Pharmacy and Pharmaceutical Sciences Commons^™

Choline Is An Intracellular Messenger Linking Extracellular Stimuli To Ip3-Evoked Ca2+ Signals Through Sigma-1 Receptors, Eugen Brailoiu, Sumita Chakraborty, G. Cristina Brailoiu, Pingwei Zhao, Jeffrey L. Barr, Marc A. Ilies, Ellen M. Unterwald, Mary E. Abood, Colin W. Taylor

College of Pharmacy Faculty Papers

Sigma-1 receptors (Sig-1Rs) are integral ER membrane proteins. They bind diverse ligands, including psychoactive drugs, and regulate many signaling proteins, including the inositol 1,4,5-trisphosphate receptors (IP₃Rs) that release Ca²⁺ from the ER. The endogenous ligands of Sig-1Rs are unknown. Phospholipase D (PLD) cleaves phosphatidylcholine to choline and phosphatidic acid (PA), with PA assumed to mediate all downstream signaling. We show that choline is also an intracellular messenger. Choline binds to Sig-1Rs, it mimics other Sig-1R agonists by potentiating Ca²⁺ signals evoked by IP₃Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and …

Formulation, Characterization And Evaluation Of Morusin Loaded Niosomes For Potentiation Of Anticancer Therapy, Srishti Agarwal, M. Sheikh Mohamed, Sreejith Raveendran, Ankit K. Rochani, Toru Maekawa, D. Sakthi Kumar

College of Pharmacy Faculty Papers

Morusin, a water-insoluble prenylated flavonoid is known for its numerous medicinal properties. It manifests its anticancer potential by suppression of genes involved in tumor progression. However, poor solubility of the drug results in low bioavailability and rapid degradation thus hindering its clinical utilization. In order to overcome this, we have synthesized a niosome system composed of non-ionic surfactant span 60 and cholesterol using a thin-layer evaporation technique to improve the aqueous-phase solubility of the drug. Highly cytocompatible niosomes of 479 nm average size with smooth and uniform spherical morphology were synthesized in a facile manner. Unlike free morusin, nanomorusin was …

Effects Of Platelet-Activating Factor On Brain Microvascular Endothelial Cells., Eugen Brailoiu, Christine L. Barlow, Servio H. Ramirez, Mary E. Abood, G. Cristina Brailoiu

College of Pharmacy Faculty Papers

Platelet-activating factor (PAF) is a potent phospholipid mediator that exerts various pathophysiological effects by interacting with a G protein-coupled receptor. PAF has been reported to increase the permeability of the blood-brain barrier (BBB) via incompletely characterized mechanisms. We investigated the effect of PAF on rat brain microvascular endothelial cells (RBMVEC), a critical component of the BBB. PAF produced a dose-dependent increase in cytosolic Ca²⁺ concentration; the effect was prevented by the PAF receptor antagonist, WEB2086. The effect of PAF on cytosolic Ca²⁺ was abolished in Ca²⁺-free saline or in the presence of L-type voltage-gated Ca^{2+ …}

Natural Bioactive Compounds: Alternative Approach To The Treatment Of Glioblastoma Multiforme, Vilas Desai, Alok Bhushan

College of Pharmacy Faculty Papers

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds …

Medication Complications In Extracorporeal Membrane Oxygenation., Ami G. Shah, Michelle Peahota, Brandi Thoma, Walter K. Kraft

College of Pharmacy Faculty Papers

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population.

Mechanisms Of Modulation Of Brain Microvascular Endothelial Cells Function By Thrombin., Eugen Brailoiu, Megan M. Shipsky, Guang Yan, Mary E. Abood, G. Cristina Brailoiu

College of Pharmacy Faculty Papers

Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic Ca

A Randomized Placebo-Controlled Pilot Study Of The Efficacy And Safety Of D-Cycloserine In People With Chronic Back Pain., Thomas J. Schnitzer, Souraya Torbey, Kristi Herrmann, Gagan Kaushal, Renita Yeasted, A. Vania Apkarian

College of Pharmacy Faculty Papers

BACKGROUND: Few effective pharmacological treatment options exist for chronic back pain, the leading cause of disability in the US, and all are associated with significant adverse effects.

OBJECTIVE: To determine the efficacy and safety of D-cycloserine, a partial agonist to the N-methyl-D-aspartate receptor, in the treatment of chronic low back pain.

METHODS: A total of 41 participants with chronic back pain who met all inclusion and exclusion criteria were enrolled in a double-blind, placebo-controlled randomized pilot trial of D-cycloserine. Treatment was administered orally for six weeks at escalating daily doses of 100 mg, 200 mg, and 400 mg, each for …

Polypharmacy And Potentially Inappropriate Medication Use In Geriatric Oncology., Manvi Sharma, Kah Poh Loh, Ginah Nightingale Pharmd, Bcop, Supriya G. Mohile, Holly M. Holmes

College of Pharmacy Faculty Papers

Polypharmacy is a highly prevalent problem in older persons, and is challenging to assess and improve due to variations in definitions of the problem and the heterogeneous methods of medication review and reduction. The purpose of this review is to summarize evidence regarding the prevalence and impact of polypharmacy in geriatric oncology patients and to provide recommendations for assessment and management. Polypharmacy has somewhat variably been incorporated into geriatric assessment studies in geriatric oncology, and polypharmacy has not been consistently evaluated as a predictor of negative outcomes in patients with cancer. Once screened, interventions for polypharmacy are even more uncertain. …

Aptamer-Hybrid Nanoparticle Bioconjugate Efficiently Delivers Mirna-29b To Non-Small-Cell Lung Cancer Cells And Inhibits Growth By Downregulating Essential Oncoproteins., Maryna Perepelyuk, Christina Maher, Ashakumary Lakshmikuttyamma, Sunday A. Shoyele

College of Pharmacy Faculty Papers

MicroRNAs (miRNAs) are potentially attractive candidates for cancer therapy. However, their therapeutic application is limited by lack of availability of an efficient delivery system to stably deliver these potent molecules intracellularly to cancer cells while avoiding healthy cells. We developed a novel aptamer-hybrid nanoparticle bioconjugate delivery system to selectively deliver miRNA-29b to MUC1-expressing cancer cells. Significant downregulation of oncoproteins DNMT3b and MCL1 was demonstrated by these MUC1 aptamer-functionalized hybrid nanoparticles in A549 cells. Furthermore, downregulation of these oncoproteins led to antiproliferative effect and induction of apoptosis in a superior version when compared with Lipofectamine 2000. This novel aptamer-hybrid nanoparticle bioconjugate …

Mechanisms Of Activation Of Nucleus Accumbens Neurons By Cocaine Via Sigma-1 Receptor-Inositol 1,4,5-Trisphosphate-Transient Receptor Potential Canonical Channel Pathways., Jeffrey L. Barr, Elena Deliu, Gabriela Cristina Brailoiu, Pingwei Zhao, Guang Yan, Mary E. Abood, Ellen M. Unterwald, Eugen Brailoiu

College of Pharmacy Faculty Papers

Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, …

Irisin Evokes Bradycardia By Activating Cardiac-Projecting Neurons Of Nucleus Ambiguus., Eugen Brailoiu, Elena Deliu, Romeo A Sporici, Gabriela Cristina Brailoiu

College of Pharmacy Faculty Papers

Irisin is a newly identified hormone induced in muscle and adipose tissues by physical activity. This protein and its encoding gene have been identified in the brain; in addition, the precursor for irisin, FNDC5, can cross the blood-brain barrier. The fact that irisin is secreted during exercise together with the lower resting heart rate in athletes prompted us to investigate the effect of irisin on cardiac-projecting vagal neurons of nucleus ambiguus, a key regulatory site of heart rate. In vitro experiments in cultured nucleus ambiguus neurons indicate that irisin activates these neurons, inducing an increase in cytosolic Ca(2+) concentration and …

Evaluation Of A Pharmacist-Led Medication Assessment Used To Identify Prevalence Of And Associations With Polypharmacy And Potentially Inappropriate Medication Use Among Ambulatory Senior Adults With Cancer., Ginah Nightingale, Emily Hajjar, Kristine Swartz, Jocelyn Andrel-Sendecki, Andrew Chapman

College of Pharmacy Faculty Papers

PURPOSE: The use of multiple and/or inappropriate medications in seniors is a significant public health problem, and cancer treatment escalates its prevalence and complexity. Existing studies are limited by patient self-report and medical record extraction compared with a pharmacist-led comprehensive medication assessment.

PATIENTS AND METHODS: We retrospectively examined medication use in ambulatory senior adults with cancer to determine the prevalence of polypharmacy (PP) and potentially inappropriate medication (PIM) use and associated factors. PP was defined as concurrent use of five or more and less than 10 medications, and excessive polypharmacy (EPP) was defined as 10 or more medications. PIMs were …

Clevidipine For Acute Blood Pressure Management In The Neurological Intensive Care Unit, Dorota K. Szarlej, Pharmd, Jessica L. Mckeon, Pharmd, Akta S. Patel, Pharmd, Bcps, Amber King

College of Pharmacy Faculty Papers

Clevidipine is a third generation intravenous dihydropyridine calcium channel antagonist approved for treatment of acute hypertension when oral therapy is not feasible or desirable. It is an arterial vasodilator that is metabolized by plasma esterases; therefore, it is eliminated independently of the liver and kidney.1 Clevidipine has been studied for the control of perioperative hypertension2-5 as well as for the management of hyper-tensive crises6 when immediate blood pressure control is clinically necessary. Benefits include its tolerability, rapid onset and offset, and easy titration with predictable response. Other continuously infused intravenous antihypertensives used in the neurocritical care patient population include nicardipine, …

Identification Of Distant Drug Off-Targets By Direct Superposition Of Binding Pocket Surfaces., Marcel Schumann, Roger S Armen

College of Pharmacy Faculty Papers

Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target ("distant off-targets"). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant …

Fibroblast Growth Factor-2 (Fgf2) And Syndecan-1 (Sdc1) Are Potential Biomarkers For Putative Circulating Cd15+/Cd30+ Cells In Poor Outcome Hodgkin Lymphoma Patients., Rajendra Gharbaran, Andre Goy, Takemi Tanaka, Jongwhan Park, Chris Kim, Nafis Hasan, Swathi Vemulapalli, Sreeja Sarojini, Madalina Tuluc, Kip Nalley, Pritish Bhattacharyya, Andrew Pecora, K Stephen Suh

College of Pharmacy Faculty Papers

BACKGROUND: High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.

METHODS AND MATERIALS: Bioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples …

Heart Failure Transition Of Care Program: The Pharmacist’S Role In Reducing Readmissions, Joseph Favatella, Pharmd Candidate 2013, Joanne Heil, Pharmd, Bcps

College of Pharmacy Faculty Papers

Presented at: ASHP Mid-Year Clinical Meeting in Las Vegas.

Introduction & Background

Current Trends¹

•Approximately 19.6% of Medicare patients are readmitted to the hospital within 30 days

•These readmissions accounted for $15 billion of Medicare spending in 2009

Changes Coming

•As part of the Affordable Care Act, Medicare will not be reimbursing hospitals for patients readmitted within 30 days of discharge

•Hospitals have already begun improving discharge protocols to provide a greater continuity of care and minimize the financial loss of future readmissions

A Model²

•Boston University Medical Center's Re-Engineered Discharge (RED) was the first program to improve …

The Use Of Glucarpidase In An Open-Label Treatment Protocol As Adjunctive Treatment For A Patient With Delayed Methotrexate Elimination, Cheryl A. Abbas, Pharmd, Anne Marie Valorie-Oberle, Bs, Pharmd, Bcop

College of Pharmacy Faculty Papers

Presented at: ASHP Clinical MidYear Meeting in Las Vegas.

Background

Methotrexate (MTX)

• Cytotoxic agent that competitively inhibits dihydrofolate reductase (DHFR), the intracellular enzyme responsible for converting folic acid to reduced folate inhibitors, necessary for DNA synthesis
• Used since 1948 in the treatment of various malignancies and as a disease-modifying agent in rheumatoid arthritis and psoriasis
• High-dose mexthotrexate (HDMTX) began in 1960s solely or in combination with other chemotherapeutic agents

Methotrexate Toxicity

• Almost exclusively cleared through the kidneys
  • Precipitation of drug occurs in the renal tubules
  • Prolonged elevations of systemic MTX concentrations results in potential serious toxicity
• Increased use of HDMTX …

Interprofessional Education In Didactic And Experiential Settings At The Jefferson School Of Pharmacy, Elena M. Umland, Cynthia A. Sanoski, Emily R. Hajjar, Bhavik Shah

College of Pharmacy Faculty Papers

Presented at: 2012 Annual Meeting of the American Association of Colleges of Pharmacy in Kissimmee, Florida.

Objective:

To evaluate the various IPE offerings at a new school of pharmacy at a large academic medical center.

Differential Subcellular Distribution Of Rat Brain Dopamine Receptors And Subtype-Specific Redistribution Induced By Cocaine., Pamela J Voulalas, John Schetz, Ashiwel S Undieh

College of Pharmacy Faculty Papers

We investigated the subcellular distribution of dopamine D(1), D(2) and D(5) receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D(1) receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D(2) receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant …

An Evidence-Based Review Of Fat Modifying Supplemental Weight Loss Products., Amy M Egras, William R Hamilton, Thomas L Lenz, Michael S Monaghan

College of Pharmacy Faculty Papers

Objective. To review the literature on fat modifying dietary supplements commonly used for weight loss. Methods. Recently published randomized, placebo-controlled trials were identified in PubMed, MEDLINE, International Pharmaceutical Abstracts, Cochrane Database, and Google Scholar using the search terms dietary supplement, herbal, weight loss, obesity, and individual supplement names. Discussion. Data for conjugated linoleic acid (CLA), Garcinia cambogia, chitosan, pyruvate, Irvingia gabonensis, and chia seed for weight loss were identified. CLA, chitosan, pyruvate, and Irvingia gabonensis appeared to be effective in weight loss via fat modifying mechanisms. However, the data on the use of these products is limited. Conclusion. Many obese …

Troglitazone Stimulates Beta-Arrestin-Dependent Cardiomyocyte Contractility Via The Angiotensin Ii Type 1a Receptor., Douglas G G. Tilley, Anny D. Nguyen, Howard A. Rockman

College of Pharmacy Faculty Papers

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR gamma-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR gamma activity, thus we hypothesized that a PPAR gamma agonist may exert physiologic effects via the angiotensin II type 1(A) receptor (AT1(A)R). In AT1(A)R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR gamma agonist troglitazone (Trog) enhanced AT1(A)R internalization and recruitment of endogenous beta-arrestin 1/2 (beta arr1/2) to the AT1(A)R. A fluorescence assay to …

Antidepressant Stimulation Of Cdp-Diacylglycerol Synthesis Does Not Require Monoamine Reuptake Inhibition, Marwa A. Aboukhatwa, Ashiwel S. Undieh

College of Pharmacy Faculty Papers

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of …

The Role Of Transdermal Estrogen Sprays And Estradiol Topical Emulsion In The Management Of Menopause-Associated Vasomotor Symptoms., Amy M Egras, Elena Umland

College of Pharmacy Faculty Papers

Vasomotor symptoms (VMS) are among the most bothersome complaints of postmenopausal women. To date, the most widely studied and effective treatment for VMS is hormone replacement therapy, consisting of estrogen (in women without a uterus) or estrogen plus progestin (in women with a uterus). Traditionally, oral estrogens have been used for treatment. However, over the years, additional estrogen formulations have been developed including transdermal patches; vaginal rings, creams, and tablets; and injectable preparations. Two newer formulations are transdermal estrogen spray and estradiol topical emulsion. This review evaluates the current literature assessing the use of these two newer formulations for the …

Subconjunctivally Implantable Hydrogels With Degradable And Thermoresponsive Properties For Sustained Release Of Insulin To The Retina., Gauri P. Misra, Ravi S.J. Singh, Tomas S. Aleman, Samuel G. Jacobson, Thomas W. Gardner, Tao L. Lowe

College of Pharmacy Faculty Papers

The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying …

Airway Smooth Muscle As An Immunomodulatory Cell., Gautam Damera, Omar Tliba, Reynold A. Panettieri, Jr.

College of Pharmacy Faculty Papers

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may also render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are shared with those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as synthetic properties of ASM.

Transcriptional Regulation Of Cytokine Function In Airway Smooth Muscle Cells., Deborah Clarke, Gautam Damera, Maria B. Sukkar, Omar Tliba

College of Pharmacy Faculty Papers

The immuno-modulatory properties of airway smooth muscle have become of increasing importance in our understanding of the mechanisms underlying chronic inflammation and structural remodeling of the airway wall in asthma and chronic obstructive pulmonary disease (COPD). ASM cells respond to many cytokines, growth factors and lipid mediators to produce a wide array of immuno-modulatory molecules which may in turn orchestrate and perpetuate the disease process in asthma and COPD. Despite numerous studies of the cellular effects of cytokines on cultured ASM, few have identified intracellular signaling pathways by which cytokines modulate or induce these cellular responses. In this review we …