Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration.

The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery.

Toward uniform implementation of parametric map Digital Imaging and Communication in Medicine standard in multisite quantitative diffusion imaging studies.

This paper reports on results of a multisite collaborative project launched by the MRI subgroup of Quantitative Imaging Network to assess current capability and provide future guidelines for generating a standard parametric diffusion map Digital Imaging and Communication in Medicine (DICOM) in clinical trials that utilize quantitative diffusion-weighted imaging (DWI). Participating sites used a multivendor DWI DICOM dataset of a single phantom to generate parametric maps (PMs) of the apparent diffusion coefficient (ADC) based on two models. The results were evaluated for numerical consistency among models and true phantom ADC values, as well as for consistency of metadata with attributes required by the DICOM standards. This analysis identified missing metadata descriptive of the sources for detected numerical discrepancies among ADC models. Instead of the DICOM PM object, all sites stored ADC maps as DICOM MR objects, generally lacking designated attributes and coded terms for quantitative DWI modeling. Source-image reference, model parameters, ADC units and scale, deemed important for numerical consistency, were either missing or stored using nonstandard conventions. Guided by the identified limitations, the DICOM PM standard has been amended to include coded terms for the relevant diffusion models. Open-source software has been developed to support conversion of site-specific formats into the standard representation.

Making methods rugged for regulated bioanalysis.

Methods started in discovery are optimized as they progress through preclinical and clinical development. Making a robust assay includes testing individual steps for consistency and points of failure. Assays may be transferred, optimized and revalidated several times. A rugged assay will not only meet regulatory requirements, but will execute with a low failure rate and confirm results under repeat analysis. Challenging aspects such as differential recovery, sample stabilization, resolution of isomers or conjugate analysis must be tackled and made routine. The proper selection of the IS can overcome limitations. It is best to know the potential points of failure before a study has started, but lessons learned from each study also provide invaluable insights to improve assay ruggedness.

Authorship and characteristics of articles in pharmacy journals: changes over a 20-year interval.

BACKGROUND: To our knowledge, no studies have evaluated authorship patterns and characteristics of articles in pharmacy journals. OBJECTIVE: To investigate changes over a 20-year period in authorship and characteristics of articles in pharmacy journals. METHODS: All articles published in the American Journal of Health-System Pharmacy, The Annals of Pharmacotherapy, and Pharmacotherapy in 1989, 1999, and 2009 were reviewed. Data collected for each article included article type, number of authors, number of physician authors, whether any author was affiliated with a pharmaceutical company, and source of funding. RESULTS: The number of articles included was 574 in 1989, 659 in 1999, and 589 in 2009. The mean number of authors per article increased from 2.5 in 1989 to 2.8 in 1999 and 3.6 in 2009 (p<0.001). Conversely, the proportion of articles with a single author decreased from 35% in 1989 to 23% in 1999 and 11% in 2009 (p<0.001), while the proportion of multi-authored articles (>6 authors) increased from 2% in 1989 to 3% in 1999 and 9% in 2009 (p<0.001). A physician author was listed on 25% of papers in 1989, which increased to 38% in 1999 and 41% in 2009 (p<0.001). Among research articles with declared funding from industry, there was an increase over time in reported author affiliation with an industry sponsor (10% of articles in 1989, 17% in 1999, and 66% in 2009; p<0.001). CONCLUSIONS: Significant changes in authorship patterns and characteristics of articles were observed from 1989 to 2009. We found an increase in the number of authors per article over time, with fewer single-author papers now published. The explanations for the changes are likely multifactorial, including increased pressure to publish, increased research complexity, and inappropriate authorship. To prevent inappropriate author-number inflation and to preserve authorship's meaning and value, authors should adhere to the criteria for authorship from the International Committee of Medical Journal Editors.

Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results.

PURPOSE: The objective of this study was to assess changes in the water apparent diffusion coefficient (ADC) and in pharmacokinetic parameters obtained from the fast-exchange regime (FXR) modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during neoadjuvant chemotherapy in breast cancer. MATERIALS AND METHODS: Eleven patients with locally advanced breast cancer underwent MRI examination prior to and after chemotherapy but prior to surgery. A 1.5-T scanner was used to obtain T1, ADC and DCE-MRI data. DCE-MRI data were analyzed by the FXR model returning estimates of K(trans) (volume transfer constant), v(e) (extravascular extracellular volume fraction) and tau(i) (average intracellular water lifetime). Histogram and correlation analyses assessed parameter changes post-treatment. RESULTS: Significant (P < .05) changes or trends towards significance (P < .10) were seen in all parameters except tau(i), although there was qualitative reduction in tau(i) values post-treatment. In particular, there was reduction (P < .035) in voxels with K(trans) values in the range 0.2-0.5 min(-1) and a decrease (P < .05) in voxels with ADC values in the range 0.99 x 10(-3) to 1.35 x 10(-3) mm2/s. ADC and v(e) were negatively correlated (r = -.60, P < .02). Parameters sensitive to water distribution and geometry (T(1), v(e), tau(i) and ADC) correlated with a multivariable linear regression model. CONCLUSION: The analysis presented here is sensitive to longitudinal changes in breast tumor status; K(trans) and ADC are most sensitive to these changes. Relationships between parameters provide information on water distribution and geometry in the tumor environment.

Purchasing, installing and operating dental amalgam separators: practical issues.

BACKGROUND: Growing environmental concern over the accumulation of mercury in some fish has led some state and local environmental agencies to pursue stricter regulation of mercury in wastewater. Dental offices are an identifiable source of mercury in the form of dental amalgam. Although mercury in dental amalgam is not immediately bioavailable (that is, it has not been shown to contribute significantly to the problem of mercury in fish tissue), environmental agencies in some locales are asking dental offices to install amalgam separators in an effort to reduce amalgam discharges beyond those already achieved through chairside traps and vacuum filters. Field experience indicates that the configuration and operation of the dental office infrastructure can significantly affect the choice of separator, as well as the operation and maintenance of the installed equipment. OVERVIEW: The authors review factors related to office infrastructure and operation that dentists should consider when investing in an amalgam separator. They also provide a cost-analysis worksheet and checklist that may be useful to dentists who are considering purchasing a separator. CONCLUSIONS AND CLINICAL IMPLICATIONS: Before purchasing or installing an amalgam separator, dentists should consider factors specific to the available models, including size and maintenance requirements. In addition, office-specific actors should be considered (such as the plumbing configuration, available space for installation and subsequent access to that space for equipment replacement and maintenance). Dentists also should research whether any local or state regulations exist that might influence product selection or installation. Dentists should consider the effect an amalgam separator could have on existing suction equipment. Finally, dentists will want to consider the short- and long-term costs (including maintenance and parts replacement) of the available options.