DOCSLIB.ORG

AHRQ Healthcare Horizon Scanning System – Status Updates

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
AHRQ Healthcare Horizon Scanning System – Status Updates AHRQ Healthcare Horizon Scanning System – Status Updates Horizon Scanning Status Update: April 2013 Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA290201000006C Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 April 30, 2013 Statement of Funding and Purpose This report incorporates data collected during implementation of the Agency for Healthcare Research and Quality (AHRQ) Healthcare Horizon Scanning System by ECRI Institute under contract to AHRQ, Rockville, MD (Contract No. HHSA290201000006C). The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. A novel intervention may not appear in this report simply because the System has not yet detected it. The list of novel interventions in the Horizon Scanning Status Update Report will change over time as new information is collected. This should not be construed as either endorsements or rejections of specific interventions. As topics are entered into the System, individual target technology reports are developed for those that appear to be closer to diffusion into practice in the United States. A representative from AHRQ served as a Contracting Officer’s Technical Representative and provided input during the implementation of the horizon scanning system. AHRQ did not directly participate in the horizon scanning, assessing the leads or topics, or provide opinions regarding potential impact of interventions. Disclaimer Regarding 508-Compliance Persons using assistive technology may not be able to fully access information in this report. For assistance contact [email protected]. Financial Disclosure Statement None of the individuals compiling this information has any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. Suggested citation: ECRI Institute. AHRQ Healthcare Horizon Scanning System Status Update. (Prepared by ECRI Institute under Contract No. HHSA290201000006C) Rockville, MD: Agency for Healthcare Research and Quality. April 2013. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. i Preface The purpose of the AHRQ Healthcare Horizon Scanning System is to conduct horizon scanning of emerging health care technologies and innovations to better inform patient-centered outcomes research investments at AHRQ through the Effective Health Care Program. The Healthcare Horizon Scanning System provides AHRQ a systematic process to identify and monitor emerging technologies and innovations in health care and to create an inventory of emerging technologies that have the highest potential for impact on clinical care, the health care system, patient outcomes, and costs. It will also be a tool for the public to identify and find information on new health care technologies and interventions. Any investigator or funder of research will be able to use the AHRQ Healthcare Horizon Scanning System to select potential topics for research. The health care technologies and innovations of interest for horizon scanning are those that have yet to diffuse into or become part of established health care practice. These health care interventions are still in the early stages of development or adoption except in the case of new applications of already-diffused technologies. Consistent with the definitions of health care interventions provided by the Institute of Medicine and the Federal Coordinating Council for Comparative Effectiveness Research, AHRQ is interested in innovations in drugs and biologics, medical devices, screening and diagnostic tests, procedures, services and programs, and care delivery. Horizon scanning involves two processes. The first is identifying and monitoring new and evolving health care interventions that are purported to or may hold potential to diagnose, treat, or otherwise manage a particular condition or to improve care delivery for a variety of conditions. The second is analyzing the relevant health care context in which these new and evolving interventions exist to understand their potential impact on clinical care, the health care system, patient outcomes, and costs. It is NOT the goal of the AHRQ Healthcare Horizon Scanning System to make predictions on the future use and costs of any health care technology. Rather, the reports will help to inform and guide the planning and prioritization of research resources. This edition of the Status Update lists interventions that have been identified and are being monitored. The next edition will be published in 2–3 months. We welcome comments on the list, which may be sent by mail to the Task Order Officer named in this report to: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to: [email protected]. Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. Director Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Elise Berliner, Ph.D. Task Order Officer Center for Outcomes and Evidence Agency for Healthcare Research and Quality ii Contents Introduction ............................................................................................................................................................. 1 Section 1. Currently Tracked Interventions: 434 Interventions .............................................................................. 3 Table 1. AHRQ Priority Condition: 01 Arthritis and Nontraumatic Joint Disease: 13 Interventions ........4 Table 2. AHRQ Priority Condition: 02 Cancer: 153 Interventions ............................................................9 Table 3. AHRQ Priority Condition: 03 Cardiovascular Disease: 37 Interventions ..................................79 Table 4. AHRQ Priority Condition: 04 Dementia (including Alzheimer’s): 9 Interventions ..................96 Table 5. AHRQ Priority Condition: 05 Depression and Other Mental Health Disorders: 19 Interventions .............................................................................................................................100 Table 6. AHRQ Priority Condition: 06 Developmental Delays, Attention-Deficit Hyperactivity Disorder, and Autism: 6 Interventions ......................................................................................109 Table 7. AHRQ Priority Condition: 07 Diabetes Mellitus: 15 Interventions .........................................112 Table 8. AHRQ Priority Condition: 08 Functional Limitations and Disability: 70 Interventions .........120 Table 9. AHRQ Priority Condition: 09 Infectious Disease, Including HIV-AIDS: 45 Interventions ....151 Table 10. AHRQ Priority Condition: 10 Obesity: 8 Interventions .........................................................172 Table 11. AHRQ Priority Condition: 11 Peptic Ulcer Disease and Dyspepsia: 14 Interventions ..........176 Table 12. AHRQ Priority Condition: 12 Pregnancy, Including Preterm Birth: 9 Interventions ............182 Table 13. AHRQ Priority Condition: 13 Pulmonary Disease, Asthma: 18 Interventions ......................186 Table 14. AHRQ Priority Condition: 14 Substance Abuse: 8 Interventions ..........................................194 Table 15. AHRQ Priority Condition: 15 Cross-Cutting: 10 Interventions .............................................198 Section 2. Interventions Added Since Last Update: 70 Interventions ............................................................... 203 Table 16. AHRQ Priority Condition: 01 Arthritis and Nontraumatic Joint Disease: 4 Interventions ....204 Table 17. AHRQ Priority Condition: 02 Cancer: 25 Interventions ........................................................206 Table 18. AHRQ Priority Condition: 03 Cardiovascular Disease: 10 Interventions ..............................216 Table 19. AHRQ Priority Condition: 04 Dementia (including Alzheimer’s): 5 Interventions ..............221 Table 20. AHRQ Priority Condition: 05 Depression and Other Mental Health Disorders: 2 Interventions .............................................................................................................................224 Table 21. AHRQ Priority Condition: 06 Developmental Delays, Attention-Deficit Hyperactivity Disorder, and Autism: 1 Intervention .......................................................................................225 Table 22. AHRQ Priority Condition: 07 Diabetes Mellitus: 3 Interventions .........................................225 Table 23. AHRQ Priority Condition: 08 Functional Limitations and Disability: 12 Interventions .......227 Table 24. AHRQ Priority Condition: 09 Infectious Disease, Including HIV-AIDS: 2 Interventions ....232 Table 25. AHRQ Priority Condition: 10 Obesity: 1 Intervention ...........................................................233 iii Table 26. AHRQ Priority Condition: 11 Peptic Ulcer Disease and Dyspepsia: 0 Interventions ............234 Table 27. AHRQ Priority Condition: 12 Pregnancy, Including Preterm Birth: 1 Intervention ..............234 Table 28. AHRQ Priority Condition: 13 Pulmonary Disease, Asthma: 1 Intervention ..........................235 Table 29. AHRQ Priority
Load more

Recommended publications
  • Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal
    testinal & in D o i tr g s e Journal of Gastrointestinal & a s t G i v f e o Narayanan et al., J Gastrointest Dig Syst 2018, 8:1 S l y a s n r ISSN: 2161-069Xt Digestive System DOI: 10.4172/2161-069X.1000553 e u m o J Research Article Open Access Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal- related Symptoms of Functional Dyspepsia Varsha Narayanan*, Amit Bhargava and Shailesh Pallewar 1Department of Medical Services and Research, Lupin Ltd., India *Corresponding author: Narayanan V, Department of Medical Services and Research, Lupin Ltd., Mumbai, India, Tel: +912266402222; E-mail: [email protected] Received date: February 09, 2018; Accepted date: February 21, 2018; Published date: February 27, 2018 Copyright: © 2018 Narayanan V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background: Functional Dyspepsia (FD) is a highly prevalent clinical condition that imposes negative economic burden on health-care system as well as greatly impairs quality of life. Treatment of non-specific and bothersome meal-related FD symptoms like post-prandial fullness, upper abdominal bloating and early satiety, is a therapeutic challenge for the clinicians as poorly-defined and ill-understood pathogenesis has hampered efforts to develop effective treatments. Acotiamide is first-in-class drug that exerts its gastro-kinetic effect by enhancing acetylcholine release. Though evidence of its efficacy and tolerance are available through randomized clinical trials, real world data from its regular in-clinic use is lacking.
    [Show full text]
  • Development of a Test That Measures Real-Time HER2 Signaling Function in Live Breast Cancer Cell Lines and Primary Cells Yao Huang1, David J
    Huang et al. BMC Cancer (2017) 17:199 DOI 10.1186/s12885-017-3181-0 RESEARCH ARTICLE Open Access Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells Yao Huang1, David J. Burns1, Benjamin E. Rich1, Ian A. MacNeil1, Abhijit Dandapat1, Sajjad M. Soltani1, Samantha Myhre1, Brian F. Sullivan1, Carol A. Lange2, Leo T. Furcht3 and Lance G. Laing1* Abstract Background: Approximately 18–20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2. This suggests that measurement of other biological factors associated with HER2 cancer, such as HER2 signaling pathway activity, should be considered as an alternative means of identifying patients eligible for HER2 therapies. Methods: A new biosensor-based test (CELxTM HSF) that measures HER2 signaling activity in live cells is demonstrated using a set of 19 human HER2+ and HER2– breast cancer reference cell lines and primary cell samples derived from two fresh patient tumor specimens. Pathway signaling is elucidated by use of highly specific agonists and antagonists. The test method relies upon well-established phenotypic, adhesion-related, impedance changes detected by the biosensor. Results: The analytical sensitivity and analyte specificity of this method was demonstrated using ligands with high affinity and specificity for HER1 and HER3. The HER2-driven signaling quantified ranged 50-fold between the lowest and highest cell lines.
    [Show full text]
  • PN0496-Acotiamide.Pdf
    Acotiamide hydrochloride hydrate (Acofide®) 盐酸阿考替胺 Z-338 in Zeria; YM-443 in Astellas Tablet, oral, EQ 100 mg acotiamide Acotiamide is a peripheral acetylcholinesterase inhibitor, indicated for the treatment of functional dyspepsia (FD), which was first-in-class drug to treat FD in the world and approved in 2013 by Japan PMDA. It was originally discovered by Zeria, and co-developed with Astellas. The drug is co-marketing in Japan with a single brand name. The human recommended starting dose is 100 mg at a time, and 3 times a day before meals. Worldwide Key Approvals Global Sales ($Million) Key Substance Patent Expiration 2016-May (US5981557A) 2016-May (EP0870765B1) 2013-Mar (JP) Not available 2021-May (JP3181919B2) 2016-May (CN1063442C) Mechanism of Action Acotiamide hydrochloride hydrate is an acetylcholinesterase (AChE) inhibitor and enhanced the acetylcholine (ACh)-induced contraction and motility of the gastric antrum and the gastric body. Target Binding Selectivity In vitro Efficacy In vivo Efficacy Mixed pattern: Ki1= 0.61 µM Effect dose of contraction in gastric sample: Significantly improved the gastrointestinal motility: Ki2= 2.7 µM ACh-induced: at 1 µM In normal and gastric hypomotility dogs: at 10 mg/kg. Inhibition: IC50= 3 µM Electrical-induced: at 0.3 µM In gastric hypomotility rats: at 100 mg/kg. Pharmacokinetics Parameters Rats Dogs Healthy Humans 3 10 3 10 50 mg 100 mg 200 mg 400 mg 800 mg Dose (mg/kg) (i.v.) (p.o.) (i.v.) (p.o.) (p.o.) (p.o.) (p.o.) (p.o.) (p.o.) Tmax (hr) - 0.08 - 0.5 2.75 2.42 2.08 2.25 2.13 Cmax
    [Show full text]
  • The Role of Biological Therapy in Metastatic Colorectal Cancer After First-Line Treatment: a Meta-Analysis of Randomised Trials
    REVIEW British Journal of Cancer (2014) 111, 1122–1131 | doi: 10.1038/bjc.2014.404 Keywords: colorectal; biological; meta-analysis The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials E Segelov1, D Chan*,2, J Shapiro3, T J Price4, C S Karapetis5, N C Tebbutt6 and N Pavlakis2 1St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2052, Australia; 2Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; 3Monash University and Cabrini Hospital, Melbourne, VIC 3800, Australia; 4The Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA 5011, Australia; 5Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, SA, 5042, Australia and 6Austin Health, VIC 3084, Australia Purpose: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. Methods: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. Results: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82–0.91, Po0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67–0.74, Po0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03–2.78, Po0.00001).
    [Show full text]
  • Targeted and Novel Therapy in Advanced Gastric Cancer Julie H
    Selim et al. Exp Hematol Oncol (2019) 8:25 https://doi.org/10.1186/s40164-019-0149-6 Experimental Hematology & Oncology REVIEW Open Access Targeted and novel therapy in advanced gastric cancer Julie H. Selim1 , Shagufta Shaheen2 , Wei‑Chun Sheu3 and Chung‑Tsen Hsueh4* Abstract The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal–epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin‑18.2, programmed death‑1 and DNA. Addition of trastuzumab to platinum‑ based chemotherapy has become standard of care as front‑line therapy in advanced GC overexpressing HER2. In the second‑line setting, ramucirumab with paclitaxel signifcantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS‑102 have demonstrated single‑agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability‑high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non‑inferior outcome in frst‑line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC. Keywords: Gastric cancer, Targeted therapy, Human epidermal growth factor receptor 2, Programmed death‑1, Vascular endothelial growth factor receptor 2 Background GC mortality which is consistent with overall decrease in Gastric cancer (GC), including adenocarcinoma of the GC-related deaths [4]. gastroesophageal junction (GEJ) and stomach, is the ffth Tere have been several eforts to perform large-scale most common cancer and the third leading cause of can- molecular profling and classifcation of GC.
    [Show full text]
  • Infant Antibiotic Exposure Search EMBASE 1. Exp Antibiotic Agent/ 2
    Infant Antibiotic Exposure Search EMBASE 1. exp antibiotic agent/ 2. (Acedapsone or Alamethicin or Amdinocillin or Amdinocillin Pivoxil or Amikacin or Aminosalicylic Acid or Amoxicillin or Amoxicillin-Potassium Clavulanate Combination or Amphotericin B or Ampicillin or Anisomycin or Antimycin A or Arsphenamine or Aurodox or Azithromycin or Azlocillin or Aztreonam or Bacitracin or Bacteriocins or Bambermycins or beta-Lactams or Bongkrekic Acid or Brefeldin A or Butirosin Sulfate or Calcimycin or Candicidin or Capreomycin or Carbenicillin or Carfecillin or Cefaclor or Cefadroxil or Cefamandole or Cefatrizine or Cefazolin or Cefixime or Cefmenoxime or Cefmetazole or Cefonicid or Cefoperazone or Cefotaxime or Cefotetan or Cefotiam or Cefoxitin or Cefsulodin or Ceftazidime or Ceftizoxime or Ceftriaxone or Cefuroxime or Cephacetrile or Cephalexin or Cephaloglycin or Cephaloridine or Cephalosporins or Cephalothin or Cephamycins or Cephapirin or Cephradine or Chloramphenicol or Chlortetracycline or Ciprofloxacin or Citrinin or Clarithromycin or Clavulanic Acid or Clavulanic Acids or clindamycin or Clofazimine or Cloxacillin or Colistin or Cyclacillin or Cycloserine or Dactinomycin or Dapsone or Daptomycin or Demeclocycline or Diarylquinolines or Dibekacin or Dicloxacillin or Dihydrostreptomycin Sulfate or Diketopiperazines or Distamycins or Doxycycline or Echinomycin or Edeine or Enoxacin or Enviomycin or Erythromycin or Erythromycin Estolate or Erythromycin Ethylsuccinate or Ethambutol or Ethionamide or Filipin or Floxacillin or Fluoroquinolones
    [Show full text]
  • Pharmacological Agents Currently in Clinical Trials for Disorders in Neurogastroenterology
    Pharmacological agents currently in clinical trials for disorders in neurogastroenterology Michael Camilleri J Clin Invest. 2013;123(10):4111-4120. https://doi.org/10.1172/JCI70837. Clinical Review Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients’ symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain. Find the latest version: https://jci.me/70837/pdf Review Pharmacological agents currently in clinical trials for disorders in neurogastroenterology Michael Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA. Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in under- standing the mechanisms of these disorders, through basic and translational research, and in targeting the recep- tors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients’ symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastropa- resis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain.
    [Show full text]
  • Regulation and Relevance for Chronic Lung Diseases
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Purinergic Signalling (2006) 2:399–408 DOI 10.1007/s11302-006-9001-7 ORIGINAL ARTICLE E-NTPDases in human airways: Regulation and relevance for chronic lung diseases Lauranell H. Burch & Maryse Picher Received: 11 January 2005 /Accepted: 21 December 2005 / Published online: 30 May 2006 # Springer Science + Business Media B.V. 2006 Abstract Chronic obstructive lung diseases are char- are characterized by higher rates of nucleotide elimi- acterized by the inability to prevent bacterial infection nation, azide-sensitive E-NTPDase activities and ex- and a gradual loss of lung function caused by recurrent pression. This review integrates the biphasic regulation inflammatory responses. In the past decade, numerous of airway E-NTPDases with the function of purine studies have demonstrated the importance of nucleo- signaling in lung diseases. During acute insults, a tide-mediated bacterial clearance. Their interaction transient reduction in E-NTPDase activities may be with P2 receptors on airway epithelia provides a rapid beneficial to stimulate ATP-mediated bacterial clear- Fon-and-off_ signal stimulating mucus secretion, cilia ance. In chronic lung diseases, elevating E-NTPDase beating activity and surface hydration. On the other activities may represent an attempt to prevent P2 hand, abnormally high ATP levels resulting from receptor desensitization and nucleotide-mediated lung damaged epithelia and bacterial lysis may cause lung damage. edema and exacerbate inflammatory responses. Air- way ATP concentrations are regulated by ecto nucle- Keywords apyrase . bacterial clearance . CD39 . oside triphosphate diphosphohydrolases (E-NTPDases) chronic obstructive lung diseases .
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Therapeutic Targeting of the IGF Axis
    cells Review Therapeutic Targeting of the IGF Axis Eliot Osher and Valentine M. Macaulay * Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK * Correspondence: [email protected]; Tel.: +44-1865617337 Received: 8 July 2019; Accepted: 9 August 2019; Published: 14 August 2019 Abstract: The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging. Keywords: IGF; type 1 IGF receptor; IGF-1R; cancer; acromegaly; ophthalmopathy; IGF inhibitor 1. Introduction Insulin like growth factors (IGFs) are small (~7.5 kDa) ligands that play a critical role in many biological processes including proliferation and protection from apoptosis and normal somatic growth and development [1]. IGFs are members of a ligand family that includes insulin, a dipeptide comprised of A and B chains linked via two disulfide bonds, with a third disulfide linkage within the A chain.
    [Show full text]
  • NIH Public Access Author Manuscript J Med Chem
    NIH Public Access Author Manuscript J Med Chem. Author manuscript; available in PMC 2012 June 23. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Med Chem. 2011 June 23; 54(12): 4018±4033. doi:10.1021/jm101591j. Pyrimidine Nucleotides with 4-Alkyloxyimino and Terminal Tetraphosphate δ-Ester Modifications as Selective Agonists of the P2Y4 Receptor Hiroshi Maruokaa, M.P. Suresh Jayasekaraa, Matthew O. Barrettb, Derek A. Franklinb, Sonia de Castroa, Nathaniel Kima, Stefano Costanzic, T. Kendall Hardenb, and Kenneth A. Jacobsona,* aMolecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0810 bDepartment of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599-7365 cLaboratory of Biological Modeling, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 Abstract P2Y2 and P2Y4 receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We varied structurally phosphate and uracil moieties in analogues of pyrimidine nucleoside 5′-triphosphates and 5′-tetraphosphate esters. P2Y4 receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N4- alkyloxycytidine derivatives. OH groups on a terminal δ-glucose phosphoester of uridine 5′- tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N4- 4 (Phenylpropoxy)-CTP 16 (MRS4062), Up4-[1]3′-deoxy-3′-fluoroglucose 34 (MRS2927) and N - (phenylethoxy)-CTP 15 exhibit ≥10-fold selectivity for human P2Y4 over P2Y2 and P2Y6 receptors (EC50 values 23, 62 and 73 nM, respectively).
    [Show full text]
  • Correlation Between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer
    Published OnlineFirst January 31, 2012; DOI: 10.1158/1078-0432.CCR-11-1135 Clinical Cancer Predictive Biomarkers and Personalized Medicine Research Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer Fei Huang, Li-an Xu, and Shirin Khambata-Ford Abstract Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC). Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate. Results: Higher IGF-1R, higher GRB7, and lower INSIG2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P ¼ 0.01), 122 versus 57 days (P ¼ 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF- 1R, higher GRB7, and lower INSIG2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P ¼ 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression.
    [Show full text]