The University of Maryland School of Pharmacy, founded in 1841, is a thriving center for life sciences research and community service. Through its education, research, and service programs, the School of Pharmacy strives to improve the health and well-being of society by aiding in the discovery, development, and use of medicines.

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  • Medical Costs of Alpha-1 Antitrypsin Deficiency-associated Chronic Obstructive Pulmonary Disease in the United States

    Sieluk, Jan; Mullins, C. Daniel; 0000-0002-1833-0273
    Objectives: The objective of this study was to isolate the healthcare resource utilization and economic burden attributable to the presence of a genetic factor among Chronic Obstructive Pulmonary Disease (COPD) patients with and without Alpha-1 Antitrypsin Deficiency (AATD), twelve months before and after their initial COPD diagnosis. Methods: Retrospective analysis of OptumLabs® Data Warehouse claims (OLDW; 2000 – 2017). The OLDW is a comprehensive, longitudinal real-world data asset with de-identified lives across claims and clinical information. AATD-associated COPD cases were matched with up to 10 unique non-AATD-associated COPD controls. Healthcare resource use and costs were assigned into the following categories: office (OV), outpatient (OP), and emergency room visits (ER), inpatients stays (IP), prescription drugs (RX), and other services (OTH). A generalized linear model was used to estimate total pre- and post-index (initial COPD diagnosis) costs from a third-party payer’s perspective (2018 USD) controlling for age, gender, race/ethnicity, census region, augmentation therapy use, oxygen use, insurance type, year of COPD diagnosis, and Charlson Comorbidity Score. Healthcare resource utilization was estimated using a negative binomial regression. Results: The study population consisted of 8,881 patients (953 cases matched with 7,928 controls). The AATD-associated COPD cohort had higher expenditures and use of OV and OTH services, as well as OV, OP, ER, RX, and OTH before and after the index date, respectively. Adjusted total cost ratios for AATD-associated COPD patients as compared to controls were 2.036 [95% CI: 1.601 – 2.590] and 1.976 [95% CI: 1.550 – 2.517] while the incremental cost difference totaled $6,861 [95% CI: $3,025 - $10,698] an $5,772 [95% CI: $1,940 - $9,604] per patient before and after the index date, respectively. Conclusions: Twelve months before and after their initial COPD diagnosis, patients with AATD incur higher healthcare utilization costs that are double the cost of similar patients without AATD. This study also suggests that increased costs of AATD-associated COPD are not solely attributable to augmentation therapy use. Future studies should further explore the relationship between augmentation therapy, healthcare resource use, and other AATD-associated COPD expenditures.
  • Advances in Mass Spectrometric Structural Biology Techniques for Pattern Recognition Receptor Ligands of Microbial Origin

    Oyler, Benjamin; Goodlett, David Robinson, 1960-
    Pattern recognition receptors (PRR) are the innate immune system’s first-line sentinels for distinguishing “self” from “non-self.” Many molecules found in the bacterial cell wall are PRR ligands, including lipopolysaccharide (LPS), cardiolipin (CL), and peptidoglycan (PGN). Molecular structural biology techniques are essential for determining both basic cell biology and host-bacteria interactions through ligand-receptor binding mechanisms. Recent interest in designer PRR ligands or PRR ligand mimetics for use in drug discovery pipelines have given this research more translational value as well. Mass spectrometry (MS) has the unique capability to derive primary structures of ions as well as monitor many different ions in complex mixtures. Several different advances in PRR ligand structure analysis were achieved in this dissertation. First, chemical structure of an LPS-derived vaccine was determined using a top down tandem MS approach. Several different instrumental configurations and methods were employed to demonstrate complementarity of data and broad applicability of the approach. Second, CL from a newly discovered Actinomycete marine sponge symbiont was analyzed and compared to CL from a terrestrial Firmicute to generate hypotheses about host-bacterium interactions. This was the first molecular analysis of any secondary metabolites from this species of bacteria. Third, PGN subunits (muropeptides) from Rickettsia typhi were analyzed in a data dependent global LC-tandem MS approach. This was the first example of PGN structure discovery for R. typhi and the first example of this approach applied to PGN structure elucidation for any Rickettsiae species. All of these developments will help to advance PRR-ligand interaction research – an emerging and promising field for development of novel disease treatment and prevention approaches. Modulation of the innate immune response to bacterial insult is a challenging task without a clear understanding of underlying molecular mechanisms and how they might be manipulated by medicine. One key step in this process is development of sensitive and specific chemical analysis methods fit to acquire unequivocally interpretable data. While all of the methods described herein were applied to specific biological problems, their applicability to other scientific questions is broad.
  • Mass Spectrometry based structural analysis and systems immunoproteomics strategies deduce specifics of host-pathogen interactions

    Khan, Mohd M.; Goodlett, David Robinson, 1960-
    The innate immune system is the first line of defense against pathogens. Pattern recognition receptors (PRRs), such as the Toll-like receptors (TLRs) sense and sample pathogen-associated molecular patterns (PAMPs). On the host myeloid cell surface, the proinflammatory Gram-negative bacterial outer membrane component lipopolysaccharide (LPS, also known as endotoxin) activates the innate immune system via TLR4. Intracellularly, LPS is detected by the noncanonical inflammasome through caspase4/5/11. In the present work, mass spectrometry (MS)-based top-down structural analysis of LPS uncovered major determinants of molecular pathogenesis, and MS-based systems immunoproteomics elucidated specific features of the immune response against endotoxin. We used targeted proteomics to profile the host response to the pathogens Escherichia coli, Staphylococcus aureus, and Burkholderia cenocepacia, and we discovered significant temporal changes in the macrophage secretome. Additionally, we identified global changes in protein secretion in TLR4- and caspase11- stimulated macrophages. Finally, we observed bacterial proteomic rewiring within the biofilm forms of Burkholderia, possibly explaining the observed lowering in sensitivity to antibiotics.
  • “Zoom in” on protein functions through integrated mass spectrometry

    Li, Wenjing; Kane, Maureen A.; 0000-0002-5387-7004
    Mass spectrometry (MS) has been a powerful tool in cracking the protein codes for human biology regarding to their structure and function. Rich information can be collected through MS either at protein level (native/intact, top-down) or peptide level (middle-down and bottom-up), however integration of these approaches in order to generate a comprehensive view of the protein(s) has been underutilized. In this thesis, strategic integration of MS platforms was developed for two protein systems with the aim of elucidating the fundamental molecular function related to protein-ligand or protein-protein interactions toward fulfilling the potential of MS-based platforms for application in drug discovery. In the first study, the integration of native top down mass spectrometry coupled with ion mobility analysis provided extensive structural information to understand gold finger protein complex that formed with the exchange of zinc. Native top down analysis identified the stoichiometry, binding residues and preferable binding sites when gold replaces zinc in the parent nonclassical zinc finger protein tristetraprolin (TTP). The subtle difference in conformation were monitored by ion mobility simultaneously. The heterogeneity of gold fingers that were reflected by MS-based assays was not obvious by other conventional assays, suggesting the unique analytical power of MS for in-depth drug-target investigations. In the second study, bottom-up and native MS were applied on interrogation of the role of cellular retinol binding protein, type I (CrbpI) in maintaining retinoid homeostasis. The endogenous level of CrbpI was confidently quantified through customized bottom-up assays, which demonstrated a positive correlation with active metabolite retinoic acid (RA). Further investigation focused on the interaction between CrbpI and its biological ligands (retinol and retinal), and the RA-producing enzyme retinal dehydrogenase 1(Raldh1), using native mass spectrometry. These studies contributed fundamental information toward elucidating the role of CrbpI in facilitating RA biosynthesis, and also suggested its potential as a disease marker.
  • Patient consent to publication and data sharing in industry and NIH-funded clinical trials

    Spence, O'Mareen; Uba, Richie Onwuchekwa; Shin, Seongbin; Doshi, Peter (BioMed Central Ltd., 2018)
    Background: Participants are recruited into clinical trials under the assumption that the research will contribute to medical knowledge. Therefore, non-publication trials-and, more recently, lack of data sharing-are widely considered to violate the trust of trial participants. Existing practices regarding patient consent to publication and data sharing have not been evaluated. Analyzing informed consent forms (ICFs), we studied what trial participants were told regarding investigators' intention to contribute to medical knowledge, publish trial results, and share de-identified trial data. Methods: We obtained 98 ICFs of industry-funded pre-marketing trials for all (17) antibiotics approved by the European Medicines Agency and 46 ICFs of publicly funded trials from the National Heart, Lung and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) data repository. Three authors independently reviewed ICFs to identify and extract what was stated or implied regarding: (1) publication of results; (2) sharing de-identified data; (3) data ownership; (4) confidentiality of identifiable data; and (5) whether the trial will produce knowledge that offers public benefit. Consensus was obtained from the two reviewers with the greatest overall agreement on all five measures. Disagreements were resolved through discussion among all authors. Results: Four (3%) trials indicated a commitment to publish trial results; 140 (97%) did not commit to publishing trial results; six (4%) indicated a commitment to share de-identified data with third party researchers. Commitments to share were more common in publicly funded trials than industry-funded trials (7% vs 3%). A total of 103 (72%) ICFs indicated the trials will or may produce knowledge that offers public benefits, while 131 (91%) ICFs left unstated who "owned" trial data; of those with statements, the sponsor always claimed ownership. Patient confidentiality was guaranteed in 137 (95%) trials. Conclusions: Our results suggest that consent forms rarely disclose investigators' intentions regarding the sharing of de-identified data or publication of trial results. Copyright 2018 The Author(s).
  • Atrial Fibrillation Risk-Stratification Schemes: Improving Patient-Centeredness and Precision

    Oehrlein, Elisabeth Maria; Perfetto, Eleanor M. (2018)
    Background: Despite treatment-guideline recommendations and availability medications to reduce stroke risk, widespread underutilization of oral anticoagulants (OACs) has been previously documented among individuals with atrial fibrillation (AF). Younger age and female gender are important in light of evidence that these groups, in particular, may not receive optimal AF care. The objective of this dissertation was to identify: 1) What are the barriers to patients initiating OACs? 2) Are providers aware of and using the RSSs and do disparities exist by age and gender? 3) Are RSSs predictive of stroke and OAC initiation among subpopulations (women and <65 years of age)? Methods: In Aim 1, we invited patients and health care providers (HCPs) to participate in in-depth interviews. In aims 2 and 3, we conducted retrospective cohort studies using Optum’s Clinformatic Data Mart (2008-2016). We used logistic regression to calculate odds ratios and 95% confidence intervals to identify whether RSSs were associated with OAC initiation and whether disparities exist by age or gender in aim 2. For Aim 3, we used a discrete time approach to estimate the risk of ischemic stroke associated with RSSs. Separately, we tested whether incorporating risk factors identified in the literature as predictive of ischemic stroke improved prediction among women and patients ≤65 years. Results: Themes from qualitative interviews include: specialists heightened perception of stroke risk compared to generalists and comorbidities/characteristics absent from RSSs also factor into risk consideration. The proportion of patients initiating OACs was only approximately 30%. CHADS2, but not CHA2DS2-VASc, scores corresponded with higher odds of OAC initiation. We found no statistically significant differences between odds of initiating OACs among OAC-recommended males/females or age categories. Among women and those ≤65 years, all CHA2DS2-VASc scores >1 and CHADS2 scores >0 were significant predictors of stroke. Prognostic models developed within subpopulations were no better at predicting stroke than existing RSSs. Conclusions: RSSs are associated with ischemic stroke among newly diagnosed females and <65 years of age patients. Initiation of OAC treatment was consistently low. More research is needed to more clearly understand why RSSs might not be followed and why OACs are not initiated.
  • Innovation of Vancomycin Treatment in Neonates Via A Bayesian Dose Optimization Toolkit For Adaptive Individualized Therapeutic Management

    Pastoor, Devin DeForest; Gobburu, Jogarao (2018)
    Personalized medicine continues to gain momentum as a topic for discussion, yet directly linking patient-level decision support to more advanced analytical techniques, such as nonlinear mixed effects modeling, is not being practiced in most hospitals. Current practice for Vancomycin therapy uses dosing nomograms to determine the dosing regimen for patients. For simplicity, these nomograms stratify patients into bins based on some combination of weight, serum creatinine, and/or age to adjust starting regimens. Yet, studies across the US and Europe have shown as few as 37% of neonates achieve recommended target concentrations using such nomograms. The purpose of this research was to develop a bayesian decision support toolkit to provide adaptive, individualized dose recommendations for neonates. First, a bayesian nonlinear mixed effect model was developed and qualified for predictive forecasting in individual patients. Second, this model was used to develop a novel algorithm for dose individualization. Finally, a web application was developed to allow clinicians to provide decision support for clinicians involved in vancomycin dosing decisions. The proposed strategy can decrease the number of patients improperly dosed up to 90%, drastically reducing the chance for treatment failure, toxicity-related adverse events, and resistance development.
  • University of Maryland School of Pharmacy. Annual Report 2015-2016

    Unknown author (University of Maryland, Baltimore. School of Pharmacy, 2016)
  • Data Snapshot 2018

    Unknown author (University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2018)
  • Lower Gastrointestinal Tract Delivery of a Tetra-specific Antibody ABAB-IgG1 for the Treatment of Clostridium Difficile Infection (CDI)

    Jiang, Bowen; Stephen W. Hoag; 0000-0003-0913-6468
    More than 246 protein or peptide therapeutics are on the market, including 47 monoclonal antibodies approved since early 1980s. Although most protein therapeutics are administered parentally, treatments for gastrointestinal diseases such as Clostridium difficile infection (CDI), ulcerative colitis and Crohn’s Disease would benefit from an oral delivery system that can target biologics to a site in the GI tract, with less systematic exposure and therefore less systematic toxicity, given the targets of disease are in the GI tract. This research focused on local delivery of a novel antibody therapeutic, ABAB-IgG1, for the treatment of CDI. The antibody was fabricated into a multi-particulate delivery system comprised of nonpareil beads and functional polymers using spray coating techniques. A proof-of-concept study was conducted using BSA as a model protein. BSA was first spray layered onto beads, then coated with pH sensitive polymers. There was no significant change in BSA conformation and aggregation profiles after the spray layering process. BSA multi-particulates were stable for at least 1 month stored at 4 ⁰C. In vitro dissolution testing showed that the enteric coated BSA beads remained intact in acidic media, while releasing BSA in higher pH buffers. A Design of Experiments strategy was used to understand how the formulation and process parameters impacted antibody stability during spray coating process and during accelerated stability studies. The formulation of novel structured antibody ABAB-IgG1 was also optimized based on the conformational and colloidal stabilities using various high throughput biophysical characterization techniques. The multi-particulate delivery system of ABAB-IgG1 was evaluated both in vitro and in vivo, and showed the feasibility of delivering ABAB-IgG1 to the lower GI tract using the multi-particulate system. The multi-particulate delivery system, which is well-studied for small molecule drugs, can be adopted to biologics without modification of existing fluid bed processing equipment, which implies the possibility of efficient scale up of this technique in existing industrial-scale equipment.
  • Maryland Mentor : 2019

    Unknown author (University of Maryland, Baltimore. School of Pharmacy. Experiential Learning Program, 2019)
  • Poison Prevention Press 2019

    Unknown author (University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2019)
  • The possible harms of statins: What do product labels, patient package inserts, and pharmacy leaflets tell us?

    Doshi, Peter; Sieluk, Jan; Hung, Anna (American Pharmacists Association, 2019)
    Objectives: To evaluate the degree to which health care professionals and patients receive consistent messages regarding the possible harms of statins. Design: Cross-sectional study of prescribing information (PI), patient package inserts (PPIs), and pharmacy leaflets for 8 statins approved by the U.S. Food and Drug Adminstration. Setting: Not applicable. Participants: Not applicable. Main Outcome Measures: All passages describing 7 adverse events (diarrhea, arthralgia, dyspepsia, confusion, memory loss, rhabdomyolysis, and kidney failure) were extracted from PIs, PPIs, and pharmacy leaflets. For each type of information source and adverse event (drug-harm pair), 2 reviewers independently judged passages as indicating either a confirmed, unconfirmed, or mixed causal relationship between statin and adverse event (drug-harm pair). Disagreements were resolved through consensus, and the consistency between information sources was calculated. Results: PI and PPI consistently conveyed the relationship between a given statin and given adverse event (either both “confirmed” or both “unconfirmed”) in 12 of 17 evaluable drug-harm pairs. PPIs and pharmacy leaflets were consistent in 10 of 10 evaluable drug-harm pairs. PIs indicated a confirmed, causal relationship in 15 drug-harm pairs that were not mentioned in pharmacy leaflets. Likewise, PPIs indicated a confirmed, causal relationship in 7 drug-harm pairs that were not listed in pharmacy leaflets. Conclusion: Despite the widespread use of statins, we discovered considerable ambiguity in language used to describe the evidence concerning their possible harms and variable consistency between PIs, PPIs, and pharmacy leaflets. Further study is needed to understand the reason why pharmacy leaflets did not list, in 15 cases, adverse events that PIs indicated were causally related to the statin.
  • ToxTidbits 2019

    Unknown author (University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2019)
  • A Method to Streamline Management of Excused Absences

    Klimas, Christopher; Tucker, Shannon R.; Coop, Andrew; Layson-Wolf, Cherokee (2018-07)
  • When to include clinical study reports and regulatory documents in systematic reviews

    Doshi, Peter (BMJ Publishing Group, 2018-10-11)
    Reporting bias is a major threat to the validity and credibility of systematic reviews. This article outlines the rationale for accessing clinical study reports and other regulatory documents (regulatory data) as a means of addressing reporting bias and identifies factors that may help decide whether (or not) to include regulatory data in systematic reviews. The article also describes the origins and current state of regulatory data access and summarises a survey of current systematic reviewers' practices in considering regulatory data for inclusion in systematic reviews. How to access and extract regulatory data is not addressed. Organisations and other stakeholders such as Cochrane should encourage the use of data from clinical study reports as an important source of data in reviews of pharmaceutical interventions particularly when the intervention in question is of high importance and the risk of reporting bias is great.
  • Maryland Poison Center Annual Report 2017

    Unknown author (University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2017)

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