicine.

Shearer J.D.,DynPort Vaccine Company | Manetz T.S.,Gene Logic Laboratories Inc. | Manetz T.S.,MedImmune Inc. | House R.V.,DynPort Vaccine Company
Vaccine | Year: 2012

A recombinant botulinum vaccine (rBV A/B) is being developed to protect adults 18-55 years of age from fatal botulism caused by inhalational intoxication with botulinum neurotoxin complex (BoNT) serotype A, subtype A1 (BoNT/A1) and BoNT serotype B, subtype B1 (BoNT/B1). Fundamental to the advanced development process is an initial demonstration of product safety in animals. A comprehensive series of studies was conducted to evaluate the general toxicity, neurobehavioral toxicity and local reactogenicity of the rBV A/B vaccine prior to first use in humans. Toxicity was evaluated in CD-1 mice vaccinated with control material and three dosages of rBV A/B with or without Alhydrogel ® by intramuscular (IM) injection on Study Days 0, 28, 56 and 70 in a volume of 100μL. Total immunizing protein given in each dose was either 0, 2, 4 or 8μg/animal. Local reactogenicity was evaluated in mice at the dosages given and in New Zealand white (NZW) rabbits using the same injection volume (0.5mL) and formulations (10, 20 and 40g/mL total antigen with 0.2% (w/v) Alhydrogel ®) intended for human use. The rBV A/B vaccine produced no apparent systemic or neurobehavioral toxicity and only transient mild inflammation at the injection site. Together these results indicated a favorable safety profile for rBV A/B and supported its use in a Phase 1 clinical trial. © 2012 Elsevier Ltd.

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