Valerio Jr. L.G.,White Oak Research Center |
Arvidson K.B.,U.S. Food and Drug Administration |
Busta E.,U.S. Food and Drug Administration |
Minnier B.L.,White Oak Research Center |
And 3 more authors.
Molecular Nutrition and Food Research | Year: 2010
Computational toxicology employing quantitative structure-activity relationship(QSAR) modeling is an evidence-based predictive method being evaluated by regulatory agencies for risk assessment and scientific decision support for toxicological endpoints of interest such as rodent carcinogenicity. Computational toxicology is being tested for its usefulness to support the safety assessment of drug-related substances (e.g. active pharmaceutical ingredients, metabolites, impurities), indirect food additives, and other applied uses of value for protecting public health including safety assessment of environmental chemicals. The specific use of QSAR as a chemoinformatic tool for estimating the rodent carcinogenic potential of phyto-chemicals present in botanicals, herbs, and natural dietary sources is investigated here by an external validation study, which is the most stringent scientific method of measuring predictive performance. The external validation statistics for predicting rodent carcinogenicity of 43 phytochemicals, using two computational software programs evaluated at the FDA, are discussed. One software program showed very good performance for predicting non-carcinogens (high specificity), but both exhibited poor performance in predicting carcinogens (sensitivity), which is consistent with the design of the models. When predictions were considered in combination with each other rather than based on any one software, the performance for sensitivity was enhanced, However, Chi-square values indicated that the overall predictive performance decreases when using the two computational programs with this particular data set. This study suggests that complementary multiple computational toxicology software need to be carefully selected to improve global QSAR predictions for this complex toxicological endpoint. © 2009 WILEY-VCH Verlag GmbH & Co.
Dobrovolsky V.N.,US Toxicology |
Elespuru R.K.,Health-U |
Bigger C.A.H.,White Oak Research Center |
Robison T.W.,White Oak Research Center |
Heflich R.H.,US Toxicology
Environmental and Molecular Mutagenesis | Year: 2011
The endogenous X-linked PIG-A gene is involved in the synthesis of glycosyl phosphatidyl inositol (GPI) anchors that tether specific protein markers to the exterior of mammalian cell cytoplasmic membranes. Earlier studies in rodent models indicate that Pig-a mutant red blood cells (RBCs) can be induced in animals treated with genotoxic agents, and that flow cytometry can be used to identify rare RBCs deficient in the GPI-anchored protein, CD59, as a marker of Pig-a gene mutation. We investigated if a similar approach could be used for detecting gene mutation in humans. We first determined the frequency of spontaneous CD59-deficient RBCs (presumed PIG-A mutants) in 97 self-identified healthy volunteers. For most subjects, the frequency of CD59-deficient RBCs was low (average of 5.1 ± 4.9 × 10 -6; median of 3.8 × 10 -6 and mutant frequency less than 8 × 10 -6 for 75% of subjects), with a statistically significant difference in median mutant frequencies between males and females. PIG-A RBC mutant frequency displayed poor correlation with the age and no correlation with the smoking status of the subjects. Also, two individuals had markedly increased CD59-deficient RBC frequencies of ∼300 × 10 -6 and ∼100 × 10 -6. We then monitored PIG-A mutation in 10 newly diagnosed cancer patients undergoing chemotherapy with known genotoxic drugs. The frequency of CD59-deficient RBCs in the blood of the patients was measured before the start of chemotherapy and three times over a period of ∼6 months while on/after chemotherapy. Responses were generally weak, most observations being less than the median mutant frequency for both males and females; the greatest response was an approximate three-fold increase in the frequency of CD59-deficient RBCs in one patient treated with a combination of cisplatin and etoposide. These results suggest that the RBC PIG-A assay can be adopted to measuring somatic cell mutation in humans. Further research is necessary to determine the assay's sensitivity in detecting mutations induced by genotoxic agents acting via different mechanisms. © 2011 Wiley-Liss, Inc.
Stockbridge M.D.,University of Maryland University College |
Taylor K.,White Oak Research Center
Therapeutic Innovation and Regulatory Science | Year: 2015
There is an increased risk of medication error and harm to a patient whenever 2 or more drug product names appear alike in sound, look, or meaning. Any ambiguity of the proprietary name (“trade” or “brand” name) of a drug product can lead to errors in ordering, dispensing, or administering medication. A drug’s name is a critical identifier, and correct product identification is important to the responsible administration of medicine. This article describes a series of tools created for regulatory reviewers to enhance the review of proprietary names under current federal regulations, with the goal of encouraging further innovation toward the goal of medication safety. These tools include measures of orthographic, phonetic, and semantic similarities and are designed be used together with the existing computerized measures of similarity. It is the hope that highlighting the importance of medication error reporting for the safety review process will further encourage health care professionals to provide adequate and detailed reporting regarding medication errors, which will lead to improvements in the overall safety review process. © 2015, © The Author(s) 2015.
Cohen E.,White Oak Research Center |
Agrawal A.,White Oak Research Center |
Connors M.,University of Maryland University College |
Hansen B.,White Oak Research Center |
And 2 more authors.
Journal of Neural Engineering | Year: 2011
We have developed a novel method to study the effects of electrical stimulation of the local retina directly under an epiretinal stimulus electrode in real time. Using optical coherence tomography (OCT) and a superfused retinal eyecup preparation, we obtained high-resolution images of the rabbit retina directly under an optically transparent saline-filled fluoropolymer stimulation tube electrode. During OCT imaging, 50 Hz trains of biphasic current pulses 1 ms/phase (23-749 νC cm -2 ph -1) were applied to the retinal surface for 5 min. After imaging, the stimulated regions were stained with the dye propidium iodide (PI) to reveal cytotoxic damage. Pulse train stimulation at 44-133 νC cm -2 ph -1 had little effect on the retina; however, trains ≥442 νC cm -2 ph -1 caused increases in the reflectance of the inner plexiform layer (IPL) and edema. The damage seen in retinal OCT images matched the pattern observed in histological sections, and in the PI staining. With pulse trains ≥442 νC cm -2 ph -1, rapid increases in the reflectivity of the IPL could be observed under the stimulus electrode. Below the electrode, we observed a ring-like pattern of retinal detachment in the subretinal space. The OCT imaging method may be useful for analyzing overstimulation of neuronal tissue by electrodes in many brain regions. © 2011 IOP Publishing Ltd.
Senior J.R.,White Oak Research Center
Clinical Pharmacology and Therapeutics | Year: 2012
Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean Not what it is too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better. © 2012 American Society for Clinical Pharmacology and Therapeutics.
Wu H.,White Oak Research Center |
Khan M.,White Oak Research Center
Sustainable Packaging Symposium 2012 | Year: 2012
As an emerging technology, THz spectroscopy has gained increasing attention in the pharmaceutical area during the last decade. This attention is due to the fact that (1) it provides a promising alternative approach for in-depth understanding of both intermolecular interaction among pharmaceutical molecules and pharmaceutical product quality attributes; (2) it provides a promising alternative approach for enhanced process understanding of certain pharmaceutical manufacturing processes; and (3) the FDA pharmaceutical quality initiatives, most noticeably, the Process Analytical Technology (PAT) initiative. In this work, the current status and progress made so far on using THz spectroscopy for pharmaceutical development and pharmaceutical PAT applications, including FDA-NIST collaboration on THz spectroscopy pharmaceutical characterization and PAT applications, are discussed. In the spirit of demonstrating the utility of first principles modeling approach for addressing model validation challenge and reducing unnecessary model validation "burden" for facilitating THz pharmaceutical PAT applications, two scientific case studies are created and discussed. Furthermore, other technical challenges and opportunities associated with adapting THz spectroscopy as a pharmaceutical PAT tool are highlighted.
Wu H.,White Oak Research Center |
White M.,White Oak Research Center |
Foringer R.,White Oak Research Center |
Khan M.,White Oak Research Center
AIChE Annual Meeting, Conference Proceedings | Year: 2012
Process Analytical Technology (PAT) has become an essential part for pharmaceutical process and product understanding, real-time process monitoring and control during the last several years. Previously, we reported the development of a novel real-time PAT-based approach to measure the nucleation induction time and elucidate the nucleation and growth mechanisms of a dynamic pharmaceutical co-precipitation process at 25°C. The goal of this work is to understand the effect of temperature (15°C, 25°C, 35°C) on nucleation induction time for a dynamic pharmaceutical co-precipitation process (naproxen-Eudragit L100-alcohol-water) at various ratios of drug/polymer. Real-time inline process monitoring and nucleation induction time (t ind) measurement have been accomplished using FBRM and PVM simultaneously. It was shown that: (1) the plots of tind vs. the ratio of naproxen to polymer (Q) display two distinct linear segments; (2) the plots of ln(tind) vs. (lnS)-2 (S is the maximum allowable super-saturation level) display two distinct linear segments which agree well with the classic nucleation theory (CNT); (3) Quantitative relationships based on CNT among the kinetic parameter A, dimensionless thermodynamic parameter B, and temperature (T) suggest that the nucleation and growth process is followed by the interface transfer mechanism. Therefore, at low S level, the nucleation is governed by primary heterogonous nucleation; while at high S level it is governed by primary homogeneous nucleation; after nucleation, the growth is controlled by the interface transfer mechanism. This work demonstrated the utility of real time process PAT monitoring on process understanding and process kinetic mechanism elucidating, thus could enhance the science-based pharmaceutical regulation in the Quality-by-Design (QbD) domain.
PubMed | White Oak Research Center
Type: Journal Article | Journal: Journal of neural engineering | Year: 2011
We have developed a novel method to study the effects of electrical stimulation of the local retina directly under an epiretinal stimulus electrode in real time. Using optical coherence tomography (OCT) and a superfused retinal eyecup preparation, we obtained high-resolution images of the rabbit retina directly under an optically transparent saline-filled fluoropolymer stimulation tube electrode. During OCT imaging, 50 Hz trains of biphasic current pulses 1 ms/phase (23-749 C cm(-2) ph(-1)) were applied to the retinal surface for 5 min. After imaging, the stimulated regions were stained with the dye propidium iodide (PI) to reveal cytotoxic damage. Pulse train stimulation at 44-133 C cm(-2) ph(-1) had little effect on the retina; however, trains 442 C cm(-2) ph(-1) caused increases in the reflectance of the inner plexiform layer (IPL) and edema. The damage seen in retinal OCT images matched the pattern observed in histological sections, and in the PI staining. With pulse trains 442 C cm(-2) ph(-1), rapid increases in the reflectivity of the IPL could be observed under the stimulus electrode. Below the electrode, we observed a ring-like pattern of retinal detachment in the subretinal space. The OCT imaging method may be useful for analyzing overstimulation of neuronal tissue by electrodes in many brain regions.
PubMed | White Oak Research Center
Type: Journal Article | Journal: Nature reviews. Nephrology | Year: 2012
Surrogate end points have the potential to facilitate drug development because effects on surrogate end points can sometimes be demonstrated more rapidly and in smaller studies than can effects on clinical outcomes of interest. Proteinuria has been repeatedly proposed as a surrogate end point for renal outcomes in drug development; however, the FDA has generally not accepted effects on proteinuria as evidence of a drugs effectiveness. Proteinuria is an early marker of some kidney diseases and increases in proteinuria can predict risk of disease progression. Whether or not treatment effects on proteinuria can reliably predict treatment effects on renal outcomes is not known. Nevertheless, it may be reasonable to use effects on proteinuria as a basis for accelerated approval of a drug if certain conditions are met. Approval under this pathway carries with it a requirement to complete a study after drug approval that verifies the anticipated treatment benefit.
News Article | December 15, 2016
SAN FRANCISCO & NEW YORK--(BUSINESS WIRE)--White Oak Global Advisors, LLC on behalf of its institutional clients (collectively “White Oak”), announced today that White Oak has expanded its asset-based lending platform through the acquisition of Capital Business Credit, LLC (“CBC”), a leading commercial finance company that provides asset-based loans, factoring and trade finance products to small and middle-market companies. As part of the transaction, White Oak acquired CBC’s existing loan portfolio, which is comprised of over $300 million of assets employed, and the CBC team along with its office locations in New York, Charlotte, Fort Lauderdale, Los Angeles, Hong Kong and Shanghai. The CBC and White Oak platform will be able to provide asset-based loans, factoring and trade finance credit facilities ranging from $1-$100 million to underserved middle-market companies. White Oak is pleased to welcome the senior leadership team of CBC including Andrew Tananbaum, Robert Grbic, Michael Fortino and the approximately 80 members of the CBC team, and believes their expertise will allow White Oak to achieve further success and scale in the commercial finance sectors. “The acquisition of CBC expands White Oak’s lending capabilities into the significant and growing asset-based lending market while providing White Oak’s investors with attractive alternative credit strategies. Capitalizing on acquisitions of platforms with disciplined lending practices, such as CBC, is an important component of White Oak’s overall strategy,” White Oak CEO Andre Hakkak said in a statement. “This transaction with White Oak provides CBC with the capability to offer a larger set of factoring and trade finance solutions and products. We now have the ability to finance larger, more complex transactions and the flexibility to offer our current clients a broader array of offerings,” said Andrew Tananbaum of CBC. “In our nearly 30 years of providing asset-based and trade finance solutions, CBC has focused on serving small and middle-market companies and we now have the breadth and capabilities to offer our best-in-class financing products to a much broader portion of the economy.” Houlihan Lokey served as an exclusive financial advisor to CBC in connection with the transaction. White Oak Global Advisors, LLC is a leading global alternative asset manager specializing in originating and providing financing solutions to facilitate the growth, refinancing and recapitalization of small and medium enterprises. Since its inception in 2007, White Oak Global Advisors, LLC’s disciplined investment process focuses on delivering risk-adjusted investment returns and establishing long term partnerships with our borrowers. More information can be found at www.whiteoaksf.com. Established in 1988, Capital Business Credit, LLC is a global financial products and services company. The Company’s solutions include full-service factoring, accounts receivable management services, inventory lending, asset-based lending, and international financing. CBC Trade Finance, a division of CBC, provides trade finance solutions for U.S.-based importers working with Asia-based suppliers (exporters). Capital Business Credit is based in New York, with offices in Hong Kong, Shanghai, Los Angeles, Charlotte, and Fort Lauderdale. Capital Business Credit is an indirect wholly-owned subsidiary of White Oak Fixed Income Fund C, L.P. More information can be found at www.capitalbusinesscredit.com. Houlihan Lokey (NYSE: HLI) is a global investment bank with expertise in mergers and acquisitions, capital markets, financial restructuring, valuation and strategic consulting. The firm serves corporations, institutions, and governments worldwide with offices in the U.S., Europe, and the Asia-Pacific region. Independent advice and intellectual rigor are hallmarks of our commitment to client success across our advisory services. Houlihan Lokey is ranked as the No. 1 M&A advisor for all U.S. transactions, the No. 1 global restructuring advisor, and the No. 1 global M&A fairness opinion advisor over the past 15 years, according to Thomson Reuters. More information can be found at www.hl.com.