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Chastek B.J.,i3 Innovus | Oleen-Burkey M.,Teva Pharmaceuticals | Lopez-Bresnahan M.V.,I3 Research
Journal of Medical Economics | Year: 2010

Objective: Relapse is a common measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objective of this study was to test the content validity of an operational algorithm for detecting relapse in claims data. Methods: A claims-based relapse detection algorithm was tested by comparing its detection rate over a 1-year period with relapses identified based on medical chart review. According to the algorithm, MS patients in a US healthcare claims database who had either (1) a primary claim for MS during hospitalization or (2) a corticosteroid claim following a MS-related outpatient visit were designated as having a relapse. Patient charts were examined for explicit indication of relapse or care suggestive of relapse. Positive and negative predictive values were calculated. Results: Medical charts were reviewed for 300 MS patients, half of whom had a relapse according to the algorithm. The claims-based criteria correctly classified 67.3 of patients with relapses (positive predictive value) and 70.0 of patients without relapses (negative predictive value; kappa 0.373: p<0.001). Alternative algorithms did not improve on the predictive value of the operational algorithm. Limitations of the algorithm include lack of differentiation between relapsing-remitting MS and other types, and that it does not incorporate measures of function and disability. Conclusions: The claims-based algorithm appeared to successfully detect moderate-to-severe MS relapse. This validated definition can be applied to future claims-based MS studies. © 2010 Informa UK Ltd All rights reserved.

Zhang R.Y.,Accurus Biosciences Inc | Shen W.D.,Teva Pharmaceuticals
Methods in Molecular Biology | Year: 2012

In the past two decades, the production levels for monoclonal antibodies in mammalian expression systems have improved dramatically. Single cell productivity for monoclonal antibodies has increased 20-50 fold due to the improvements in expression hosts, expression vectors, cell culture media, and production processes. However, most of these improvements are proprietary to large pharmaceutical/biotech companies and involve large steel-tank bioreactors. Therefore, these processes are difficult for small companies and academic labs to reproduce. Transient expression in mammalian cells has recently been used very widely for monoclonal antibody expression. Cell line and expression vector engineering increased expression levels to several hundred milligrams per liter. The availability of highly effective transfection reagents and disposable bioreactors make the transient expression process an efficient and cost-effective way to make recombinant antibodies in large quantity. Here, we describe the protocols for small- to mid-scale transient expression of monoclonal antibodies in shake-flasks and for large-scale production in WAVE bioreactors. © 2012 Springer Science+Business Media, LLC.

Zhou C.,Southern Medical University | Shen W.D.,Teva Pharmaceuticals
Methods in Molecular Biology | Year: 2012

Display technology has been developed and widely used in antibody screening and selecting. While phage can only display antibody fragments, mammalian cells can display not only fragments but full-length antibodies. Here we described the display of full length antibody on the surface of 293 cells. Both heavy chain and light chain genes were cloned in a single mammalian expression vector containing dual mammalian expression cassettes. While transfected into 293 cells of the vector, both heavy and light chains were expressed. With the help of transmembrane domain of platelet-derived growth factor receptor (PDGFR-TM) fused at the 3′-end of heavy chain in frame, expressed full-length antibodies were displayed on the cell surface and can be easily detected and analyzed by flow cytometry. © 2012 Springer Science+Business Media, LLC.

Makarov A.,Novartis | LoBrutto R.,Teva Pharmaceuticals | Karpinski P.,Novartis
Journal of Chromatography A | Year: 2013

There are several spectroscopic techniques such as IR and CD, that allow for analyzing protein secondary structure in solution. However, a majority of these techniques require using purified protein, concentrated enough in the solution, to produce a relevant spectrum. Fundamental principles for the usage of reversed-phase ultra high pressure liquid chromatography (UHPLC) as an alternative technique to study protein secondary structures in solution were investigated. Several "model" proteins, as well as several small ionizable and neutral molecules, were used for these studies. The studies were conducted with UHPLC in isocratic mode, using premixed mobile phases at constant flow rate and temperature. The pressure was modified by a backpressure regulator from about 6000. psi to about 12,000. psi. It was found that when using a mobile phase composition at which proteins were fully denatured (loss of alpha-helix secondary structure), the retention factors of the proteins increased upon pressure increase in the same manner as non-proteins. When using a mobile phase composition in which proteins were not fully denatured, it was observed that the retention factors of the proteins displayed a much steeper (by one order of magnitude) increase in retention upon pressure increase. It was concluded that in a mobile phase in which the protein is not initially fully denatured, the increase of pressure may facilitate the folding back of the protein to its native state (alpha-helix secondary structure). The impact of different mobile phase compositions on the denaturation of the proteins was studied using CD (Circular Dichroism). Moreover, the effect of flow rate on retention of proteins and small molecules was studied at constant pressure on the different pore size silicas and the impact of internal frictional heating was evaluated. © 2013 Elsevier B.V.

Hauser R.A.,University of South Florida | Silver D.,Coastal Neurological Medical Group | Choudhry A.,Teva Pharmaceuticals | Eyal E.,Teva Pharmaceutical Industries
Movement Disorders | Year: 2014

Dopamine agonists (DA) are often used as first-line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase-B (MAO-B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18-week, randomized, double-blind, placebo-controlled trial of rasagiline 1 mg/d as an add-on to DA therapy (ropinirole≥6 mg/d or pramipexole≥1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent-to-treat (ITT) population included 321 subjects whose mean±SD age was 62.6±9.7, and duration of PD was 2.1±2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference±SE, -2.4±0.95; 95% confidence interval [CI], -4.3, -0.5; P=0.012). Mean improvement (LS mean±SE) was -3.6±0.68 in the rasagiline group and -1.2±0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society.

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