Parasitic Nematode Ion Channels: Improving Understanding of Pharmacology and Genetic Composition Samuel Buxton Iowa State University

Total Page:16

File Type:pdf, Size:1020Kb

Parasitic Nematode Ion Channels: Improving Understanding of Pharmacology and Genetic Composition Samuel Buxton Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2012 Parasitic nematode ion channels: improving understanding of pharmacology and genetic composition Samuel Buxton Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Parasitology Commons, Pharmacology Commons, and the Toxicology Commons Recommended Citation Buxton, Samuel, "Parasitic nematode ion channels: improving understanding of pharmacology and genetic composition" (2012). Graduate Theses and Dissertations. 12965. https://lib.dr.iastate.edu/etd/12965 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Parasitic nematode ion channels: improving understanding of pharmacology and genetic composition by Samuel Buxton A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Toxicology Program of Study Committee: Richard J. Martin, Major Professor Alan P. Robertson, Major Professor Anumantha G. Kanthasamy Heather M. W. Greenlee Jeffrey K. Beetham Jacques Cabaret Iowa State University Ames, Iowa 2012 Copyright © Samuel Buxton, 2012. All rights reserved. ii TABLE OF CONTENTS ABSTRACT .............................................................................................................................. x CHAPTER 1 General Introduction ........................................................................................... 1 1.1 Introduction ..................................................................................................................... 1 1.2 Thesis Organization ........................................................................................................ 2 CHAPTER 2 Literature Review ............................................................................................. 4 2.1 Soil Transmitted Helminths ............................................................................................ 4 2.1.1 Ascaris spp. and Ascariasis ...................................................................................... 7 2.1.2 Oesophagostomum spp. and Oesophagostomiasis ................................................. 11 2.2 Nematode Muscular and Nervous Systems .................................................................. 14 2.2.1 Nematode Muscular System .................................................................................. 14 2.2.2 Nematode Nervous System .................................................................................... 17 2.2.3 Electrophysiology of Somatic Muscle ................................................................... 20 2.3 Nicotinic Acetylcholine Receptors, nAChR ................................................................. 23 2.3.1 Vertebrate nAChR ................................................................................................. 24 2.3.2 Caenorhabditis elegans AChR .............................................................................. 30 2.3.3 Parasitic nematodes AChR .................................................................................... 36 2.4 Voltage-activated calcium-dependent potassium channels .......................................... 41 iii 2.5 Anthelmintics and anthelmintic resistance ................................................................... 46 2.5.1 Emodepside ............................................................................................................ 46 2.5.2 Levamisole, pyrantel, tribendimidine .................................................................... 51 2.5.3 Anthelmintic resistance .......................................................................................... 53 2.6 Heterologous expression systems: Xenopus laevis oocytes .......................................... 57 CHAPTER 3 On the mode of action of emodepside: slow effects in Ascaris suum .............. 61 3.1 Abstract ......................................................................................................................... 61 3.2 Introduction ................................................................................................................... 62 3.3 Materials and Methods .................................................................................................. 64 3.3.1 Collection and Maintenance of worms .................................................................. 64 3.3.2 Sequence and gene expression analysis ................................................................. 65 3.3.3 Somatic muscle preparation ................................................................................... 66 3.3.4 Electrophysiology of Somatic Muscle ................................................................... 66 3.3.5 Time control experiments ...................................................................................... 70 3.3.6 Data analysis .......................................................................................................... 70 3.3.7 Materials ................................................................................................................ 72 3.4 Results ........................................................................................................................... 72 3.4.1 slo-1 and lat-1 homologous genes from A. suum expressed at adult stage ........... 72 3.4.2 Emodepside has an inhibitory effect on spiking .................................................... 76 iv 3.4.3 Effect of emodepside on membrane potential and input conductance .................. 79 3.4.4 Emodepside effect on membrane potential: role of NO and PKC ......................... 82 3.4.5 Effect of emodepside (1 µM) on voltage-activated K+ currents ............................ 83 3.4.6 Effect of emodepside (10 µM) on voltage-activated K+ currents .......................... 86 3.4.7 Ca2+ is required for effects of emodepside on K+ currents .................................... 89 3.4.8 Emodepside effects on K+ currents: role of NO and PKC ..................................... 89 + 3.4.9 The 4-aminopyridine-sensitive K current includes Ia ........................................... 95 3.4.10 Effect of iberiotoxin ............................................................................................. 96 3.4.11 Emodepside effects on voltage-activated Ca2+ currents ...................................... 98 3.5 Discussion ................................................................................................................... 100 3.5.1 Different mode of action ...................................................................................... 100 3.5.2 Emodepside is not a GABA receptor agonist ...................................................... 100 3.5.3 K+-dependent hyperpolarization by releasing inhibitory neuropeptides ............. 101 3.5.4 Latrophilin Receptors........................................................................................... 102 3.5.5 SLO-1 as a target for emodepside in C. elegans .................................................. 103 3.5.6 SLO-1 as a target for emodepside in Ascaris suum ............................................. 103 3.6 Acknowledgements ..................................................................................................... 105 3.7 Supplementary information ........................................................................................ 107 3.7.1 Diethylcarbamazine (DEC) potentiates emodepside effect ................................. 108 v Chapter 4 Levamisole-sensitive acetylcholine receptors of O. dentatum ............................. 112 4.1 Abstract ....................................................................................................................... 112 4.2 Author Summary ......................................................................................................... 113 4.3 Introduction ................................................................................................................. 114 4.4 Materials and Methods ................................................................................................ 116 4.4.1 Ethical Concerns .................................................................................................. 116 4.4.2 Accession numbers .............................................................................................. 117 4.4.3 Nematode Isolates ................................................................................................ 117 4.4.4 Molecular Biology ............................................................................................... 117 4.4.5 Electrophysiological studies in oocytes ............................................................... 118 4.4.6 Data analysis ........................................................................................................ 118 4.5 Results ......................................................................................................................... 119 4.5.1 Identification of unc-29, acr-8, unc-38 and unc-63 homologs………………….119 4.5.2 Four receptor subtypes reconstituted with four AChR subunit genes ................
Recommended publications
  • The Functional Parasitic Worm Secretome: Mapping the Place of Onchocerca Volvulus Excretory Secretory Products
    pathogens Review The Functional Parasitic Worm Secretome: Mapping the Place of Onchocerca volvulus Excretory Secretory Products Luc Vanhamme 1,*, Jacob Souopgui 1 , Stephen Ghogomu 2 and Ferdinand Ngale Njume 1,2 1 Department of Molecular Biology, Institute of Biology and Molecular Medicine, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium; [email protected] (J.S.); [email protected] (F.N.N.) 2 Molecular and Cell Biology Laboratory, Biotechnology Unit, University of Buea, Buea P.O Box 63, Cameroon; [email protected] * Correspondence: [email protected] Received: 28 October 2020; Accepted: 18 November 2020; Published: 23 November 2020 Abstract: Nematodes constitute a very successful phylum, especially in terms of parasitism. Inside their mammalian hosts, parasitic nematodes mainly dwell in the digestive tract (geohelminths) or in the vascular system (filariae). One of their main characteristics is their long sojourn inside the body where they are accessible to the immune system. Several strategies are used by parasites in order to counteract the immune attacks. One of them is the expression of molecules interfering with the function of the immune system. Excretory-secretory products (ESPs) pertain to this category. This is, however, not their only biological function, as they seem also involved in other mechanisms such as pathogenicity or parasitic cycle (molting, for example). Wewill mainly focus on filariae ESPs with an emphasis on data available regarding Onchocerca volvulus, but we will also refer to a few relevant/illustrative examples related to other worm categories when necessary (geohelminth nematodes, trematodes or cestodes).
    [Show full text]
  • The Anthelmintic Niclosamide Is a Potent TMEM16A Antagonist That Fully Bronchodilates Airways
    bioRxiv preprint doi: https://doi.org/10.1101/254888; this version posted January 27, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. The anthelmintic niclosamide is a potent TMEM16A antagonist that fully bronchodilates airways Kent Miner1, Benxian Liu1, Paul Wang2, Katja Labitzke2,†, Kevin Gaida1, Jian Jeffrey Chen3, Longbin Liu3,†, Anh Leith1,†, Robin Elliott1, Kathryn Henckels1, Esther Trueblood4,†, Kelly Hensley4, Xing-Zhong Xia1, Oliver Homann5, Brian Bennett1, Mike Fiorino1, John Whoriskey1, Sabine Escobar1, Gang Yu1, Joe McGivern2, Min Wong1, Teresa L. Born1,†, Alison Budelsky1,†, Mike Comeau1, Dirk Smith1,†, Jonathan Phillips1, James A. Johnston1, Kerstin Weikl2,†, David 2 1,* 2,†.* 1,† ,* Powers , Deanna Mohn , Andreas Hochheimer , John K. Sullivan 1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA 2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany 3Department of Medicinal Chemistry, Amgen Inc., Thousand Oaks, CA, USA 4Department of Comparative Biology and Safety Sciences, Amgen Inc., Seattle, WA, Thousand Oaks, CA and South San Francisco, CA, USA 5Genome Analysis Unit, Amgen Inc., South San Francisco, CA, USA †Present address; see Additional Information section *Corresponding authors. E-mails: [email protected] (J.K.S); [email protected] (A.H.); [email protected] (D.M.) Abstract There is an unmet need in severe asthma where approximately 40% of patients exhibit poor -agonist responsiveness, suffer daily symptoms and show frequent exacerbations. 2+ Antagonists of the Ca -activated-Cl¯ channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease.
    [Show full text]
  • Natural Variation in Caenorhabditis Elegans Responses to the Anthelmintic Emodepside
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.05.425329; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Natural variation in Caenorhabditis elegans responses to the anthelmintic 2 emodepside 3 4 Janneke Wita, Steffen R. Hahnela, Briana C. Rodrigueza, and Erik. C. Andersena,‡ 5 aMolecular Biosciences, Northwestern University, Evanston, IL 60208 6 7 ‡Corresponding Author: 8 Erik C. Andersen, Ph.D. 9 Department of Molecular Biosciences 10 Northwestern University 11 4619 Silverman Hall 12 2205 Tech Drive 13 Evanston, IL 60208 14 847-467-4382 15 [email protected] 16 17 Janneke Wit: 0000-0002-3116-744X 18 Steffen R. Hahnel: 0000-0001-8848-0691 19 Briana C. Rodriguez: 0000-0002-5282-0815 20 Erik C. Andersen: 0000-0003-0229-9651 21 22 Journal: IJP DDR 23 Keywords: Emodepside, natural variation, C. elegans, anthelmintics, hormetic effect 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.05.425329; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 24 Graphical abstract 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.05.425329; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Skin Probiotics ACCELERATING INNOVATION
    ACCELERATING INNOVATION James Madison University technologies are available for licensing through its nonprofit affiliate, James Madison Innovations, Inc. Skin Probiotics Inventors: Reid Harris and Kevin Minbiole Department: Biology and Chemistry Overview Research Funding and Source: National Science Foundation James Madison University inventors have filed a patent Years of Development: 4 years application on a helpful bacterium that could potentially be Technology Readiness: Research Development used as a therapy for human skin fungus such as athlete’s foot. Patent Status: U.S. patent pending 20110002891 The JMU inventors have developed a potential process to Contact: Mary Lou Bourne, Director of Technology Transfer deliver a helpful microbe, Janthinobacterium Lividum to the James Madison University skin using a pharmaceutically acceptable carrier. The microbe Phone: (540)568-2865 E-mail: [email protected] has been shown to suppress bacterial and fungal growth on animals and in lab demonstrations. Tech Transfer and Business Model Infections can be a problem for a wide array of hosts. For JMI is interested in identifying an existing company or example, there are a variety of infections, such as bacterial, entrepreneur interested in commercializing the technology viral and/or fungal infections, that affect a large percentage of either under an exclusive or a non-exclusive license. A the human population. Tricophyton rubrum, the fungus that small company or entrepreneur could further develop the causes athlete’s foot, is responsible for approximately 46% to technology, possibly using SBIR or STTR funding. 72% of cutaneous and nail mycoses worldwide. Onychomycosis, a common and persistent fungal infection, is Market and Competition In 2008, the U.S.
    [Show full text]
  • ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential
    pharmaceuticals Review ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential Subrata Deb * , Anthony Allen Reeves, Robert Hopefl and Rebecca Bejusca Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (R.H.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +224-310-7870 Abstract: On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By Citation: Deb, S.; Reeves, A.A.; understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of Hopefl, R.; Bejusca, R. ADME and remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized Pharmacokinetic Properties of by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases.
    [Show full text]
  • Anthelmintic Activity of Yeast Particle-Encapsulated Terpenes
    molecules Article Anthelmintic Activity of Yeast Particle-Encapsulated Terpenes Zeynep Mirza 1, Ernesto R. Soto 1 , Yan Hu 1,2, Thanh-Thanh Nguyen 1, David Koch 1, Raffi V. Aroian 1 and Gary R. Ostroff 1,* 1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; [email protected] (Z.M.); [email protected] (E.R.S.); [email protected] (Y.H.); [email protected] (T.-T.N.); [email protected] (D.K.); raffi[email protected] (R.V.A.) 2 Department of Biology, Worcester State University, Worcester, MA 01602, USA * Correspondence: gary.ostroff@umassmed.edu; Tel.: 508-856-1930 Academic Editor: Vaclav Vetvicka Received: 2 June 2020; Accepted: 24 June 2020; Published: 27 June 2020 Abstract: Soil-transmitted nematodes (STN) infect 1–2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many instances of reduced activity. Terpenes are a class of compounds with anthelmintic activity. Thymol, a natural monoterpene phenol, was used to help eradicate hookworms in the U.S. South circa 1910. However, the use of terpenes as anthelmintics was discontinued because of adverse side effects associated with high doses and premature stomach absorption. Furthermore, the dose–response activity of specific terpenes against STNs has been understudied. Here we used hollow, porous yeast particles (YPs) to efficiently encapsulate (>95%) high levels of terpenes (52% w/w) and evaluated their anthelmintic activity on hookworms (Ancylostoma ceylanicum), a rodent parasite (Nippostrongylus brasiliensis), and whipworm (Trichuris muris). We identified YP–terpenes that were effective against all three parasites.
    [Show full text]
  • Extensive Larva Migrans
    Case Report Extensive larva migrans Vandana Rai Mehta, S. D. Shenoi Department of Skin and STD, Kasturba Medical College, Manipal, India. Address for correspondence: Dr. S. D. Shenoi, Professor and Head, Dept of Skin and STD, Kasturba Medical College, Manipal - 576104, Karnataka, India. E-mail: [email protected] ABSTRACT Larva migrans is characterized by tortuous migratory lesions of the skin caused by larvae of nematodes. A 26-year-old fisherman presented to us with complaints of an itchy eruption on his back and arms of two months’ duration. Clinical examination revealed multiple wavy serpentine tracts and fork like lesions with a raised absolute eosinophil count of 3800 cells/cmm. Biopsy was inconclusive. This case is reported to highlight the extensive involvement by larva migrans. KEY WORDS: Larva migrans, Fisherman INTRODUCTION Cutaneous larva migrans is a common tropically acquired dermatosis. It presents as an erythematous, serpiginous, pruritic, cutaneous eruption caused by percutaneous penetration and subsequent migration of larvae of various nematode parasites. CASE REPORT A 26-year-old male came with complaints of an itchy eruption on his back and arms of 2 months’ duration. He was a fisherman by occupation and gave a history of sleeping on the beach for long hours. He was treated Figure 1: Wavy serpiginous tracts with fork like lesions with antihistamines, but without any response. Cutaneous examination revealed multiple erythematous The baseline laboratory parameters were normal, with papules, plaques and wavy serpentine tracts on the back a raised absolute eosinophil count of 3800 cell/cmm. A and posterior aspect of arms (Figure 1). biopsy from the lesion showed only spongiosis with How to cite this article: Mehta VR, Shenoi SD.
    [Show full text]
  • Tuesday June 2 Wednesday June 3
    Tuesday June 2 14:00- Registration 18:30 19:30 Welcome reception Wednesday June 3 08:00- Registration 09:00 09:00- Welcome and Introduction 09:15 09:15- Targeting Ebola Chair: Steven Kern 10:45 09:15- Conducting clinical trials in challenging Steven Kern 09:30 environments 09:30- France Estimating an effective dose for a repurposed 09:55 Mentré drug to treat Ebola: the case of favipiravir Estimating an effective dose for a new drug to 09:55- Matthias treat Ebola with incomplete information: the 10:20 Machacek case of Zmapp 10:20- An Adaptive Platform Trial for Ebola: Scott Berry 10:45 Application to Future Epidemics 10:45- Coffee break, Poster and Software session I 12:15 Posters in Group I (with poster numbers starting with I-) are accompanied by their presenter 12:15- Diabetes Chair: IñakiTrocóniz 12:55 Page | 1 12:15- Roberto A model of glucose clearance to improve the 12:35 Bizzotto description of glucose homeostasis A longitudinal HbA1c model elucidates genes 12:35- Rada Savic linked to disease progression on metformin 12:55 therapy 12:55- Lunch 14:25 On the 20th anniversary of 'Nonlinear 14:25- Chair: France models for repeated measurement 15:15 Mentré data' 14:25- David Why write a book in 1995 on nonlinear mixed 14:50 Giltinan effects modeling? 14:50- Marie Subsequent developments in nonlinear mixed 15:15 Davidian effects modeling 15:15- Tea break, Poster and Software session II 16:40 Posters in Group II (with poster numbers starting with II-) are accompanied by their presenter 16:40- Other diseases Chair: Ana Ruiz 17:40 José
    [Show full text]
  • Natural Variation in Caenorhabditis Elegans Responses to the Anthelmintic Emodepside
    International Journal for Parasitology: Drugs and Drug Resistance 16 (2021) 1–8 Contents lists available at ScienceDirect International Journal for Parasitology: Drugs and Drug Resistance journal homepage: www.elsevier.com/locate/ijpddr Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside Janneke Wit, Briana C. Rodriguez, Erik C. Andersen * Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA ARTICLE INFO Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug Keywords: arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic Emodepside drug effective against gastrointestinal and filarialnematodes. Nematodes that are resistant to other anthelmintic Natural variation drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from C. elegans previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and + Anthelmintics genetic selection and in vitro experiments implicated slo-1, a large K conductance (BK) channel gene, in emo­ Hormetic effect depside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1, but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring pro­ duction in low concentrations of emodepside (a hormetic effect). We find that natural variation affects emo­ depside sensitivity, supporting the suitability of C.
    [Show full text]
  • Insecurities and Dogs: an Obstacle to the Eradication of Dracunculiasis
    dicine & Me S l u a r ic g e p r o y r T ISSN: 2329-9088 Tropical Medicine & Surgery Review Article Insecurities and Dogs: An Obstacle to the Eradication of Dracunculiasis Aja Kalu1*,Nwufo Amanda2 Department of Care of the Elderly, Barking, Havering and Redbridge University Hospital, NHS Trust, Romford, Essex, UK; 2 Department of Public Health, University of Chester, Chester, UK. ABSTRACT Dracunculiasis is a parasitic worm infection also known as Guinea Worm Disease (GWD). It is caused by a nematode called Dracunculiasis Medinensis. It belongs to a group of communicable disease named Neglected Tropic Disease (NTD). Dracunculiasis is caused by drinking water contaminated with the vector copepods (water fleas). Although the disease is not fatal, the sores caused by the emerging worm in the lower limb can become secondarily infected and complications such as sepsis, tetanus can ensue. Also, the sores can cause abscess and cellulitis, leaving the individual incapacitated for weeks which extends beyond the emergence of the worm. Over the last three decades, the prevalence of Guinea worm disease has reduced drastically through cost effective intervention provided by The Cater Center, WHO, UNICEF with the disease targeted for eradication. Some African countries like Nigeria, Ghana, South Africa, and Kenya being the most recent, have eliminated the disease. Guinea worm is still present in Chad, Cameroon, Mali, Ethiopia where political instability, social inequalities and infection of dogs by the worm pose an increasing threat and obstacle to the elimination of the disease. Dracunculiasis represents a disease that can be eradicated without a drug or vaccine but with a cost-effective intervention that involves community efforts.
    [Show full text]
  • Procox (As Published in May 2011)
    3 May 2011 EMA/CVMP/236066/2011 Veterinary Medicines and Product Data Management Scientific discussion This module reflects the initial scientific discussion for the approval of Procox (as published in May 2011). For information on changes after this date please refer to module 8. 1. Summary of the dossier Procox, an oral suspension, contains the active substances emodepside and toltrazuril and is presented in bottles of 7.5 ml or 20 ml. The target species is dogs (puppies). It is indicated for dogs suffering from, or at risk from, mixed parasitic infections caused by roundworms and coccidia of certain specified species. The applicant for this veterinary medicinal product is Bayer Animal Health GmbH, Germany. The product was eligible for the Centralised procedure under Article 3 of Regulation (EC) No 726/2004. The two active substances in Procox are emodepside (0.9 mg/ml) and toltrazuril (18 mg/ml). Emodepside is a depsipeptide antiparasiticide which acts at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of the parasites. Toltrazuril is an anticoccidial which acts against all intracellular development stages of the coccidia, resulting in their death. The benefits of Procox are its efficacy against the replication of coccidia and the shedding of oocysts at all stages of coccidial infection. The most common side effects are slight and transient digestive tract disorders, such as vomiting or loose stools. The approved indication is: For dogs, when mixed parasitic infections caused by roundworms and coccidia of the following species are suspected or demonstrated: Roundworms (Nematodes): - Toxocara canis (mature adult, immature adult, L4) - Uncinaria stenocephala (mature adult) - Ancylostoma caninum (mature adult) Coccidia: - Isospora ohioensis complex - Isospora canis Procox is effective against the replication of Isospora and also against the shedding of oocysts.
    [Show full text]
  • Natural Products As Potential Antiparasitic Drugs
    Natural Products as potential antiparasitic drugs OLIVER KAYSER1, ALBRECHT F. KIDERLEN2, SIMON L. CROFT3 1Freie Universität Berlin Institut für Pharmazie, Pharmazeutische Biotechnologie Kelchstraße 31, 12169 Berlin, Germany 2Robert Koch-Institut Nordufer 20 13353 Berlin, Germany 3London School of Hygiene and Tropical Medicine Department of Infectious and Tropical Diseases Keppel Street London, WC1E 7HT, United Kingdom ABSTRACT: Pharmaceutical research in natural products represents a major strategy for discovering and developing new drugs. The use of medicinal plants for the treatment of parasitic diseases is well known and documented since ancient times e.g. by the use of Cinchona succiruba (Rubiaceae) as an antimalarial. This chapter provides a comprehensive review of the latest results in the field of antiparasitic drug development from biologic sources (plants, bacteria, fungi and marine organisms) focussing on the treatment of protozoal infections (Plasmodium, Leishmania, Trypanosoma spp.). The status of validated in vitro and in vivo assays is reviewed, discussing their different features, problems and limitations. Because of the high number of natural products tested against the aforesaid protozoa in the last years, we limit the discussion to lignans, phenolics, terpenoids, and alkaloids as defined natural product classes. The review also covers essential research topics of recent publications on specific natural products (e.g. licochalcone A, benzyl- and naphthylisoquinoline alkaloids, and artemisinin) and gives an outlook to semi- synthetic approaches of drugs already introduced in clinics or in clinical trial studies. 1. INTRODUCTION The fascination of natural products, mostly as used as a preparation from a plant with known medicinal properties, goes back to ancient times. The discovery of pure compounds as active principles in plants was first described at the beginning of the 19th century, and the art of exploiting natural products has become part of the molecular sciences.
    [Show full text]