10 North Greene St. Baltimore Va Medical Center
Baltimore MD 21201
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Building a roadmap to biomarker qualification: challenges and opportunities. - Biomarkers in medicine
The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program.
Evaluation of a rapid microbiological method with a mixed culture biofilm model. - PDA journal of pharmaceutical science and technology / PDA
During the past decade, rapid microbiological methods (RMMs) have continued to make inroads into the pharmaceutical and medical device industries. This has led to the development of guidelines for the validation of alternative microbiological methods for both quantitative and qualitative applications. Many studies regarding RMMs have focused on testing performed with planktonic microorganisms. In some applications there is the possibility that microorganisms may also be present as biofilms. When evaluating an RMM, consideration should be given to the potential for biofilm formation within the context of the application and whether microorganisms derived from biofilm would influence the response of the method. This study reflects the evaluation of an RMM with both planktonic microorganisms and microorganisms derived from a mixed culture biofilm.Many new rapid microbiological methods (RMMs) have been developed that have the potential to replace conventional microbiological methods in a wide range of applications including sterility testing, microbial enumeration, environmental monitoring, microbial identification, and other areas. Qualification of these new methods is frequently based on testing performed with planktonic (non-aggregated) microorganisms. However, microorganisms can aggregate together to form biofilms in both natural and manufacturing environments. Purified water systems in particular may be susceptible to the development of biofilms. Because the properties of microorganisms in a biofilm may differ from those in a planktonic state, qualification of an RMM with microorganisms derived from a relevant biofilm model may be appropriate depending on the application and the potential for biofilm formation. This study describes the evaluation of one such RMM, the Chemunex ScanRDIÂ®, with both planktonic microorganisms and microorganisms derived from a mixed culture biofilm model.
Ophthalmic viscoelastic devices as a cleaning challenge. - Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation
Common practice when validating the cleaning of medical devices is to employ clinically relevant test soils as a challenge to the cleaning process. During use, medical devices may come into contact with a variety of materials that are difficult to clean. One example of this is the use of ophthalmic viscoelastic devices (OVDs) in cataract surgery. This study evaluated the effectiveness of a procedure for cleaning the lumens of a phacoemulsification handpiece using two different OVDs as test soils. The results of this study demonstrate that effective cleaning of the aspiration and irrigation lumens of a phacoemulsification handpiece may be achieved if the manufacturer's recommended cleaning procedures are followed.
PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate. - ACS nano
Tumor-associated inflammation mediates the development of a systemic immunosuppressive milieu that is a major obstacle to effective treatment of cancer. Inflammation has been shown to promote the systemic expansion of immature myeloid cells which have been shown to exert immunosuppressive activity in laboratory models of cancer as well as cancer patients. Consequentially, significant effort is underway toward the development of therapies that decrease tumor-associated inflammation and immunosuppressive cells. The current study demonstrated that a previously described deep tissue imaging modality, which utilized indocyanine green-loaded calcium phosphosilicate nanoparticles (ICG-CPSNPs), could be utilized as an immunoregulatory agent. The theranostic application of ICG-CPSNPs as photosensitizers for photodynamic therapy was shown to block tumor growth in murine models of breast cancer, pancreatic cancer, and metastatic osteosarcoma by decreasing inflammation-expanded immature myeloid cells. Therefore, this therapeutic modality was termed PhotoImmunoNanoTherapy. As phosphorylated sphingolipid metabolites have been shown to have immunomodulatory roles, it was hypothesized that the reduction of immature myeloid cells by PhotoImmunoNanoTherapy was dependent upon bioactive sphingolipids. Mechanistically, PhotoImmunoNanoTherapy induced a sphingosine kinase 2-dependent increase in sphingosine-1-phosphate and dihydrosphingosine-1-phosphate. Furthermore, dihydrosphingosine-1-phosphate was shown to selectively abrogate myeloid lineage cells while concomitantly allowing the expansion of lymphocytes that exerted an antitumor effect. Collectively, these findings revealed that PhotoImmunoNanoTherapy, utilizing the novel nontoxic theranostic agent ICG-CPSNP, can decrease tumor-associated inflammation and immature myeloid cells in a sphingosine kinase 2-dependent manner. These findings further defined a novel myeloid regulatory role for dihydrosphingosine-1-phosphate. PhotoImmunoNanoTherapy holds the potential to be a revolutionary treatment for cancers with inflammatory and immunosuppressive phenotypes.
Nephrogenic systemic fibrosis and class labeling of gadolinium-based contrast agents by the Food and Drug Administration. - Radiology
In 2007, the Food and Drug Administration requested that manufacturers of all approved gadolinium-based contrast agents (GBCAs), drugs widely used in magnetic resonance imaging, use nearly identical text in their product labeling to describe the risk of nephrogenic systemic fibrosis (NSF). Accumulating information about NSF risks led to revision of the labeling text for all of these drugs in 2010. The present report summarizes the basis and purpose of this class-labeling approach and describes some of the related challenges, given the evolutionary nature of the NSF risk evidence. The class-labeling approach for presentation of product risk is designed to decrease the occurrence of NSF and to enhance the safe use of GBCAs in radiologic practice.Â© RSNA, 2012.
Nanoliposomal minocycline for ocular drug delivery. - Nanomedicine : nanotechnology, biology, and medicine
Nanoliposomal technology is a promising drug delivery system that could be employed to improve the pharmacokinetic properties of clearance and distribution in ocular drug delivery to the retina. We developed a nanoscale version of an anionic, cholesterol-fusing liposome that can encapsulate therapeutic levels of minocycline capable of drug delivery. We demonstrate that size extrusion followed by size-exclusion chromatography can form a stable 80-nm liposome that encapsulates minocycline at a concentration of 450 Â± 30 Î¼M, which is 2% to 3% of loading material. More importantly, these nontoxic nanoliposomes can then deliver 40% of encapsulated minocycline to the retina after a subconjunctival injection in the STZ model of diabetes. Efficacy of therapeutic drug delivery was assessed via transcriptomic and proteomic biomarker panels. For both the free minocycline and encapsulated minocycline treatments, proinflammatory markers of diabetes were downregulated at both the messenger RNA and protein levels, validating the utility of biomarker panels for the assessment of ocular drug delivery vehicles.Authors developed a nano-liposome that can encapsulate minocycline for optimized intraocular drug delivery. These nontoxic nanoliposomes delivered 40% of encapsulated minocycline to the retina after a subconjunctival injection in a diabetes model.Copyright Â© 2013 Elsevier Inc. All rights reserved.
Ceramide kinase regulates TNFÎ±-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells. - Cellular signalling
A persistent inflammatory reaction is a hallmark of chronic and acute pathologies in the central nervous system (CNS) and greatly exacerbates neuronal degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNFÎ±) plays a pivotal role in the initiation and progression of inflammatory processes provoking oxidative stress, eicosanoid biosynthesis, and the production of bioactive lipids. We established in neuronal cells that TNFÎ± exposure dramatically increased Mg(2+)-dependent neutral sphingomyelinase (nSMase) activity thus generating the bioactive lipid mediator ceramide essential for subsequent NADPH oxidase (NOX) activation and oxidative stress. Since many of the pleiotropic effects of ceramide are attributable to its metabolites, we examined whether ceramide kinase (CerK), converting ceramide to ceramide-1-phosphate, is implicated both in NOX activation and enhanced eicosanoid production in neuronal cells. In the present study, we demonstrated that TNFÎ± exposure of human SH-SY5Y neuroblastoma caused a profound increase in CerK activity. Depleting CerK activity using either siRNA or pharmacology completely negated NOX activation and eicosanoid biosynthesis yet, more importantly, rescued neuronal viability in the presence of TNFÎ±. These findings provided evidence for a critical function of ceramide-1-phospate and thus CerK activity in directly linking sphingolipid metabolism to oxidative stress. This vital role of CerK in CNS inflammation could provide a novel therapeutic approach to intervene with the adverse consequences of a progressive CNS inflammation.Copyright Â© 2011 Elsevier Inc. All rights reserved.
Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. - Cancer biology & therapy
Poor prognosis cancers, such as pancreatic cancer, represent inherent challenges for ceramide-based nanotherapeutics due to metabolic pathways, which neutralize ceramide to less toxic or pro-oncogenic metabolites. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a bioactive lipid that is pro-apoptotic to many cancer cells, but not to normal cells. In this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide (Lip-C6) with either gemcitabine or an inhibitor of glucosylceramide synthase. We first assessed the biological effect of Lip-C6 in PANC-1 cells, a gemcitabine-resistant human pancreatic cancer cell line, and found that low doses alone did not induce cell toxicity. However, cytotoxicity was achieved by combining Lip-C6 with either non-toxic sub-therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Furthermore, these combinations with Lip-C6 cooperatively inhibited PANC-1 tumor growth in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine did not. Furthermore, by including PDMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS3, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we have demonstrated that nanoliposomal ceramide can be an effective anti-pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization.
Targeted indocyanine-green-loaded calcium phosphosilicate nanoparticles for in vivo photodynamic therapy of leukemia. - ACS nano
Leukemia is one of the most common and aggressive adult cancers, as well as the most prevalent childhood cancer. Leukemia is a cancer of the hematological system and can be divided into a diversity of unique malignancies based on the onset of the disease as well as the specific cell lineages involved. Cancer stem cells, including recently identified leukemia stem cells (LSCs), are hypothesized to be responsible for cancer development, relapse, and resistance to treatment, and new therapeutics targeting these cellular populations are urgently needed. Nontoxic and nonaggregating calcium phosphosilicate nanoparticles (CPSNPs) encapsulating the near-infrared fluoroprobe indocyanine green (ICG) were recently developed for diagnostic imaging and drug delivery as well as for photodynamic therapy (PDT) of solid tumors. Prior studies revealed that specific targeting of CPSNPs allowed for enhanced accumulation within breast cancer tumors, via CD71 targeting, or pancreatic cancer tumors, via gastrin receptor targeting. In the present study, ICG-loaded CPSNPs were evaluated as photosensitizers for PDT of leukemia. Using a novel bioconjugation approach to specifically target CD117 or CD96, surface features enhanced on leukemia stem cells, in vitro ICG-CPSNP PDT of a murine leukemia cell line and human leukemia samples were dramatically improved. Furthermore, the in vivo efficacy of PDT was dramatically enhanced in a murine leukemia model by utilizing CD117-targeted ICG-CPSNPs, resulting in 29% disease-free survival. Altogether, this study demonstrates that leukemia-targeted ICG-loaded CPSNPs offer the promise to effectively treat relapsing and multidrug-resistant leukemia and to improve the life of leukemia patients.
Wastewater dilution index partially explains observed polybrominated diphenyl ether flame retardant concentrations in osprey eggs from Columbia River Basin, 2008-2009. - Ecotoxicology (London, England)
Several polybrominated biphenyl ether (PBDE) congeners were found in all 175 osprey (Pandion haliaetus) eggs collected from the Columbia River Basin between 2002 and 2009. Î£PBDE concentrations in 2008-2009 were highest in osprey eggs from the two lowest flow rivers studied; however, each river flowed through relatively large and populous metropolitan areas (Boise, Idaho and Spokane, Washington). We used the volume of Wastewater Treatment Plant (WWTP) discharge, a known source of PBDEs, as a measure of human activity at a location, and combined with river flow (both converted to millions of gallons/day) created a novel approach (an approximate Dilution Index) to relate waterborne contaminants to levels of these contaminants that reach avian eggs. This approach provided a useful understanding of the spatial osprey egg concentration patterns observed. Individual osprey egg concentrations along the Upper Willamette River co-varied with the Dilution Index, while combined egg data (geometric means) from rivers or segments of rivers showed a strong, significant relationship to the Dilution Index with one exception, the Boise River. There, we believe osprey egg concentrations were lower than expected because Boise River ospreys foraged perhaps 50-75% of the time off the river at ponds and lakes stocked with fish that contained relatively low Î£PBDE concentrations. Our limited temporal data at specific localities (2004-2009) suggests that Î£PBDE concentrations in osprey eggs peaked between 2005 and 2007, and then decreased, perhaps in response to penta- and octa-PBDE technical mixtures no longer being used in the USA after 2004. Empirical estimates of biomagnification factors (BMFs) from fish to osprey eggs were 3.76-7.52 on a wet weight (ww) basis or 4.37-11.0 lipid weight. Our earlier osprey study suggested that Î£PBDE egg concentrations >1,000Â ng/g ww may reduce osprey reproductive success. Only two of the study areas sampled in 2008-2009 contained individual eggs with Î£PBDE concentrations >1,000Â ng/g, and non-significant (PÂ >Â 0.30) negative relationships were found between Î£PBDEs and reproductive success. Additional monitoring is required to confirm not only the apparent decline in PBDE concentrations in osprey eggs that occurred during this study, but also to better understand the relationship between PBDEs in eggs and reproductive success.
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