Provides a review of novel pharmaceutical approaches for Tuberculosis drugs * Presents a novel perspective on tuberculosis prevention and treatment * Considers the nature of disease, immunological responses, vaccine and drug delivery, disposition and response * Multidisciplinary appeal, with contributions from microbiology, immunology, molecular biology, pharmaceutics, pharmacokinetics, chemical and mechanical engineering
List of Contributors xvi Foreword xviii Series Preface xxi Preface xxiii 1 Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery 1 A.J. Hickey 1.1 Background 1 1.2 Dosage Form Classification 3 1.3 Controlled and Targeted Delivery 5 1.4 Physiological and Disease Considerations 6 1.5 Therapeutic Considerations 7 1.6 Conclusion 8 References 8 Section 1 Pathogen and Host 11 2 Host Pathogen Biology for Airborne Mycobacterium tuberculosis: Cellular and Molecular Events in the Lung 13 Eusondia Arnett, Nitya Krishnan, Brian D. Robertson and Larry S. Schlesinger 2.1 Introduction 13 2.2 Lung 14 2.3 General Aspects of Mucus and Surfactant 17 2.4 General M. tuberculosis 18 2.5 M. tuberculosis Interaction with the Lung Macrophage 19 2.6 M. tuberculosis Interaction with other Respiratory Immune Cells 23 2.7 TB Granuloma 29 2.8 Conclusion 30 References 30 3 Animal Models of Tuberculosis 48 David N. McMurray 3.1 Introduction 48 3.2 What is an Animal Model of TB? 49 3.3 How are Animal Models of TB Used? 50 3.4 TB Animal Models Currently Used for TB Drug and Vaccine Evaluation 51 3.5 Summary 58 References 59 Section 2 Immunological Intervention 67 4 Vaccine Preparation: Past, Present, and Future 69 Dominique N. Price, Nitesh K. Kunda, Amber A. McBride and Pavan Muttil 4.1 Introduction 69 4.2 Early Efforts in TB Vaccine Development 71 4.3 Current BCG Vaccine Formulation 73 4.4 Novel TB Vaccination Strategies 76 4.5 Future Perspective 84 4.6 Conclusions 85 References 85 5 TB Vaccine Assessment 91 Andre G. Loxton, Mary K. Hondalus and Samantha L. Sampson 5.1 Introduction 91 5.2 Preclinical Vaccine Assessment 92 5.3 Clinical Assessment of Vaccines 97 5.4 Laboratory Immunological Analysis and Assessment of Vaccine Trials 102 5.5 How well do the Available Preclinical Models Predict Vaccine Success in Humans? 103 References 105 Section 3 Drug Treatment 111 6 Testing Inhaled Drug Therapies for Treating Tuberculosis 113 Ellen F. Young, Anthony J. Hickey and Miriam Braunstein 6.1 Introduction 113 6.2 The Need for New Drug Treatments for Tuberculosis 114 6.3 Inhaled Drug Therapy for Tuberculosis 114 6.4 Published Studies of Inhalation Therapy for TB 115 6.5 The Guinea Pig Model for Testing Inhaled Therapies for TB 116 6.6 Guinea Pig Study Design 117 6.7 Purchase and Grouping Animals 118 6.8 Infecting Guinea Pigs with Virulent Mycobacterium tuberculosis 118 6.9 Dosing Groups of Guinea Pigs with TB Drugs 119 6.10 Collecting Data 121 6.11 Aerosol Dosing Chambers and Practice 122 6.12 Nebulizer Aerosol Delivery Systems for Liquids 123 6.13 Dry -Powder Aerosol Delivery Systems for Solids 125 6.14 Summary 127 Acknowledgements 127 References 127 7 Preclinical Pharmacokinetics of Antitubercular Drugs 131 Mariam Ibrahim and Lucila Garcia -Contreras 7.1 Introduction 131 7.2 Factors Influencing the Pharmacokinetic Behavior of Drugs 132 7.3 Pulmonary Delivery of Anti -TB Drugs 138 7.4 Pharmacokinetic Study Design 140 7.5 Implications of PK Parameters on Efficacy 144 7.6 Case Studies (Drugs Administered by Conventional and Pulmonary Routes) 146 References 152 8 Drug Particle Manufacture Supercritical Fluid, High -Pressure Homogenization 156 Kimiko Makino and Hiroshi Terada 8.1 Introduction 156 8.2 Preparation of Nano - and Micro -particles 157 References 159 9 Spray Drying Strategies to Stop Tuberculosis 161 Jennifer Wong, Maurizio Ricci and Hak -Kim Chan 9.1 Introduction 161 9.2 Overview of Spray Drying 162 9.3 Advances in Spray Drying Technology 174 9.4 Anti -Tuberculosis Therapeutics Produced by Spray Drying 179 9.5 Conclusion 187 9.6 Acknowledgements 187 References 187 10 Formulation Strategies for Antitubercular Drugs by Inhalation 197 Francesca Buttini and Gaia Colombo 10.1 Introduction 197 10.2 Lung Delivery of TB Drugs 198 10.3 Powders for Inhalation and Liquids for Nebulization 200 10.4 Antibacterial Powders for Inhalation: Manufacturing of Respirable Microparticles 202 10.5 Antibacterial Powders for Inhalation: Devices and Delivery Strategies 208 10.6 Conclusions and Perspectives 211 References 211 11 Inhaled Drug Combinations 213 Sanketkumar Pandya, Anuradha Gupta, Rajeev Ranjan, Madhur Sachan, Atul Kumar Agrawal and Amit Misra 11.1 Introduction 213 11.2 Standard Combinations in Oral and Parenteral Regimens 214 11.3 The Rationale for Inhaled Therapies of TB 216 11.4 Combinations of Anti -TB Drugs with Other Agents 222 11.5 Formulation of Inhaled Drug Combinations 224 11.6 Conclusions 230 References 230 12 Ion Pairing for Controlling Drug Delivery 239 Stefano Giovagnoli, Aurelie Schoubben and Carlo Rossi 12.1 Introduction 239 12.2 Ion Pairing Definitions and Concepts 240 12.3 Ion Pairs, Complexes and Drug Delivery 245 12.4 Remarks 252 References 254 13 Understanding the Respiratory Delivery of High Dose Anti -Tubercular Drugs 258 Shyamal C. Das and Peter J. Stewart 13.1 Introduction 258 13.2 Tuberculosis 259 13.3 Drugs Used to Treat Tuberculosis, Doses, Challenges and Requirements for Therapy in Lungs 260 13.4 Approaches for Respiratory Delivery of Drugs 262 13.5 Current DPI Formulations and Their Mechanisms of Aerosolization 262 13.6 DPI Formulations for Tuberculosis and Requirements 264 13.7 Issues to Consider in Respiratory Delivery of Powders for Tuberculosis 264 13.8 Relationship between De -agglomeration and Tensile Strength 266 13.9 Strategies to Improve De -agglomeration 268 13.10 DPI Formulations having High Aerosolization 269 13.11 Devices for High Dose Delivery 270 13.12 Future Considerations 271 References 272 Section 4 Alternative Approaches 275 14 Respirable Bacteriophage Aerosols for the Prevention and Treatment of Tuberculosis 277 Graham F. Hatfull and Reinhard Vehring 14.1 Introduction 277 14.2 Treatment or Prevention of Tuberculosis Using Phage -based Agents 282 14.3 Selection of Mycobacteriophages 284 14.4 Respiratory Drug Delivery of Phages 285 14.5 Summary and Outlook 288 Acknowledgements 288 References 288 15 RNA Nanoparticles as Potential Vaccines 293 Robert DeLong 15.1 Introduction 293 15.2 Nanoparticles 293 15.3 RNA Nanoparticle Vaccines 294 15.4 Progression of Nanomedicines into the Clinic 295 15.5 The Stability Problem 295 15.6 The Delivery Problem 298 15.7 RNA as Targeting Agent or Adjuvant? 298 15.8 Challenges for RNA Nanoparticle Vaccine Characterization 300 15.9 On the Horizon 301 References 301 16 Local Pulmonary Host -Directed Therapies for Tuberculosis via Aerosol Delivery 307 Mercedes Gonzalez -Juarrero 16.1 Introduction 307 16.2 Lung Immunity to Pulmonary M. tuberculosis Infection 309 16.3 Host -Directed Therapies 313 16.4 Limitations of Preclinical Studies to Develop Inhalational Host -Directed Therapies for Tuberculosis 317 16.5 Preclinical Testing of Inhaled Small Interference RNA as Host -Directed Therapies for Tuberculosis 318 Acknowledgements 319 References 319 Section 5 Future Opportunities 325 17 Treatments for Mycobacterial Persistence and Biofilm Growth 327 David L. Hava and Jean C. Sung 17.1 Introduction 327 17.2 Mycobacterial Persistence and Drug Tolerance 328 17.3 Mycobacterial Multicellular Growth 329 17.4 Mycobacterial Lipids Involved in Biofilm Formation 330 17.5 Therapies to Treat Mycobacterial Biofilms and Persistence 332 17.6 Conclusion 339 References 339 18 Directed Intervention and Immunomodulation against Pulmonary Tuberculosis 346 Dominique N. Price and Pavan Muttil 18.1 Introduction 346 18.2 TB Immunology 347 18.3 Animal Models of Immunotherapies and Vaccines for TB 351 18.4 The Current TB Vaccine Bacille Calmette Guerin 353 18.5 Other Vaccines Platforms 357 18.6 Pulmonary Immunization 361 18.7 Immunotherapeutic Agents against TB 364 18.8 Conclusion 367 References 367 Section 6 Clinical Perspective 379 19 Clinical and Public Health Perspectives 381 Ruvandhi R. Nathavitharana and Edward A. Nardell 19.1 Introduction 381 19.2 Background 382 19.3 Clinical Considerations 382 19.4 Public Health Considerations 385 19.5 Inhaled Drugs and Other Alternative Delivery Systems 387 19.6 Clinical Trials of Inhaled Injectable Drugs 388 19.7 Other Novel Delivery Strategies 393 19.8 Pediatric Delivery Systems 393 19.9 Conclusion 394 References 394 20 Concluding Remarks: Prospects and Challenges for Advancing New Drug and Vaccine Delivery Systems into Clinical Application 400 P. Bernard Fourie and Richard Hafner 20.1 Introduction 400 20.2 Progress in the Formulation and Manufacturing of Drugs and Vaccines for Tuberculosis 401 20.3 Considerations in the Development of TB Drug and Vaccine Delivery Options 404 20.4 Concluding Remarks 410 References 411 Index 415
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