DOCSLIB.ORG

United States Patent (19) 11) Patent Number: 5,532,219 Mcgeer Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent (19) 11) Patent Number: 5,532,219 Mcgeer Et Al US005532219A United States Patent (19) 11) Patent Number: 5,532,219 McGeer et al. 45) Date of Patent: Jul. 2, 1996 (54) DAPSONE AND PROMIN FOR THE Van Saane P. and Timmerman H., "Pharmacohistochemical TREATMENT OF DEMENTIA Aspects of Leprosy. Recent Developments and Prospects for New Drugs”, Pharm. Weekbl. 1989; 11:3-8 Abstract. 75 Inventors: Patrick L. McGeer, Vancouver, McGeer P. L., et al., “Anti-inflammatory Drugs and Alzhe Canada; Nobua Harada, Oku-gun; mier's Disease', Lancet 1990; 335:1037. Horoshi Kimura, Otsu, both of Japan; Evans D. A., et al., "Prevalence of Alzheimer Disease in a Edith G. McGeer; Michael Schulzer, Community Population of Older Persons', JAMA 1989; both of Vancouver, Canada 262:2551-6. Mortimer J. A., "Alzheimer's Disease and Dementia: Preva 73) Assignee: The University of British Columbia, lence and Incidence", In: Reisberg B (ed) Alzheimer's Vancouver, Canada Disease, Glencoe, Free Press, 1983. Sulkava R., et al., "Prevalence of Severe Dementia in 21) Appl. No.: 42,658 Finland", Neurology 1985; 35:1025-9. 22 Filed: Apr. 5, 1993 Zhang M., et al., “The Prevalence of Dementia and Alzhe imer's Disease in Shanghai, China: Impact of Age, Gender Related U.S. Application Data and Education', Ann Neurol. 1990: 27:428-37. Itagaki S., et al., "Presence of T-cytotoxic Suppressor and I63) Continuation-in-part of Ser. No. 689,498, Apr. 23, 1991, Leucocyte Common Antigen Positive Cells in Alzheimer's abandoned. Disease Brain Tissue', Neurosci. Lett. 1988; 91:259-64. 151 Int. Cl. ........................ A61K 31/13 McGeer P. L., et al., "Reactive Microglia in Patients with Senile Dementia of the Alzheimer Type are Positive for the (52) U.S. Cl. ................................. 514/42, 514/645 Histocompatibility Glycoprotein, HLA-DR.', Neurosci. 58) Field of Search ........................................ 514/42, 645 Lett. 1987; 79:195-200. 56) References Cited Rogers.J., et al., "Expression of Immune System-Associated Antigen by Cells of the Human Central Nervous System. U.S. PATENT DOCUMENTS Relationship to the Pathology of Alzheimer's Disease", 4,791,099 12/1988 Aroonsakul ................................. 514/2 Neurobiol. Aging 1988; 9:330–49. 4,855,308 8/1989 Kester et al. ........................... 514/332 McGeer P. L., et al., "Immune System Response in Alzhe imer's Disease', Can. J. Neurol. Sci. 1989; 16:516-27. FOREIGN PATENT DOCUMENTS McGeer P. L., et al., "Activation of hite Classical Comple 3923088 1/1991 Germany. ment Pathway in Brain Tissue of Alzheimer Patients', Neurosci. Lett. 1989; 107:341-6. OTHER PUBLICATIONS Akiyama H. and McGeer P. L., "Brain Microglia Constitu “The Merck Index', 1989, Merck & C., Inc., Rahway, N.J., tively Express B-2 Integrins', J. Neurolimmunol. 1990; U.S.A., #2820, 4357,8667, 8664, 8947, 9237. 30:81-93. "The Merck Index', 10th Ed., #2808, 4324 1983. Eikelenboom P., et al., "Complement Activation in Amyloid Capsticket al., 84CA:993 111W, 1976. Plaques in Alzheimer's Dementia", Virchows Arch. (Cell Stendahl et al., 98CA:1914689, 1983. Pathol.) 1989; 56:259-62. P. L. McGeer et al., Dementia, vol. 3, No. 3, 1992 pp. Cowdry, E. V. and Ruangsivi C., "Influence of Promin, 146-149, "Prevalence of Dementia Amongst Elderly Japa Starch and Heptaldehyde on Experimental Leprosy in Rats", nese with Leprosy: Apparent Effect of Chronic Drug Arch. Pathol. 32:632, 1941. Therapy'. Primary Examiner-Russell Travers Shibayama, H., et al., "Prevalence of Dementiain a Japanese Attorney, Agent, or Firm-Oyen Wiggs Green & Mutala Elderly Population", Actua, Psychiat., Scand. 1986; 74: 144-51. (57) ABSTRACT Zuidema, J., et al., "Clinical Pharmacokinetics of Dapsone', Clin. Pharmacokinetics 1986; 11:299-315. This invention pertains to the novel use of 4,4'-diamino Boesen., P., et al., "Dapsone in Temporal Arteritis and diphenylsulfone and its didextrose sulfonate derivative and Polymaglia Rheumatica”, J. Rheumatol. 1988; 15:879-80. other closely related sulfones in the prevention and treat Lindskov, R. and Reyman F., "Dapsone in the Treatment of ment of dementia (Alzheimer's disease). A method of pre Cutaneous Lupus Erythematosus', Dermatologia 1986; venting and treating dementia in a human being suffering 172:214-17. from dementia which comprises administering to the human Sharquie K. E., "Suppression of Behcet's Disease with being a therapeutic amount of a substance selected from the Dapsone', Brit. J. Dermatol. 1984; 110:493-4. group consisting of 4,4'-diaminodiphenylsulfone, its didex Guillevin L., “Treatment of Polyarteritis Nodosa with Dap trose sulfonate derivative, and sulfoxone, sulfetrone and sone', Scand. J. Rheumatol. 1986; 15:95-6. thiazolsulfone, and therapeutically acceptable salts thereof. Gabriel S. E., et al., “Rifampin Therapy in Rheumatol Arthritis', J. Rheumatoid. 1990; 17:163-6. 11 Claims, 2 Drawing Sheets U.S. Patent Jul. 2, 1996 Sheet 1 of 2 5.532,219 Treated E. Untreated 65-69 70-74 779 80-84 28 5 AGE RANGE FIGURE 1 U.S. Patent Jul. 2, 1996 Sheet 2 of 2 5,532,219 FIGURE 2 FIGURE 3 5,532,219 1 2 DAPSONE AND PROMN FOR THE The substance can be effectively administered to the TREATMENT OF DEMENTIA human being suffering from dementia at dosage rates which can vary widely, and on schedules which can vary from This application is a continuation-in-part of application twice daily to once weekly. The substance can be either Ser. No. 07/689,498, filed Apr. 23, 1991, now abandoned. 4,4'-diaminodiphenylsulfone, its didextrose sulfonate derivative, other closely related derivatives as mentioned FIELD OF THE INVENTION above or pharmaceutically acceptable salts thereof. Typical therapeutic dosages will be in the range of 2 to 20 micro This invention pertains to the novel use of 4,4'-diamino moles per kg body weight per day, and the preferred route diphenylsulfone and its didextrose sulfonate derivative and O will be oral. Typical dosage rate will be between about 50 closely related anti-lepromatous sulfones in the treatment of mg and 300 mg per day. dementia (Alzheimer's disease) in human beings. The invention also pertains to a composition useful for treating dementia comprising substances selected from the BACKGROUND OF THE INVENTION group consisting of 4,4'-diaminodiphenylsulfone, the didex 15 Alzheimer's Disease is by far the most common cause of trose sulfonate derivative of 4,4'-diaminodiphenylsulfone, primary dementia. Either by itself, or in combination with sulfoxone, sulfetrone, thiazolsulfone, and pharmaceutically multiple infarcts, it accounts for almost 80% of all cases. No acceptable salts thereof, and a pharmaceutically acceptable treatment has been established which will prevent the onset carrier. or delay the progression of Alzheimer's Disease. It is 20 possible that known drugs would have an as yet unrecog DRAWINGS nized efficacy in this respect. 4,4'-diaminodiphenylsulfone dapsone and its didextrose In the drawings: sulfonate derivative Promin'TM were first shown to have a FIG. 1 represents a block graphical comparison of demen favourable effect in treating rat leprosy in 1941 (Cowdry and 25 tia percentage among treated and untreated patients from the Ruangsiri, Arch. Pathol. 32:632, 1941). Successful clinical age of 65 to over 85. trials for the treatment of human leprosy followed and these FIGS. 2 and 3 represent block graphical comparisons of two compounds are now the most important anti-leprosy frequency of NFT's and SP's among leprosy and non drugs. The two drugs have since been used for treating a leprosy subjects aged over 70 years. variety of skin diseases such as dermatitis herpetiformis and 30 efficacy has been reported in several disorders of presumed autoimmune origin such as rheumatoid arthritis, lupus DETAILED DESCRIPTION OF A PREFERRED erythematosus and Behcet's disease. Dapsone is a drug that EMBODEMENT OF THE INVENTION has been used worldwide for over 40 years. It has been found Immunohistochemical studies on Alzheimer brain tissue to have few side effects and these are well understood due 35 have suggested a chronic inflammatory process may play a to extensive experience with patients taking the drug con role in the observed neuronal degeneration. Dapsone, 4,4'- tinuously for many years. To the applicants' knowledge, diaminodiphenylsulfone, is effective in several chronic 4,4'-diaminodiphenylsulfone and its didextrose sulfonate inflammatory disorders. derivative, and closely related antilepromatous sulfones have never been used or considered for the treatment of 40 Leprosy patients are almost universally treated with 44 dementia. diaminodiphenylsulfone (dapsone), the didextrose sulfonate derivative (Promin'M), or other closely related sulfones, Leprosy is no longer a fatal disorder, due in substantial over prolonged periods. As a result of such treatment, and measure to treatment with dapsone. It has anti-inflammatory the availability of these drugs, leprosy is no longer fatal, and action, which may seem paradoxical for treatment of an in many cases apparent cures can lead to drug withdrawal. infectious disease. However. M. leprae survives in macroph 45 The applicants have noted unexpectedly that the prevalence ages, and one of the deleterious consequences of the infec of dementia (Alzheimer disease) amongst elderly leprosy tion, which is reduced by dapsone, is widespread amyloi patients being treated with either of the two drugs noted has dosis. Dapsone has also been reported to be effective for the been unusually low. treatment of various presumed autoimmune diseases, includ ing dermatitis herpetiformis, rheumatoid arthritis, temporal 50 The applicants have conducted a formal survey of leprosy arteritis, polymyalgia rheumatica, cutaneous lupus erythe hospitals in Japan and have determined that there was matosus, Behcet's disease and polyarteritis nodosa. The significantly less prevalence of dementia amongst dapsone alternative antileprosy drugs, clofazimine and rifampicin, and Promin'M treated leprosy patients compared with those have also been reported to have efficacy in anti-inflamma who had been off such drugs for at least five years. It has tory therapeutic applications. 55 therefore been concluded that dapsone and Promin'TM, when administered on a daily dosage basis to the elderly patient, have a preventative action against dementia.
Load more

Recommended publications
  • Toman's Tuberculosis Case Detection, Treatment, and Monitoring
    TOMAN’S TUBERCULOSIS TOMAN’S TUBERCULOSIS CASE DETECTION, TREATMENT, AND MONITORING The second edition of this practical, authoritative reference book provides a rational basis for the diagnosis and management of tuberculosis. Written by a number of experts in the field, it remains faithful to Kurt Toman’s original question-and-answer format, with subject matter grouped under the three headings Case detection, Treatment, and Monitoring. It is a testament to the enduring nature of the first edition that so much CASE DETECTION, TREA material has been retained unchanged. At the same time, the new edition has had not only to address the huge resurgence of tuber- culosis, the emergence of multidrug-resistant bacilli, and the special needs of HIV-infected individuals with tuberculosis, but also to encompass significant scientific advances. These changes in the profile of the disease and in approaches to management have inevitably prompted many new questions and answers and given a different complexion to others. Toman’s Tuberculosis remains essential reading for all who need to AND MONITORING TMENT, QUESTIONS learn more about every aspect of tuberculosis – case-finding, manage- ment, and effective control strategies. It provides invaluable support AND to anyone in the front line of the battle against this disease, from ANSWERS programme managers to policy-makers and from medical personnel to volunteer health workers. SECOND EDITION ISBN 92 4 154603 4 WORLD HEALTH ORGANIZATION WHO GENEVA Toman’s Tuberculosis Case detection, treatment, and monitoring – questions and answers SECOND EDITION Edited by T. Frieden WORLD HEALTH ORGANIZATION GENEVA 2004 WHO Library Cataloguing-in-Publication Data Toman’s tuberculosis case detection, treatment, and monitoring : questions and answers / edited by T.
    [Show full text]
  • Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication?
    pharmaceutics Review Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication? Luíse L. Chaves 1,2,*, Yuri Patriota 2, José L. Soares-Sobrinho 2 , Alexandre C. C. Vieira 1,3, Sofia A. Costa Lima 1,4 and Salette Reis 1,* 1 Laboratório Associado para a Química Verde, Rede de Química e Tecnologia, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; [email protected] (A.C.C.V.); slima@ff.up.pt (S.A.C.L.) 2 Núcleo de Controle de Qualidade de Medicamentos e Correlatos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil; [email protected] (Y.P.); [email protected] (J.L.S.-S.) 3 Laboratório de Tecnologia dos Medicamentos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil 4 Cooperativa de Ensino Superior Politécnico e Universitário, Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal * Correspondence: [email protected] (L.L.C.); shreis@ff.up.pt (S.R.) Received: 30 October 2020; Accepted: 4 December 2020; Published: 11 December 2020 Abstract: Leprosy disease remains an important public health issue as it is still endemic in several countries. Mycobacterium leprae, the causative agent of leprosy, presents tropism for cells of the reticuloendothelial and peripheral nervous system. Current multidrug therapy consists of clofazimine, dapsone and rifampicin. Despite significant improvements in leprosy treatment, in most programs, successful completion of the therapy is still sub-optimal. Drug resistance has emerged in some countries. This review discusses the status of leprosy disease worldwide, providing information regarding infectious agents, clinical manifestations, diagnosis, actual treatment and future perspectives and strategies on targets for an efficient targeted delivery therapy.
    [Show full text]
  • Dapsone and Sulfones in Dermatology: Overview and Update
    CLINICAL REVIEW Dapsone and sulfones in dermatology: Overview and update Y. Isabel Zhu, PhD, and Matthew J. Stiller, MD New York, New York In their 60-year history, dapsone and the sulfones have been used as both antibacterial and anti- inflammatory agents. Dapsone has been used successfully to treat a range of dermatologic disorders, most successfully those characterized by abnormal neutrophil and eosinophil accumulation. This article reviews and updates the chemistry, pharmacokinetics, clinical application, mechanism of action, adverse effects, and drug interactions of dapsone and the sulfones in dermatology. (J Am Acad Dermatol 2001;45:420-34.) he father of sulfones is Emil Fromm, a profes- sor in chemistry at the Freiburg/Br University Abbreviations used: 1 T in Germany. In 1908, Fromm and Wittmann DH: dermatitis herpetiformis first described the synthesis of sulfones from p- G6PD: glucose 6-phosphate dehydrogenase nitrothiophenole. In vivo sulfone research was not IgA: immunoglobulin A initiated until 1937, when Buttle, Stephenson, and LTB4: leukotriene B4 Smith2 in England and Fourneau, Trefouel, and Nitti3 MPO: myeloperoxidase in France treated experimental streptococcal infec- PCP: Pneumocystis carinii pneumonia tions in mice with dapsone and other sulfones, and PG: pyoderma gangrenosum Heitz, Nitti, and Trefouel4 treated human gonorrhea RA: rheumatoid arthritis with a disubstituted sulfone that had results compa- SWD: Sneddon-Wilkinson disease TMP-SMX: trimethoprim-sulfamethoxazole rable to those with sulfonamide. Dapsone deriva- WHO: World Health Organization tives rather than the parent compound were tested in humans initially, for fear of more severe side effects with dapsone. Later in 1937, a sulfone derivative (sodium salt of considerable number of cases.
    [Show full text]
  • Legacies of Leprosy
    Chapter 1 Legacies of Leprosy The world’s “seven billion human beings are all equal,” asserted the Dalai Lama on his March 2014 visit to the Tahirpur Leprosy Complex in the megacity of New Delhi. He continued, “People should not look down on others. It is totally wrong. Discrimination is a sin” (“Condemning Discrimination” 2014). And yet, as a longtime resident of the Tahirpur complex declared, echoing the senti- ments of people living with Hansen’s disease in many parts of the world, “We face a thousand indignities every day” (“Stigma Hinders” 2014).1 Four thousand miles away, on a remote island in Japan’s Inland Sea, Tomita Mikio, a healthy, middle-aged resident of the Ōshima National Sanitarium (国立療養所大島 青松園, Kokuritsu Ryōyōjo Ōshima Seishōen), lamented that he had attempt- ed many times to live outside the sanitarium but was unable to do so. He had not even been able to obtain a driver’s license, having been dismissed from driving school when the staff learned he was from Ōshima and therefore had been treated for leprosy. And so, he says, “I was lucky that I had a place to come back to [i.e., Ōshima] … a place where I felt at home and normal” (Sims 2001).2 Caused by the bacterium Mycobacterium leprae, leprosy, also known as Han- sen’s disease, is a chronic infectious condition that often first manifests with spots on the skin or numbness in a finger or toe.3 Although greatly feared be- cause of how drastically it can alter physical appearance and cause physical impairment, Hansen’s disease is one of the least contagious of the contagious diseases, since the vast majority of the world’s population has natural immu- nity.
    [Show full text]
  • Highlights of Our History
    Stigma The stigma associated with leprosy is deeply ingrained in human history. Many religious traditions considered the disease a "curse from God" rather than a medical condition. Fear that the disease was highly contagious (it is not) led to quarantine. The Germ Gerhard Henrik Armauer Hansen, a Norwegian Doctor, discovered the germ in 1871 Mycobacterium leprae, the germ that causes leprosy, is a bacillus. It is related to tuberculosis (T.B.), but unlike T.B., leprosy is not easy to catch. Only 5% of the world's population is susceptible to the disease. In the 20th century, "leprosy" was renamed "Hansen's disease" in honor of Dr. Hansen's historic achievement. Effects on the Body Fingers and toes can become deformed over time due to nerve damage with subsequent injury and tissue absorption. Hansen's disease affects the nerves and skin. Nerve damage can cause muscle weakness and lack of feeling. Repetitive injury and infection over time can create deformity. The eyes can also become damaged resulting in blindness. State Law The Louisiana Leper Home was established in 1892 following passage of Act 85 which required all people with leprosy in Louisiana to be confined in an institution. In 1894, Act 80 created a Board of Control for the Louisiana Leper Home. The board selected a site for the home in Carville, Louisiana. Daughters of Charity Sisters with young patient in the early 20th century. The Daughters of Charity of St. Vincent de Paul arrived in 1896 to nurse the patients and provide management of the Louisiana Leper Home. The Catholic order of nursing sisters served their Catville mission until 2005.
    [Show full text]
  • Multidrug Therapy Against Leprosy
    Multidrug therapy against leprosy Development and implementation over the past 25 years World Health Organization Geneva 2004 WHO Library Cataloguing-in-Publication Data Multidrug therapy against leprosy : development and implementation over the past 25 years / [editor]: H. Sansarricq. 1.Leprosy - drug therapy 2.Leprostatic agents - therapeutic use 3.Drug therapy, Combination 4.Health plan implementation - trends 5.Program development 6.World Health Organization I.Sansarricq, Hubert. ISBN 92 4 159176 5 (NLM classification: WC 335) WHO/CDS/CPE/CEE/2004.46 © World Health Organization 2004 All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. The named authors alone are responsible for the views expressed in this publication. Printed by the WHO Document Production Services, Geneva, Switzerland Contents ________________________________________________ Acknowledgements ……………………………………………………………….
    [Show full text]
  • Clofazimine: an Old Drug for Never-Ending Diseases
    Review For reprint orders, please contact: [email protected] Clofazimine: an old drug for never-ending diseases Niccolo` Riccardi*,1,2, Andrea Giacomelli2,3,4, Diana Canetti2,5,6, Agnese Comelli7 , Enrica Intini2,8, Giovanni Gaiera6, Mama M Diaw2,9, Zarir Udwadia10, Giorgio Besozzi2, Luigi Codecasa2,11 & Antonio Di Biagio2,12 1Department of Infectious, Tropical Diseases & Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy 2StopTB Italia Onlus, Milan, Italy 3III Infectious Diseases Unit, ASST Fatebenefratelli Sacco, Milano, Italy 4Department of Biomedical & Clinical Sciences “Luigi Sacco”, Universita` degli Studi di Milano, Italy 5Vita-Salute San Raffaele University, Milan, Italy 6Clinic of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy 7Department of Infectious & Tropical Diseases, Spedali Civili, Brescia, Italy 8Division of Respiratory Medicine, A. Gemelli University Hospital, Catholic University of the Sacred Heart, Rome, Italy 9Medecin´ coordonnateur lutte contre la TB, Region´ medicale´ de Thies,` Thies,` Sen´ egal´ 10Department of Pulmonary Medicine, PD. Hinduja National Hospital & Medical Research Centre, Mumbai, Maharashtra, India 11Regional TB Reference Centre & Laboratory, Villa Marelli Institute/ASST Niguarda Ca’ Granda, Milan, Italy 12Clinic of Infectious Diseases, IRCCS AOU San Martino-IST, Genoa, Italy *Author for correspondence: Tel.: +390456014620; [email protected] Clofazimine (CFZ), an old hydrophobic riminophenazine, has a wide range
    [Show full text]
  • Preparation of the Study Group on Chemotherapy of Leprosy ______
    Chapter 1 Preparation of the Study Group on Chemotherapy of Leprosy __________________________________________________ 1.1 Scientific factors (1972–1981) L. Levy Modern chemotherapy of leprosy may be said to have begun with the trial of Promin® (glucosulfone) at Carville in the early 1940s (1). Over the next 20 years, a number of agents – including dapsone, thiambutosine, ethionamide, thiacetazone, and clofazimine – were employed as monotherapies in clinical trials that were supported only by clinical observation and interval measurements of the bacterial index. Until Shepard’s development of the mouse footpad technique, first reported in 1960 (2, 3), there had been no means existed for assaying the antimicrobial activity of a drug against Mycobacterium leprae outside the body of the leprosy patient. Moreover, the change in bacterial index proved to be a very insensitive measure of the patient’s response to antimicrobial chemotherapy. The decrease was slow – approximately one order of magnitude (one “plus”) per year – and it was impossible to distinguish more potent from less potent drugs by this method. During the decade that followed Shepard’s report of the multiplication of M. leprae in the hind footpad of the immunologically intact mouse (2, 3), individual drugs were screened for antimicrobial activity against the organism, primarily in Shepard’s laboratory (4–8), but also at the National Institute for Medical Research in London, England (9) and in San Francisco (10–14). Initially, each drug was screened at the highest concentration tolerated by the mice by the “continuous” method: drug administration began when the organisms were inoculated and continued for the duration of the experiment.
    [Show full text]
  • Therapy of Leprosy
    ISSN: 2469-5750 Chauhan et al. J Dermatol Res Ther 2020, 6:093 DOI: 10.23937/2469-5750/1510093 Volume 6 | Issue 2 Journal of Open Access Dermatology Research and Therapy REVIEW ARTICLE Therapy of Leprosy- Present Strategies and Recent Trends with Immunotherapy Divya Chauhan1, Raj Kamal1* and Aditya Saxena2 1Clinical Division, National JALMA Institute for Leprosy & Other Mycobacterial Disease (ICMR), Tajganj, Agra, UP 282001, India 2Department of Biotechnology, GLA University, Delhi Road, Mathura, Chumuhan, UP, 281406, India *Corresponding author: Dr. Raj Kamal, MD, FICMCH, Scientist E (Medical), Head Clinical Division, Check for National JALMA Institute for Leprosy & Other Mycobacterial Disease, P.O Box 101, Dr Miyazaki Road updates Tajganj, Agra, UP-282001, India, Tel: 0562-2331751 (Ext- 247, 302) tients, and often give patients the feeling of stigma. Lep- Abstract rosy, perhaps the most serious human illness identified Leprosy is a complex infectious diseases cause by My- cobacterium Leprae. As the nation is passing through the by Gerhard Armer Hansen of Norway in 1873, is still a eradication phase of leprosy, reports are suggesting a major issue in many parts of the world, which mainly af- change in epidemiology and symptomatology of the dis- fects the skin and peripheral nerves, but may also affect ease. Current therapeutic strategies like multidrug therapy the muscles and other parts of the body [1]. (MDT) although effective in treating the majority of cases but not sufficient to eradicate still the new leprosy cases alone The global leprosy situation has improved dramati- and with the complication of diseases like deformities, re- lapses, and recurrence of cases are occurring in the soci- cally over the last four decades since the implementa- ety.
    [Show full text]
  • Drug-Resistant Leprosy: Monitoring and Current Status
    Lepr Rev (2012) 83, 269–281 Drug-resistant leprosy: Monitoring and current status DIANA L. WILLIAMS & THOMAS P. GILLIS HRSA, BPHC, National Hansen’s Disease Programs, Laboratory Research Branch Accepted for publication 30 August 2012 Introduction Leprosy control depends solely on case detection and treatment with multi-drug therapy (MDT).1–3 This strategy is based on the principle that identifying and treating chronic infectious diseases with combinations of effective antibiotics limits the emergence and spread of new or existing antibiotic resistant pathogens.2 According to the World Health Organization (WHO), MDT formulated for leprosy has been effective at reducing both the prevalence and incidence of leprosy globally.3–5 According to official reports from 130 countries and territories, the global registered prevalence of leprosy at the beginning of 2011 was 192,246 cases, while the number of new cases detected during 2010 was 228,474.5 The most important indicator for the effectiveness of a chemotherapeutic regimen is the rate of relapse following successful completion of the scheduled course of treatment. Information from a number of leprosy control programmes suggests that the relapse rate is very low for both paucibacillary (PB) leprosy (0·1% per year) and multibacillary (MB) leprosy (0·06% per year).5 Lessons learned from tuberculosis strongly suggest that relapse cases are at risk for drug resistance and can undermine existing control measures.6,7 Therefore establishing the success of a strategy like MDT for leprosy control requires thorough evaluation of treatment failures, including drug susceptibility testing. Several studies have documented relapses after MDT8–14 and drug-resistant strains of Mycobacterium leprae have been identified.15 – 26 In contrast to what we know for tuberculosis, the current prevalence of primary and secondary resistance to rifampicin; dapsone, and clofazimine is virtually unknown for leprosy.
    [Show full text]
  • Drug Resistance in Leprosy
    Jpn. J. Infect. Dis., 63, 1-7, 2010 Invited Review Drug Resistance in Leprosy Masanori Matsuoka* Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan (Received October 7, 2009) CONTENTS 1. Introduction 2-5. Minocycline 2. Chemotherapy of leprosy 3. Drug susceptibility testing 2-1. Dapsone 3-1. Mouse footpad method 2-2. Rifampicin 3-2. Mutation detection by sequencing 2-3. Ofloxacin 3-3. Mutation detection by DNA microarray 2-4. Clofazimine 4. Perspectives SUMMARY: Leprosy is caused by Mycobacterium leprae. Currently, leprosy control is mainly based on WHO- recommended multi-drug treatment; thus, emergence of drug resistance is a major concern. M. leprae isolates resistant to single and multiple drugs have been encountered. In this review, the history of chemotherapy and drug resistance in leprosy and molecular biological insights for drug resistance are described. New methodolo- gies to test susceptibility to anti-leprosy drugs instead of the traditional mouse footpad method are introduced. Awareness of the need to monitor drug resistance to prevent the spread of resistant cases is emphasized. resistance increased (7) and multi-drug resistant cases 1. Introduction emerged (8–10). The purpose of this review is to describe the Leprosy is a chronic infectious disease caused by an obli- chemotherapy of leprosy, drug resistance to current treat- gate intracellular pathogen Mycobacterium leprae. Newly ments, molecular biological methods to detect drug-resistant detected cases in Japan have markedly decreased during the mutants, and a global strategy to combat the emergence of last two decades. Recently, there have been fewer than 10 drug resistance.
    [Show full text]
  • Mechanisms of Action and Therapeutic Efficacies of the Lipophilic Antimycobacterial Agents Clofazimine and Bedaquiline
    J Antimicrob Chemother 2017; 72: 338–353 doi:10.1093/jac/dkw426 Advance Access publication 20 October 2016 Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline Moloko C. Cholo1*, Maborwa T. Mothiba1, Bernard Fourie2 and Ronald Anderson3 1Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; 2Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; 3Institute for Cellular and Molecular Medicine, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa *Corresponding author. Department of Immunology, P.O. Box 2034, Pretoria 0001, South Africa. Tel: +27 12 319 2162; Fax: +27 12 323 0732; E-mail: [email protected] Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treat- ment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the ‘re-purposed’ riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis. In the case of bedaquiline, the primary target is the key respira- tory chain enzyme F1/F0-ATPase, whereas clofazimine is less selective, apparently inhibiting several targets, which may underpin the extremely low level of resistance to this agent.
    [Show full text]