Jefferson School of Pharmacy Faculty Papers Copyright (c) 2013 Thomas Jefferson University All rights reserved. http://jdc.jefferson.edu/pharmacyfp Recent documents in Jefferson School of Pharmacy Faculty Papers en-us Fri, 22 Feb 2013 17:21:53 PST 3600 The Use of Glucarpidase in an Open-Label Treatment Protocol as Adjunctive Treatment for a Patient with Delayed Methotrexate Elimination http://jdc.jefferson.edu/pharmacyfp/13 http://jdc.jefferson.edu/pharmacyfp/13 Wed, 09 Jan 2013 13:20:30 PST 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 resulted in recognizable toxicities
    • Myelosuppression
    • Mucositis
    • Nephrotoxicity
    • Acute hepatitis
    • Fatal toxicity à secondary to renal failure or sepsis

Prevention of Methotrexate Toxicity

  • Hydration
  • Alkalinization of urine
    • Sodium bicarbonate administration for urine pH ≥ 7
  • Leucovorin
    • Counteracts cellular damage caused by MTX as it is converted to tetrahydrofolate, a precursor of DNA synthesis
    • Does NOT reduce the amount of circulating MTX

Glucarpidase (Voraxaze®)

  • An enzyme produced in Escherichia Coli that hydrolyzes the carboxyl terminal glutamate from folic acid and its analogues, including MTX, resulting in inactive metabolites
  • Offers an alternative to rapidly reducing the amount of MTX in systemic circulation
  • Evaluated in 3 clinical studies à produced a clinically important reduction (CIR) in MTX concentrations in majority of patients (72/116, 62%)
    • Most frequently reported adverse events: allergic reaction and non-allergic paraesthesia

]]> Cheryl A. Abbas, PharmD et al. Heart Failure Transition of Care Program: The Pharmacist’s role in reducing readmissions http://jdc.jefferson.edu/pharmacyfp/12 http://jdc.jefferson.edu/pharmacyfp/12 Wed, 09 Jan 2013 13:16:16 PST 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 discharge protocols.

•RED documented lower readmission rates with enhanced discharge medication counseling and reducing the time between discharge and outpatient physician follow up

Changing the Standard of Care

•Using RED as a model, Thomas Jefferson University Hospital began its own multidisciplinary patient education and post-discharge follow-up program

•The hospital began with heart failure patients, since this disease state has one of the highest readmission rates

]]> Joseph Favatella, PharmD Candidate 2013 et al. Interprofessional Education in Didactic and Experiential Settings at the Jefferson School of Pharmacy http://jdc.jefferson.edu/pharmacyfp/11 http://jdc.jefferson.edu/pharmacyfp/11 Fri, 02 Nov 2012 11:14:25 PDT 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.

]]> Elena M. Umland et al. Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine. http://jdc.jefferson.edu/pharmacyfp/10 http://jdc.jefferson.edu/pharmacyfp/10 Thu, 07 Apr 2011 06:27:20 PDT 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 membrane fractions, yet were not present in buoyant membranes. Most D(5) receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D(5) receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D(1) receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D(5) and D(2) receptor subtypes were not significantly altered by cocaine treatment. These data imply that D(5) receptors are predominantly cytoplasmic, D(2) receptors are diffusely distributed within the cell, whereas D(1) receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation.

]]> Pamela J Voulalas et al. An evidence-based review of fat modifying supplemental weight loss products. http://jdc.jefferson.edu/pharmacyfp/9 http://jdc.jefferson.edu/pharmacyfp/9 Tue, 16 Nov 2010 09:44:15 PST 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 people use dietary supplements for weight loss. To date, there is little clinical evidence to support their use. More data is necessary to determine the efficacy and safety of these supplements. Healthcare providers should assist patients in weighing the risks and benefits of dietary supplement use for weight loss.

]]> Amy M Egras et al. Troglitazone stimulates beta-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor. http://jdc.jefferson.edu/pharmacyfp/8 http://jdc.jefferson.edu/pharmacyfp/8 Wed, 07 Jul 2010 07:53:23 PDT 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 measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1(A)R-G(q) protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of beta arr1/2 was selective to AT1(A)R as the response was prevented by an ARB- and Trog-mediated beta arr1/2 recruitment to beta1-adrenergic receptor (beta 1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be beta arr2-dependent, as cardiomyocytes isolated from beta arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR gamma agonist Trog acts at the AT1(A)R to simultaneously block G(q) protein activation and induce the recruitment of beta arr1/2, which leads to an increase in cardiomyocyte contractility.

]]> Douglas G G. Tilley et al. Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition http://jdc.jefferson.edu/pharmacyfp/7 http://jdc.jefferson.edu/pharmacyfp/7 Wed, 24 Feb 2010 06:59:28 PST 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 brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol.

Results: Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.

Conclusion: Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.

]]> Marwa A. Aboukhatwa et al. Title: Student Readiness For Interprofessional Learning: Baseline and Midpoint in the Jefferson Health Mentor Program http://jdc.jefferson.edu/pharmacyfp/6 http://jdc.jefferson.edu/pharmacyfp/6 Wed, 27 Jan 2010 11:05:58 PST Objectives: To measure pharmacy student readiness for interprofessional education (IPE) and compare the results to medical, nursing, occupational therapy (OT), and physical therapy (PT) student peers using the Readiness for Interprofessional Learning Scale (RIPLS).

Methods: First-year medical, nursing, OT, pharmacy, and PT students (n=544) participate in a 2-year longitudinal, interdisciplinary curriculum where they are assigned to a team including a Health Mentor (patient volunteer with chronic condition). Aims include understanding team roles and patient-centered care. All students complete the RIPLS at baseline and after completing years 1 and 2. RIPLS contains 3 subscales related to readiness for IPE: 1.)teamwork and collaboration; 2.)professional identity; and 3.)roles and responsibilities.

Results: At baseline, using the total RIPLS score, significant differences were observed between medicine and nursing, OT, and pharmacy (all p-values <0.05) with the latter 3 disciplines appearing to be more ready for IPE. Pharmacy (n=70) scored significantly higher than medicine in subscale 1 (p=0.028), subscale 2 (p=0.003), and subscale 3 (p=0.005). The RIPLS results for this cohort at the end of year 1 will be collected and analyzed in April 2009.

Implications: Identifying differences in baseline readiness for IPE allows all programs participating in the delivery of this longitudinal curriculum to recognize the strengths and areas of improvements. Information will be used in improving the orientation to and curricular components of the program.

]]> Elena M. Umland et al. Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina. http://jdc.jefferson.edu/pharmacyfp/5 http://jdc.jefferson.edu/pharmacyfp/5 Thu, 03 Dec 2009 12:44:24 PST 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 the ratio between NIPAAm and Dex-lactateHEMA and altering the physical size of the hydrogels. The hydrogels are not toxic to R28 retinal neuron cells in culture medium with 100% cell viability. The hydrogels can be implanted under the conjunctiva without causing adverse effects to the retina based on hematoxylin and eosin stain, immunostaining for microglial cell activation, and electroretinography. These subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases.

]]> Gauri P. Misra et al. Transcriptional regulation of cytokine function in airway smooth muscle cells. http://jdc.jefferson.edu/pharmacyfp/4 http://jdc.jefferson.edu/pharmacyfp/4 Thu, 08 Oct 2009 08:20:56 PDT 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 provide an overview of the transcriptional mechanisms as well as intracellular signaling pathways regulating cytokine functions in ASM cells. The recent discovery of toll-like receptors in ASM cells represents a significant development in our understanding of the immuno-modulatory capabilities of ASM cells. Thus, we also review emerging evidence of the inflammatory response to toll-like receptor activation in ASM cells.

]]> Deborah Clarke et al. Airway smooth muscle as an immunomodulatory cell. http://jdc.jefferson.edu/pharmacyfp/3 http://jdc.jefferson.edu/pharmacyfp/3 Tue, 06 Oct 2009 12:57:55 PDT 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.

]]> Gautam Damera et al. Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring http://jdc.jefferson.edu/pharmacyfp/2 http://jdc.jefferson.edu/pharmacyfp/2 Mon, 27 Oct 2008 08:57:15 PDT Previous studies documented significant behavioral changes in the offspring of cocaine-exposed mothers. We now explore the hypothesis that maternal cocaine exposure could alter the fetal epigenetic machinery sufficiently to cause lasting neurochemical and functional changes in the offspring. Pregnant CD1 mice were administered either saline or 20 mg/kg cocaine twice daily on gestational days 8-19. Male pups from each of ten litters of the cocaine and control groups were analyzed at 3 (P3) or 30 (P30) days postnatum. Global DNA methylation, methylated DNA immunoprecipitation followed by CGI(2) microarray profiling and bisulfite sequencing, as well as quantitative real-time RT-PCR gene expression analysis, were evaluated in hippocampal pyramidal neurons excised by laser capture microdissection. Following maternal cocaine exposure, global DNA methylation was significantly decreased at P3 and increased at P30. Among the 492 CGIs whose methylation was significantly altered by cocaine at P3, 34% were hypermethylated while 66% were hypomethylated. Several of these CGIs contained promoter regions for genes implicated in crucial cellular functions. Endogenous expression of selected genes linked to the abnormally methylated CGIs was correspondingly decreased or increased by as much as 4-19-fold. By P30, some of the cocaine-associated effects at P3 endured, reversed to opposite directions, or disappeared. Further, additional sets of abnormally methylated targets emerged at P30 that were not observed at P3. Taken together, these observations indicate that maternal cocaine exposure during the second and third trimesters of gestation could produce potentially profound structural and functional modifications in the epigenomic programs of neonatal and prepubertal mice.

]]> Svetlana I. Novikova et al. Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain http://jdc.jefferson.edu/pharmacyfp/1 http://jdc.jefferson.edu/pharmacyfp/1 Thu, 22 May 2008 06:54:33 PDT BACKGROUND: Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [3H]cytidine-labeled CDP-diacylglycerol and [3H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors.

RESULTS: Multiple compounds from each antidepressant category significantly stimulated [3H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants can mobilize CDP-diacylglycerol from additional pools lying outside of the inositol cycle. Further, unlike direct serotonergic, muscarinic, or alpha-adrenergic agonists that elicited comparable or lower effects on CDP-diacylglycerol versus inositol phosphates, the antidepressants dose-dependently induced significantly greater accumulations of CDP-diacylglycerol.

CONCLUSION: Chemically divergent antidepressant agents commonly and significantly enhanced the accumulation of CDP-diacylglycerol. The latter is not only a derived product of phosphoinositide hydrolysis but is also a crucial intermediate in the biosynthesis of several signaling substrates. Hence, altered CDP-diacylglycerol signaling might be implicated in the pathophysiology of depression or the mechanism of action of diverse antidepressant medications.

]]> Kimberly R. Tyeryar et al.