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OCCASION This Publication Has Been Made Available to the Public on The OCCASION This publication has been made available to the public on the occasion of the 50th anniversary of the United Nations Industrial Development Organisation. DISCLAIMER This document has been produced without formal United Nations editing. The designations employed and the presentation of the material in this document do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations Industrial Development Organization (UNIDO) concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries, or its economic system or degree of development. Designations such as “developed”, “industrialized” and “developing” are intended for statistical convenience and do not necessarily express a judgment about the stage reached by a particular country or area in the development process. Mention of firm names or commercial products does not constitute an endorsement by UNIDO. FAIR USE POLICY Any part of this publication may be quoted and referenced for educational and research purposes without additional permission from UNIDO. However, those who make use of quoting and referencing this publication are requested to follow the Fair Use Policy of giving due credit to UNIDO. CONTACT Please contact [email protected] for further information concerning UNIDO publications. For more information about UNIDO, please visit us at www.unido.org UNITED NATIONS INDUSTRIAL DEVELOPMENT ORGANIZATION Vienna International Centre, P.O. Box 300, 1400 Vienna, Austria Tel: (+43-1) 26026-0 · www.unido.org · [email protected] DOC Coll·" ,. ,., Dis tr •. VIC Lib rFJ '-"---.....! 1 0 SEP 1985 LIMITED _,... _______ "···-···-· UNIDO/I0.618 2 August 1985 .UNITED NATIONS INDUSTRIAL DEVELOPMENT ORGANIZATION ENGLISH REVIEW ON THE DEVELOPMENT OF ANTIBIOTICS INDUSTRY IN SELECTED COUNTRIES RP/INT/84/016 Technical report: Antibiotic industry in Japan, history and development* Prepared by the United Nations Industrial Development Organization Based on the work of Minoru Aizawa, UNIDO consultant ..'' *This document has been reproduced without formal editing. The views expressed in it are those of the consultant and do not necessarily reflect the views of the secretariat of UNIDO. V.85-29528 CONTENTS Page PREFACE 4 SUMMARY 6 CHAPTER I HISTORICAL REVIEW ON THE DEVELOPMENT OF ANTIBIO'rIC 8 INDUSTRIES IN JAPAN CHAPTER II INTRODUCTION OF VARIOUS ANTIBIOTICS CURRENTLY 14 MARKETED IN JAPAN Section 1. Beta-lactam Antibiotics 14 Section 2. Aminoglycoside Antibiotics 24 CHAPTER III BACKGROUND OF PROGRESS IN THE ANTIBIOTIC INDUSTRY 28 Section 1. Chemical Modification of the Structure of Parent 29 Antibiotics A) Tetracyclines 30 B) Beta-lactam Antibiotics 38 C) Aminoglycoside Antibiotics 43 Section 2. Establishment of S6reening Process for the 47 Selection of Microorganisms which may elaborate Novel Beta-lactam Antibiotics as well as Beta­ lactamase Inhibitors A) Screening Procedures using Beta-lactam­ 47 hypersensi tive Organisms B) Screening Procedures for Beta-lactamase 53 Inhibitors 2 List of Annf'xes 56 Figure 1. Beta - Lactam Ring Systems 57 Figure lA. Penam Compounds (1) 58 Figure lB. Penam Compounds (2) 59 Figure lC. 3-Cephem Compounds (1) Figure lD. 3-Cephem Compunds (2) 60 Figure 2. Chemical Structure of Aminoglycoside 61 Antibiotic (1 to 3) Figure 3. Relative antibacterial activity of 64 Cephem Antibiotics Figure 4. Naphthacenic Antibiotics, Tetracyclines 65 and Anthracyclines Figure 5. 7-Acylamino Groups taken up by Bacterial 66 Acylases Figure 6. Probable Biosynthetic Pathways of 67 Aminoglycoside Antibiotics Figure 7. Reactions Catalyzed by Peptidoglycan 68 Transpeptidase and D-Alanine Catboxy peptidase in E. Coli Figure 8. Beta-Lactamase inhibitors and Monocyclic 69 Azetidinone Antibiotics 71 Table 1. Manufacturers for Listed Antibiotic Drugs in Japan in 1982 74 Table 2. Historical Review on Antibiotics Marketed in Japan Table 3. Antibiotic Drugs Listed in Social Security 78 Organization in Japan Table 4. Mdin Journals of English Edition Concern­ 81 i11g the topics of Novel Antibiotics and its Related Technology, Published in Japan Table 5. Literature cited 82 Table 6. Summary of Beta-Lactamases Classified by 88 Richmond Table 7. Presence of Aminoglycoside-Inactivating 89 Enzymes in Clinical Isolates 90 Table 8. Function and Enzyme Activity of PC~inding proteins in E. Coli 3 List of Annexes (Continued) Table 9. Beta-Lactum - Hypersensitivity Shown 91 by PBP - I Bs - Less Mutant strains of Escherichia Coli Table 10. Minimal Inhibitary Concentration of 92 Antibiotics Against Esche.richia Coli_ NIHJ JC-2 and Its Mutant Hypersensitive to PC G. - 4 - PREFACE This case study on antibiotics industry in Japan, history and develop­ ment is part of an effort by the UNIDO Secretariat to undertake case studies which would review the development of this important industry in selected developed and developing countries with the aim of promoting the growth and development of antibiotics industry in developing countries. The present study highlights the outstanding progress achieved in Japan in terms of research and development towards new antibiotics. The discovery of a broad variety of therapeutic agents to treat a number of pathologic conditions and the launching of medicaments utilized to treat or cure a large number of ailments had a strong impact on the world consumption of pharmaceuticals. The structure of world consumption of pharmaceuticals presents an interesting pattern in a large number of countries. The incidence of a broad variety of microbial diseases places the antimicrobials, and out of this group, the antibiotics as the leader in world consumption. While systemic antibiotics ranked during 1979 No. 1 in Brazil, Japan, Pakistan, Philippines and Venezuela, they ranked No. 3 in the U.S.A. and No. 7 in the Federal Republic of Germany. The market share of systemic antibiotics during the same year in developing countries was 25 percent in Pakistan, 19 percent in Philippines, and 14 percent in Brazil and Venezuela. As regards developed countries, the market share of systematic antibiotics in 1979 was 26 percent in Japan, 7 percent in the U.S.A. and 4 percent in the Federal Republic of Germany. While the value of world wide consumption of antibiotics in 1980 was $2,259 millions, the share of developing countries was only 20.05 percent. With the exception of a few, most of the developing countries totally depend on the import of antibiotics either in the form of finished products or as active ingredients to produce pharmaceuticals in dosage form. The non-availability of adequate amounts of convertible currency is limiting the imports of these essential drugs, which in turn adversely affect the health care programmes in these countries . Further several raw materials used in the manufacture of antibiotics are products of agriculture and these are available in plerity in most of the developing countries. In 5 view of this local production of antibiotics could result in achieving self reliance in this area to the extent feasible. Some developing countries in Latin America, Asia and few in Africa have some base and infrastructure necessary for the production of antibiotics through fermentation and these include Algeria, Argentina, China, Cuba, Egypt, India, Iraq, Mexico, Pakistan, Peru, Republic of Korea and Thailand. While this industry is at initial stages of development in some of these countries, it has made significant progress in others. It is also proposed to carry out the case study on antibiotics industry in one of the latter developing countries. The study was prepared by Minoru Aizawa, Adviser for Overseas Operation and ex-Managing Director of Toyo Jozo Co. Ltd., Japan, which made a significant contribution to the development of this industry world wide. 6 SUMMARY The antibiotics industry in Japan virtually came into existence with the production of Penicillin just after World War II with the assistance of the allied occupation forces. Subsequencly production of Streptomycin, Chlorampenicol and Tetracycline was taken up under licensing agreements. Later on new antibiotics of Japanese origin such as Colistin, Kitasamycin, Kanamycin followed by Mitomycin, Bleomycin the anticancer antibiotics came on the scene. This trend led to the production of many new Beta-Lactam compounds based on 6-APA and 7-ACA. MajorJapaneseantibiotic producers may be broadly classified into three categories - a) authentic local pharmaceutical industries, b)_ foreign subsidiaries/joint ventures and c) local industries other than pharmaceutical. In total, 73 companies were listed in 1982. The gross output of antibiotic drugs in 1982 was 865,148 million Japanese Yen (US$ 3,366 million) which amounted to 21.7 percent of the total output of pharmaceutical products in Japan - 3,980,232 million Japanese Yen (US$ 15,487 million). Beta-lactam family and the aminoglucoside family constitute major groups of antibiotics currently used in Japan. B-lactam antibiotics are the derivatives of a bicyclic ring system. The Penicillin ring system called Penam contains a four membered beta-lactam ring fused with a five membered thiazolidine ring, whereas the cephalosporin ring system, 3 cephem contains the same beta-lactam ring fused with an unsaturated six-membered dihydrothiazine ring. According to the structure-activity relationships, the Penam family members can be characterized in four sub-groups - a) oral form, b) anti­ staphylococcal - beta-lactamase compounds, c) wide spectrum compounds
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