Orphan Drug Designation List
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WHO Drug Information Vol. 12, No. 3, 1998
WHO DRUG INFORMATION VOLUME 12 NUMBER 3 • 1998 RECOMMENDED INN LIST 40 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 3, 1998 World Health Organization, Geneva WHO Drug Information Contents Seratrodast and hepatic dysfunction 146 Meloxicam safety similar to other NSAIDs 147 Proxibarbal withdrawn from the market 147 General Policy Issues Cholestin an unapproved drug 147 Vigabatrin and visual defects 147 Starting materials for pharmaceutical products: safety concerns 129 Glycerol contaminated with diethylene glycol 129 ATC/DDD Classification (final) 148 Pharmaceutical excipients: certificates of analysis and vendor qualification 130 ATC/DDD Classification Quality assurance and supply of starting (temporary) 150 materials 132 Implementation of vendor certification 134 Control and safe trade in starting materials Essential Drugs for pharmaceuticals: recommendations 134 WHO Model Formulary: Immunosuppressives, antineoplastics and drugs used in palliative care Reports on Individual Drugs Immunosuppresive drugs 153 Tamoxifen in the prevention and treatment Azathioprine 153 of breast cancer 136 Ciclosporin 154 Selective serotonin re-uptake inhibitors and Cytotoxic drugs 154 withdrawal reactions 136 Asparaginase 157 Triclabendazole and fascioliasis 138 Bleomycin 157 Calcium folinate 157 Chlormethine 158 Current Topics Cisplatin 158 Reverse transcriptase activity in vaccines 140 Cyclophosphamide 158 Consumer protection and herbal remedies 141 Cytarabine 159 Indiscriminate antibiotic -
Cancer Subtype Identification Using Somatic Mutation Data
www.nature.com/bjc ARTICLE Genetics and Genomics Cancer subtype identification using somatic mutation data Marieke Lydia Kuijjer 1,2, Joseph Nathaniel Paulson1,2,3, Peter Salzman4, Wei Ding5 and John Quackenbush1,2,6 BACKGROUND: With the onset of next-generation sequencing technologies, we have made great progress in identifying recurrent mutational drivers of cancer. As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis. Classification of patients with similar mutation profiles may help identifying subgroups of patients who might benefit from specific types of treatment. However, classification based on somatic mutations is challenging due to the sparseness and heterogeneity of the data. METHODS: Here we describe a new method to de-sparsify somatic mutation data using biological pathways. We applied this method to 23 cancer types from The Cancer Genome Atlas, including samples from 5805 primary tumours. RESULTS: We show that, for most cancer types, de-sparsified mutation data associate with phenotypic data. We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available. We identify subtype–drug associations for 14 additional subtypes. Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways. CONCLUSIONS: This study is an important step toward understanding mutational patterns in cancer. British Journal of Cancer (2018) 118:1492–1501; https://doi.org/10.1038/s41416-018-0109-7 INTRODUCTION However, subtype classification using somatic mutations in Cancer is a heterogeneous disease that can develop in different cancer is challenging, mainly because the data are very sparse: tissues and cell types. -
An Overview of the Role of Hdacs in Cancer Immunotherapy
International Journal of Molecular Sciences Review Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy Debarati Banik, Sara Moufarrij and Alejandro Villagra * Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, 800 22nd St NW, Suite 8880, Washington, DC 20052, USA; [email protected] (D.B.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +(202)-994-9547 Received: 22 March 2019; Accepted: 28 April 2019; Published: 7 May 2019 Abstract: Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. -
Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
Synthesis and Evaluation of Chromone Derivatives As Inhibitors of Monoamine Oxidase
Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase AN Mpitimpiti 21253005 Dissertation submitted in fulfilment of the requirements for the degree Magister Scientiae in Pharmaceutical Chemistry at the Potchefstroom Campus of the North-West University Supervisor: Dr ACU Lourens Co-supervisors: Dr A Petzer Prof JP Petzer November 2014 The financial assistance of the National Research Foundation (NRF) and the Medical Research Council (MRC) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at are those of the author and are not necessarily to be attributed to the NRF or MRC. Acknowledgements • All glory be to God. • I am deeply indebted to the following for their immense support and contribution: o My supervisor - Dr A.C.U Lourens (your guidance is truly boundless). o My co-supervisors, Prof J.P Petzer and Dr A. Petzer. o Dr J.Jordaan. • My mother, Magret Chigeza (for your unconditional love and support). • My family and friends. • All those who knowingly and unknowingly supported me through out this journey. Psalm 115 verse 1: ‘Not to us, O Lord, not to us, but to Your Name be the glory, because of Your love and faithfulness’ i Table of Contents Abstract ...........................................................................................................................iv Opsomming ....................................................................................................................vii List of abbreviations .......................................................................................................xi -
Suppression of Signal Transducer and Activator of Transcription 3 Activation by Butein Inhibits Growth of Human Hepatocellular Carcinoma in Vivo
Author Manuscript Published OnlineFirst on December 3, 2010; DOI: 10.1158/1078-0432.CCR-10-1123 AuthorPublished manuscripts OnlineFirst have been on peer December reviewed and 3, accepted 2010 as for 10.1158/1078-0432.CCR-10-1123 publication but have not yet been edited. Suppression of Signal Transducer and Activator of Transcription 3 Activation by Butein Inhibits Growth of Human Hepatocellular Carcinoma in vivo Peramaiyan Rajendran1, Tina H. Ong2, Luxi Chen1,3, Feng Li1, Muthu K Shanmugam1, Shireen Vali4, Taher Abbasi4, Shweta Kapoor4, Ashish Sharma4, Alan Prem Kumar1,3, Kam M. Hui2,5 Gautam Sethi1,5 1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, 2Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research National Cancer Centre, Singapore 169610, 3Cancer Science Institute of Singapore, National University of Singapore, and 4Cellworks Group Inc., California 95070; 4Cellworks Research India Pvt. Ltd, Bangalore 560066, India. Running title: Butein inhibits STAT3 signaling in vitro and in vivo in HCC. 5To whom correspondence should be addressed: 1. Dr. Gautam Sethi, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Phone: +65-65163267; Fax: +65- 68737690; Email: [email protected] Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Copyright © 2010 American Association for Cancer Research Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2010 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 3, 2010; DOI: 10.1158/1078-0432.CCR-10-1123 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
Cytotoxic Chemotherapy: Still the Mainstay of Clinical Practice for All
G Model ONCH-2130; No. of Pages 14 ARTICLE IN PRESS Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc Cytotoxic chemotherapy: Still the mainstay of clinical practice for all subtypes metastatic breast cancer a,b b,∗ c c Chris Twelves , Maria Jove , Andrea Gombos , Ahmad Awada a Leeds Institute of Cancer and Pathology, St. James’s University Hospital, Leeds, UK b St James’s Institute of Oncology, St. James’s University Hospital, Bexley Wing, Level 4, Beckett Street, LS9 7TF Leeds, UK c Medical Oncology Clinic, Jules Bordet Institute, Université Libre de Bruxelles, Boulevard de Waterloo 121, B-1000 Brussels, Belgium Contents 1. Introduction . 00 2. Current therapeutic options for anthracycline- and taxane pretreated MBC . 00 2.1. Rechallenge with, or reformulation of, an anthracyclines or taxane . 00 2.2. Capecitabine . 00 3. Newer antimicrotubule agents . 00 3.1. Ixabepilone . 00 3.2. Eribulin . 00 4. Emerging new agents . 00 4.1. Vinflunine . 00 4.2. Etirinotecan pegol (NKTR-102). .00 4.2.1. Pharmacology. .00 4.2.2. Early clinical trials . 00 4.2.3. The BEACON trial . 00 5. Conclusions . 00 Conflict of interest . 00 Acknowledgments . 00 References . 00 Biography . 00 a r t i c l e i n f o a b s t r a c t Article history: Cytotoxic chemotherapy remains central to the treatment of all subtypes of metastatic breast cancer Received 13 October 2015 (MBC). We review evidence-based chemotherapy options for women with MBC after an anthracycline Received in revised form and a taxane including re-challenge with anthracycline or taxane, capecitabine, eribulin and ixabepilone 24 December 2015 as a single agent or combination with capecitabine (not approved in the EU); and the vinca alkaloid Accepted 20 January 2016 vinflunine as single agent or combined with either capecitabine/gemcitabine (also not approved EU or USA). -
The Double Stranded RNA Analog Poly-IC Elicits Both Robust IFN-Λ Production and Oncolytic Activity in Human Gastrointestinal Cancer Cells
www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 77), pp: 34471-34484 Research Paper The double stranded RNA analog poly-IC elicits both robust IFN-λ production and oncolytic activity in human gastrointestinal cancer cells Chantal Bou-Hanna1,*, Anne Jarry1,2,*, Jean-François Mosnier1,3, Céline Bossard1,2,3 and Christian L. Laboisse1,3 1University of Nantes, EA4273 Biometadys, Nantes, France 2Current address: CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France 3Pathology Department, Nantes University Hospital, Nantes, France *Equal co-authors Correspondence to: Christian L. Laboisse, email: [email protected]; [email protected] Keywords: dsRNA/poly-IC; IFN-λ; immunoadjuvant; oncolysis; human gastrointestinal cancer Received: February 09, 2018 Accepted: September 06, 2018 Published: October 02, 2018 Copyright: Bou-Hanna et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: Type III IFN (IFN-λ) is the dominant frontline response over type I IFN in human normal intestinal epithelial cells upon viral infection, this response being mimicked by the dsRNA analog poly-IC. Poly-IC also induces cell death in murine intestinal crypts ex vivo. Here we examined whether these innate defense functions of normal intestinal epithelial cells are recapitulated in gastrointestinal carcinoma cells so that they could be harnessed to exert both immunoadjuvant and oncolytic functions, an unknown issue yet. Experimental design: Four human gastrointestinal carcinoma cell lines versus the Jurkat lymphoma cell line were used to assess the effects of intracellular poly-IC on i) IFN-λ secretion and cell proliferation and ii) role of NFκB signaling using the NFκB inhibitory peptide SN50 as a screening probe and a siRNA approach. -
Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A And
www.nature.com/scientificreports OPEN Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Received: 20 September 2016 Accepted: 23 February 2017 Muscle Cells Published: 03 April 2017 Cibely C. Fontes-Oliveira1, Maarten Steinz1, Peter Schneiderat2, Hindrik Mulder3 & Madeleine Durbeej1 Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. Skeletal muscle is the largest organ in the human body and is used to respond to a broad range of functional demands in each animal species. -
Management of Brain and Leptomeningeal Metastases from Breast Cancer
International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. -
Biological Pathways and in Vivo Antitumor Activity Induced by Atiprimod in Myeloma
Leukemia (2007) 21, 2519–2526 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu ORIGINAL ARTICLE Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma P Neri1,2,3, P Tassone1,2,3, M Shammas1, H Yasui2, E Schipani4, RB Batchu1, S Blotta1,2,3, R Prabhala1, L Catley2, M Hamasaki2, T Hideshima2, D Chauhan2, GS Jacob5, D Picker5, S Venuta3, KC Anderson2 and NC Munshi1,2 1Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2Boston VA Healthcare System, Department of Medicine, Harvard Medical School, MA, USA; 3Department of Experimental and Clinical Medicine, University of ‘Magna Græcia’ and Cancer Center, Catanzaro, Italy; 4Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA and 5Callisto Pharmaceuticals Inc., New York, NY, USA Atiprimod (Atip) is a novel oral agent with anti-inflammatory tion.7,8 Atip inhibits the inflammatory response and preserves properties. Although its in vitro activity and effects on signaling bone integrity in murine models of rheumatoid arthritis (RA),9–12 in multiple myeloma (MM) have been previously reported, here targets macrophages, inhibits phospholipase A and C in rat we investigated its molecular and in vivo effects in MM. Gene 13,14 expression analysis of MM cells identified downregulation of alveolar macrophages and exhibits antiproliferative and 15–17 genes involved in adhesion, cell-signaling, cell cycle and bone antiangiogenic activities in human cancer models. Impor- morphogenetic protein (BMP) pathways and upregulation of tantly, we have previously reported that Atip inhibits MM cell genes implicated in apoptosis and bone development, follow- growth, induces caspase-mediated apoptosis, blocks the phos- ing Atip treatment. -
Hr23b Expression Is a Potential Predictive Biomarker for HDAC Inhibitor Treatment in Mesenchymal Tumours and Is Associated with Response to Vorinostat
The Journal of Pathology: Clinical Research J Path: Clin Res April 2016; 2: 59–71 Original Article Published online 23 December 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/cjp2.35 HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat Michaela Angelika Ihle,1 Sabine Merkelbach-Bruse,1 Wolfgang Hartmann,1,2 Sebastian Bauer,3 Nancy Ratner,4 Hiroshi Sonobe,5 Jun Nishio,6 Olle Larsson,7 Pierre A˚ man,8 Florence Pedeutour,9 Takahiro Taguchi,10 Eva Wardelmann,1,2 Reinhard Buettner1 and Hans-Ulrich Schildhaus1,11* 1 Institute of Pathology, University Hospital Cologne, Cologne, Germany 2 Gerhard Domagk Institute of Pathology, University Hospital M€unster, M€unster, Germany 3 Sarcoma Center, West German Cancer Center, University of Essen, Essen, Germany 4 US Department of Pediatrics, Cincinnati Children’s Hospital Medical Centre, Cincinnati, OH, USA 5 Department of Laboratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima, Japan 6 Faculty of Medicine, Department of Orthopaedic Surgery, Fukuoka University, Fukuoka, Japan 7 Department of Oncology and Pathology, The Karolinska Institute, Stockholm, Sweden 8 Sahlgrenska Cancer Centre, University of Gothenburg, Gothenburg, Sweden 9 Faculty of Medicine, Laboratory of Genetics of Solid Tumours, Institute for Research on Cancer and Aging, Nice, France 10 Division of Human Health & Medical Science, Graduate School of Kuroshio Science, Kochi University Nankoku, Kochi, Japan 11 Institute of Pathology, University Hospital G€ottingen, G€ottingen, Germany *Correspondence to: Hans-Ulrich Schildhaus,Institute of Pathology,University Hospital G€ottingen,Robert-Koch-Strasse40,D-37075G€ottingen, Germany.e-mail: [email protected] Abstract Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sar- comas.