Medicine and Health Sciences Commons^™

Functional Assessment Of Missense Variants In The Abcc6 Gene Implicated In Pseudoxanthoma Elasticum, A Heritable Ectopic Mineralization Disorder., Luke Kowal, Jianhe Huang, Hongbin Luo, Jagmohan Singh, Adam E Snook, Jouni Uitto, Qiaoli Li

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6

Development And Preclinical Investigation Of Physically Cross-Linked And Ph-Sensitive Polymeric Gels As Potential Vaginal Contraceptives, Ankit K. Rochani, Vivek Agrahari, Neelima Chandra, Onkar N Singh, Timothy J Mccormick, Gustavo F Doncel, Meredith R Clark, Gagan Kaushal

Department of Pharmacology and Experimental Therapeutics Faculty Papers

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of …

Pharmacologic Ascorbic Acid As Early Therapy For Hospitalized Patients With Covid-19: A Randomized Clinical Trial, Dagan Coppock, Pierre-Christian Violet, Gustavo Vasquez, Katherine Belden, Michael Foster, Bret Mullin, Devon Magee, Isabelle Mikell, Lokesh Shah, Victoria Powers, Brian Curcio, Daniel A. Monti, Mark Levine

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic …

T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C …

A Prospective Cohort Study Of The Clinical Predictors Of Bacteremia In Under-Five Children With Acute Undifferentiated Fever Attending A Secondary Health Facility In Northwestern Nigeria, Taofik Oluwaseun Ogunkunle, Timothy Olanrewaju Adedoyin, Samuel Kolade Ernest, Fatimah Hassan-Hanga, Abdulazeez Imam, Rasaq Olaosebikan, Stephen K Obaro

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Children with acute febrile illness with no localizing signs often receive antibiotics empirically in most resource-poor settings. However, little is known about the burden of bacteremia in this category of patients, and an appraisal is thus warranted. This will guide clinical practice and promote rational antibiotics use.

Methods: We prospectively followed up 140 under-five children who presented with acute undifferentiated fever at the emergency/outpatient pediatric unit of a secondary healthcare facility. Baseline clinical and laboratory information was obtained and documented in a structured questionnaire. We compared baseline characteristics between participants with bacteremia and those without bacteremia. We further fitted …

Spatial Metrics Of Interaction Between Cd163-Positive Macrophages And Cancer Cells And Progression-Free Survival In Chemo-Treated Breast Cancer, Brenton Maisel, Misung Yi, Amy R Peck, Yunguang Sun, Jeffrey A Hooke, Albert J Kovatich, Craig D Shriver, Hai Hu, Marja T Nevalainen, Takemi Tanaka, Nicole L Simone, Li Lily Wang, Hallgeir Rui, I Chervoneva

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor-associated macrophages (TAMs) promote progression of breast cancer and other solid malignancies via immunosuppressive, pro-angiogenic and pro-metastatic effects. Tumor-promoting TAMs tend to express M2-like macrophage markers, including CD163. Histopathological assessments suggest that the density of CD163-positive TAMs within the tumor microenvironment is associated with reduced efficacy of chemotherapy and unfavorable prognosis. However, previous analyses have required research-oriented pathologists to visually enumerate CD163+ TAMs, which is both laborious and subjective and hampers clinical implementation. Objective, operator-independent image analysis methods to quantify TAM-associated information are needed. In addition, since M2-like TAMs exert local effects on cancer cells through direct juxtacrine cell-to-cell interactions, …

Longitudinal Evaluation Of Azithromycin And Cytokine Concentrations In Amniotic Fluid Following One-Time Oral Dosing In Pregnancy., Rupsa C. Boelig, Edwin Lam, Ankit Rochani, Gagan Kaushal, Amanda Roman, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

To utilize noninvasive collection of amniotic fluid in the setting of preterm premature rupture of membranes (PPROMs) to report the time concentration profile of azithromycin in amniotic fluid over 7 days from a single dose, and evaluate the correlation between azithromycin concentration and inflammatory markers in amniotic fluid. Prospective cohort study of five pregnant patients admitted with PPROMs and treated with a single 1 g oral azithromycin dose. Amniotic fluid was collected from pads and used to quantify azithromycin concentration as well as TNFa, IL-1a, IL-1b, IL-6, IL-8, and IL-10 concentrations. Primary outcome was time/concentration profile of azithromycin in amniotic …

Correlations Between Coffee Consumption And Metabolic Phenotypes, Plasma Folate, And Vitamin B12: Nhanes 2003 To 2006., Pratibha V Nerurkar, Krupa Gandhi, John J Chen

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Metabolic syndrome (MetS) is prevalent not only among the overweight and obese but also normal weight individuals, and the phenotype is referred to as a metabolically unhealthy phenotype (MUHP). Besides normal weight individuals, overweight/obese individuals are also protected from MetS, and the phenotype is known as a metabolically healthy phenotype (MHP). Epidemiological studies indicate that coffee and micronutrients such as plasma folate or vitamin B12 (vit. B12) are inversely associated with MetS. However, correlations among coffee consumption metabolic phenotypes, plasma folate, and vit. B12 remain unknown. Our objective was to investigate the correlation between coffee consumption, metabolic phenotypes, plasma folate, …

Apc-Β-Catenin-Tcf Signaling Silences The Intestinal Guanylin-Gucy2c Tumor Suppressor Axis., Erik S Blomain, Jeffrey A Rappaport, Amanda M Pattison, Babar Bashir, Ellen Caparosa, Jonathan Stem, Adam E Snook, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation …

Functional Blockade Of E-Selectin In Tumor-Associated Vessels Enhances Anti-Tumor Effect Of Doxorubicin In Breast Cancer, Yoshihiro Morita, Macall Leslie, Hiroyasu Kameyama, Ganesh L R Lokesh, Norihisa Ichimura, Rachel Davis, Natalie Hills, Nafis Hasan, Roy Zhang, Yuji Kondo, David G Gorenstein, David E Volk, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both …

Unexpected Cell Type-Dependent Effects Of Autophagy On Polyglutamine Aggregation Revealed By Natural Genetic Variation In C. Elegans., J Alexander-Floyd, S Haroon, M Ying, A A Entezari, C Jaeger, M Vermulst, T Gidalevitz

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown.

RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to …

Autocatalytic Tissue Polymerization Reaction Mechanism In Colorectal Cancer Development And Growth., Bruce M Boman, Arthur Guetter, Ryan M Boman, Olaf A Runquist

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The goal of our study was to measure the kinetics of human colorectal cancer (CRC) development in order to identify aberrant mechanisms in tissue dynamics and processes that contribute to colon tumorigenesis. The kinetics of tumor development were investigated using age-at-tumor diagnosis (adenomas and CRCs) of familial adenomatous coli (FAP) patients and sporadic CRC patients. Plots of age-at-tumor diagnosis data as a function of age showed a distinct sigmoidal-shaped curve that is characteristic of an autocatalytic reaction. Consequently, we performed logistics function analysis and found an excellent fit (p < 0.05) of the logistic equation to the curves for age-at-tumor diagnoses. These findings indicate that the tissue mechanism that becomes altered in CRC development and growth involves an autocatalytic reaction. We conjecture that colonic epithelium normally functions as a polymer of cells which dynamically maintains itself in a steady state through an autocatalytic polymerization mechanism. Further, in FAP and sporadic CRC patients, mutation in the adenomatous polyposis coli (APC) gene increases autocatalytic tissue polymerization and induces tumor …

No Meaningful Drug Interactions With Doravirine, Lamivudine And Tenofovir Disoproxil Fumarate Co-Administration., Matt S. Anderson, Jocelyn Gilmartin, Li Fan, Ka Lai Yee, Walter K. Kraft, Ilias Triantafyllou, Christina Reitmann, Ying Guo, Rachael Liu, Marian Iwamoto

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with co-administration.

METHODS: Two trials were conducted. Study 1: two-period, fixed-sequence; 8 healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, co-administration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment …

Pharmacokinetics Of Ketamine At Dissociative Doses In An Adult Patient With Refractory Status Asthmaticus Receiving Extracorporeal Membrane Oxygenation Therapy., Edwin Lam, Ankit K. Rochani, Gagan Kaushal, Brandi N. Thoma, Julian Tanjuakio, Frances Mae West, Hitoshi Hirose

Department of Pharmacology and Experimental Therapeutics Faculty Papers

PURPOSE: First-line management of severe asthma exacerbations include the use of inhaled short-acting β-agonists, anticholinergics, and systemic corticosteroids. Continuous intravenous ketamine given at dissociative doses may be a pharmacologic option in patients who are intubated with life-threatening severe bronchospasm unresponsive to standard therapy. We describe the case of a 44-year-old man admitted to the intensive care unit for status asthmaticus requiring intubation and mechanical ventilation.

METHODS: The patient developed severe refractory hypercapnic respiratory failure necessitating additional respiratory support with veno-venous extracorporeal membrane oxygenation (ECMO) therapy. Ketamine treatment was initiated at 0.5 mg/kg/h continuous infusion on the day of admission for …

Effect Of Vorapaxar Alone And In Combination With Aspirin On Bleeding Time And Platelet Aggregation In Healthy Adult Subjects., Walter K. Kraft, J H Gilmartin, D L Chappell, F Gheyas, B M Walker, S Nagalla, U P Naik, J C Horrow, R E Wrishko, S Zhang, M S Anderson

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The effect of the protease-activated receptor-1 (PAR-1) antagonist vorapaxar on human bleeding time is not known. This was a randomized, two-period, open-label trial in healthy men (n = 31) and women (n = 5). In period 1, subjects received 81 mg aspirin q.d. or a vorapaxar regimen achieving steady-state plasma concentrations equivalent to chronic 2.5 mg q.d. doses, for 7 days. In period 2, each group added 7 days of the therapy alternate to that of period 1 without washout. Bleeding time and platelet aggregation using arachidonic acid, ADP, and TRAP agonists were assessed. Bleeding time geometric mean ratio (90% …

Pharmacologic And Clinical Evaluation Of Posaconazole., Jason N. Moore, Jason R. Healy, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be …

No Evidence Of A Drug-Drug Interaction Between Letermovir (Mk-8228) And Mycophenolate Mofetil, Wl Marshall, C. Badshah, F. Liu, Walter K. Kraft, Md, F. Colon-Gonzalez, A. Van Schanke, Cr. Cho, E. Hulskotte, Jr Butterton, Ee Marcantonio

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction:

Letermovir (MK-8228) is a potent, oncedaily inhibitor of the cytomegalovirus (CMV) terminase complex that is being developed for the prophylaxis of CMV infection in transplant patients. This study evaluated the pharmacokinetic interactions, safety, and tolerability of letermovir when coadministered in healthy subjects with mycophenolate mofetil (MMF), which is the morpholinoethyl ester prodrug of mycophenolic acid (MPA).

Methods:

This was an open-label trial in 14 healthy female subjects that explored the pharmacokinetic parameters of a single 1 g oral dose of MMF administered alone on Day 1 and coadministered on Day 12 with 480 mg oral once-daily letermovir given on …

Posaconazole Tablet Pharmacokinetics: Lack Of Effect Of Concomitant Medications Altering Gastric Ph And Gastric Motility In Healthy Subjects., Walter K. Kraft, Peter S. Chang, Marlou L P S Van Iersel, Hetty Waskin, Gopal Krishna, Wendy M Kersemaekers

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and …

Tumor Radiation Therapy Creates Therapeutic Vaccine Responses To The Colorectal Cancer Antigen Gucy2c., Matthew Witek, Erik S Blomain, Michael Sullivan Magee, Bo Xiang, Scott A Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

PURPOSE: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined.

METHODS AND MATERIALS: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses …

Managing The Innovation Supply Chain To Maximize Personalized Medicine., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. Although the transformative power of personalized medicine is generally recognized by physicians, patients, and payers, the complexity of translating discoveries into new modalities that transform health care is less appreciated. We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application …

The Impact Of Community Use Of Novel Oral Anticoagulants On An Academic Medical Center, Luis Eraso, Md, Taki Galanis, Md, Kristina Kipp, Pharm.D., Walter K. Kraft, Md, Michael Palladino, Pharm.D., Cacp, Alejandro Perez, Md, Kimberle Ferebee-Spruill, Crnp, Geno Merli, Md, Brian G. Swift, Pharm.D., Mba, Lynda Thomson, Brittany Vining

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Warfarin has been a mainstay of therapy for treatment and prevention of venous thromboembolic disease (VTED) and prevention of stroke and systemic embolism for over 50 years. Recent FDA approval of several novel oral anticoagulants has offered more extensive treatment options for management of these disease states.

The availability of the novel anticoagulants offers an attractive alternative to warfarin therapy for patients due to their convenience of use. In comparison to warfarin, dabigatran, rivaroxaban and apixaban offer: - a fixed dosage regimen

- a relatively small potential drug interaction profile

- minimal laboratory monitoring

- little to no dietary restrictions. …

Increased Levels Of Plasma Soluble Sema4d In Patients With Heart Failure., Qiongyu Lu, Ningzheng Dong, Qi Wang, Wenxiu Yi, Yuxin Wang, Shengjie Zhang, Haibo Gu, Xin Zhao, Xiaorong Tang, Boquan Jin, Qingyu Wu, Lawrence F Brass, Li Zhu

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Semaphorin 4D (Sema4D/CD100) is a 150-kDa transmembrane glycoprotein expressed by platelets and T-cells. When these cells are activated, Sema4D is cleaved proteolytically, generating a biologically active 120-kDa fragment (soluble Sema4D) capable of targeting receptors on platelets, B-cells, endothelial cells and tumor cells. However, its plasma levels and significance in heart failure (HF) have not been reported. In this study, we established an ELISA and detected soluble Sema4D in human plasma. In healthy controls, plasma Sema4D levels were higher in men than women (5.15±3.30 ng/mL, n = 63, vs. 4.19±2.39 ng/mL, n = 63, P

Dysregulation Of Mir-31 And Mir-21 Induced By Zinc Deficiency Promotes Esophageal Cancer, Hansjuerg Alder, Cristian Taccioli, Hongping Chen, Yubao Jiang, Karl Smalley, Paolo Fadda, Hatice G. Ozer, Kay Huebner, John Farber, Carlo M. Croce, Louise Fong

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Presented at: Hallmarks and Cancer Conference, October 29-31 in San Francisco.

And AICR Annual Meeting, November 1-2, 2012.

Dietary zinc (Zn) deficiency (ZD) in rats induces an inflammatory gene signature that fuels esophageal squamous cell cancer (ESCC). Using nanoStringTM technology, we show that the inflammation is accompanied by altered expression of specific microRNAs in esophagus, as well as skin, lung, pancreas, liver, prostate, and PBMC, predictive of disease development. Particularly, the ZD esophagus has a microRNA signature resembling human ESCC/tongue SCC miRNAomes with overexpression of miR-31 and miR-21 and downregulation of their respective tumor suppressor targets PPP2R2A and …

Mk-0448, A Specific Kv1.5 Inhibitor: Safety, Pharmacokinetics And Pharmacodynamic Electrophysiology In Experimental Animal Models And In Humans., Behzad B. Pavri, Howard E Greenberg, Walter K. Kraft, Nicole Lazarus, Joseph J Lynch, Joseph J Salata, Mark T Bilodeau, Christopher P Regan, Gary Stump, Li Fan, Anish Mehta, John A Wagner, David E Gutstein, Daniel Bloomfield

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: -We evaluated the viability of I(Kur) as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I(Kur) inhibitor. METHODS AND RESULTS: -In vitro MK-0448 studies demonstrated strong inhibition of I(Kur) with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained AF was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led …

Pharmacologic Management Of The Opioid Neonatal Abstinence Syndrome., Walter K. Kraft, John N Van Den Anker

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Opioid use in pregnant women has increased over the last decade. Following birth, infants with in utero exposure demonstrate signs and symptoms of withdrawal known as the neonatal abstinence syndrome (NAS). Infants express a spectrum of disease, with most requiring the administration of pharmacologic therapy to ensure proper growth and development. Treatment often involves prolonged hospitalization. There is a general lack of high-quality clinical trial data to guide optimal therapy, and significant heterogeneity in treatment approaches. Emerging trends in the treatment of infants with NAS include the use of sublingual buprenorphine, transition to outpatient therapy, and pharmacogenetic risk stratification.

Effect Of Concomitant Medications Affecting Gastric Ph And Motility On Posaconazole Tablet Pharmacokinetics, Walter K. Kraft, P. Chang, Mlps Van Iersel, H. Waskin, G. Krishna, W. Kersemaekers

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Poster presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy (52^nd ICAAC) held in San Francisco 9/9-9/12

Background: Posaconazole (POS) oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new POS tablet formulation has demonstrated improved bioavailability over oral suspension in healthy adults in the fasting state. This study evaluated the effect of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and motility (metoclopramide) on the pharmacokinetics of POS tablet.

Methods: This was a prospective, open-label, 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg (100 …

Phosphorylation Of Vasodilator-Stimulated Phosphoprotein Ser239 Suppresses Filopodia And Invadopodia In Colon Cancer., David S Zuzga, Joshua Pelta-Heller, Peng Li, Alessandro Bombonati, Scott A Waldman, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) …

Molecular Staging Individualizing Cancer Management, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, ∼30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. J. Surg. Oncol. 2012; 105:468-474. © 2012 Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

The Value Proposition Of Molecular Medicine., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Individualized patient management is rapidly evolving, driven by the emergence of insights in discovery, development, regulatory, and comparative effectiveness sciences.^1-4 The pace of discovery is accelerating, enabled by platforms, including “omics”, stem cell biology, network medicine, and medical and biological informatics that provide unanticipated insights into pathophysiology.^{2, 4-6} The integration of these paradigms has established a model for identifying the mechanistic underpinnings of disease, offering novel opportunities to individualize diagnostics that shape how modern therapies are deployed, including markers of disease prognosis, clinical predictors of therapeutic responses, and molecular determinants that optimize clinical management.^7-10 Importantly, deconvolution of …

Formulation Of Buprenorphine For Sublingual Use In Neonates., Ellena A Anagnostis, Rania E Sadaka, Linda A Sailor, David E Moody, Kevin C Dysart, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

OBJECTIVES: The only medication used sublingually in the neonate is buprenorphine for the treatment of neonatal abstinence syndrome (NAS). Compared with morphine, buprenorphine reduces the length of treatment and length of hospitalization in neonates treated for NAS. The objective of this study was to characterize the stability of ethanolic buprenorphine for sublingual administration.

METHODS: Buprenorphine solution was prepared and stored in amber glass source bottles at either 68°F to 77°F (20°C-25°C) or 36°F to 46°F (2.2°C-7.8°C). Samples were collected from each of these batches on days 0, 3, 7, 14, and 30. Additional samples were withdrawn at baseline from each …