Contents

Cure Arthritis Naturally

Cure Arthritis Naturally

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1 Introduction: Definition and Classification of Biologics

1.1 Aims 1

1.2 Perspectives 2

1 Development and Pre-clinical Pharmacology of Biologics

2 Infliximab: From the Idea to the Product

M. Wiekowski, Ch.E. Antoni 5

2.1 Characteristics and Biological Activity 5

2.1.1 Antibody Characteristics 5

2.1.2 Other Mechanisms of Infliximab Activity 5

2.2 Administration 6

2.3 Therapeutic Indications 6

2.4 Pharmacokinetics 7

2.4.1 Pharmacokinetics in Rheumatoid Arthritis Patients 7

2.4.2 Pharmacokinetics in Crohn's Disease 9

2.4.3 Pharmacokinetics in Psoriasis 9

2.4.4 Pharmacokinetics in Pediatric Crohn's Patients 9

2.5 Relationship Between Infliximab Concentration and Clinical Response ... 10

2.6 Antibody Formation Against Infliximab 10

2.6.1 HACA Formation and Clinical Response 11

2.7 Infusion Reactions/Delayed Hypersensitivity Reactions 11

2.8 Alternative Routes of Administration 11

2.9 Summary 12

References 12

3 Adalimumab

J. Salfeld, H. Kupper 14

3.1 Pharmacology 15

3.1.1 Mode of Action 15

3.1.2 Pharmacodynamics 16

3.1.3 Pharmacokinetics 16

3.1.4 Adalimumab Comparisons with Infliximab and Etanercept 16

3.2 Indications 18

3.3 Pivotal Studies in Rheumatoid Arthritis 18

3.3.1 Adalimumab Plus Methotrexate 19

3.3.2 Monotherapy 19

3.3.3 Adalimumab Plus Traditional DMARDs 22

3.3.4 Early Rheumatoid Arthritis 22

3.4 Pivotal Studies in Psoriatic Arthritis 23

3.5 Pivotal Study in Ankylosing Spondylitis 25

3.6 Future Indications 25

3.6.1 Psoriasis 25

3.6.2 Crohn's Disease 25

3.7 Safety 26

3.8 Summary 27

References 28

4 Etanercept

Ch.T. Molta 32

4.1 Structure 32

4.2 Pharmacokinetics 32

4.2.1 Absorption 32

4.2.2 Distribution 34

4.2.3 Metabolism and Elimination 34

4.2.6 Patients with Renal or Hepatic Insufficiency 34

4.2.7 Drug Interactions 35

4.3 Pharmacodynamics 35

4.3.1 Mode of Action 35

4.3.2 Pharmacodynamics in Disease States 36

4.4 Indications 38

4.5 Summary 40

Key References 40

References 40

5 Efalizumab: Antibody Characteristics, Mode of Action and Preclinical Development

5.1 Introduction 42

5.2 Development and Characterization of the Antibody 43

5.3 Efalizumab: From Mode of Action to the Treatment of Psoriasis 44

5.3.1 Psoriasis: Prevalence, Characteristics and Therapeutic Options 44

5.3.2 Pathogenesis of Psoriasis: Targets for Efalizumab 45

5.3.3 Efalizumab: Mechanism of Action 46

5.4 Pharmacology and Toxicology of Efalizumab 47

5.4.1 Preclinical Studies 47

5.4.2 Pharmacodynamics 47

5.4.3 Pharmacokinetics 48

5.5 Indication(s) 49

5.6 Summary 49

References 49

6 Monoclonal Antibody Targeted Radiation Cancer Therapy L.M.M. Keller, C.A. Boswell, D.E. Milenic, Erik D. Brady,

Martin W. Brechbiel 50

6.1 Overview 50

6.2 Introduction and Background 50

6.3 The Radioisotope 51

6.4 Linking the Radionuclide to Protein 54

6.5 The Protein Vehicle 56

6.6 Conclusions 57

References 57

7 The Production of Biopharmaceuticals

7.1 Introduction 59

7.2 The Success of Modern Biotechnology 60

7.3 The Science and Technology Behind Modern Biopharmaceuticals 61

7.4 Process Development 62

7.5 Biopharmaceutical Manufacturing 63

7.6 Quality Assurance and Quality Control 64

7.7 Facility Considerations 64

7.8 Biosimilar Products (or Follow-on Biologics) 65

7.9 Conclusion 65

Key References 65

Full Reference List 66

II Disease-Specific Applications and Clinical Trials

8 Treating Autoimmune Bullous Skin Disorders with Biologics

R. Eming, A. Niedermeier, M. Pfütze, A. Jacobi, M. Hertl 69

8.1 Introduction 69

8.1.1 Autoimmune Bullous Skin Disorders 69

8.1.2 Immune Pathogenesis of Bullous Autoimmune Disorders 71

8.2 Rituximab (Anti-CD20 Monoclonal Antibody) in the Treatment of Autoimmune Bullous Skin Disorders 72

8.2.1 Biological Activity of Rituximab 72

8.2.2 Clinical Experience with Rituximab Therapy 73

8.2.3 Rituximab in Pemphigus 73

8.2.4 Rituximab in Epidermolysis Bullosa Acquisita 74

8.2.5 Toxicity of Rituximab Treatment and Adverse Effects 76

8.2.6 Contraindications for Treatment with Rituximab 76

8.3 Inhibitors of TNF-a in the Treatment of Autoimmune Bullous

Skin Disorders 76

8.3.1 Central Role of TNF-a in Inflammation 76

8.3.2 Inhibition of TNF-a by Biologics 77

8.3.3 Inhibition of TNF-a in Pemphigus Vulgaris 78

8.3.4 Inhibition of TNF-a in Bullous Pemphigoid 79

8.4 Summary 79

References 80

9 Biologies in Psoriasis

9.1 Introduction 81

9.1.1 Psoriasis 81

9.1.2 Mechanism of Disease 85

9.2 Etanercept 86

9.2.1 Structure and Mode of Action 86

9.2.2 Pharmacokinetics and Pharmacodynamics 86

9.2.3 Efficacy 87

9.2.4 Safety 88

9.2.5 Off-Label Use 89

9.3 Efalizumab 89

9.3.1 Structure and Mode of Action 89

9.3.2 Pharmacokinetics and Pharmacodynamics 89

9.3.3 Efficacy 90

9.3.4 Safety 91

9.3.5 Off-Label Use 92

9.4 Alefacept 92

9.4.1 Structure and Mode of Action 92

9.4.2 Pharmacokinetics and Pharmacodynamics 93

9.4.3 Efficacy 93

9.4.4 Safety 94

9.4.5 Off-Label Use 95

9.5 Infliximab 95

9.6 Adalimumab 95

References 96

10 Biologic Agents in Psoriatic Arthritis

10.1 Introduction 97

10.2 Classification and Epidemiology 97

10.3 Genetic Epidemiology 97

10.4 Immunopathology 98

10.5 Clinical Features 98

10.6 Outcome Measures 101

10.7 Treatment 101

10.8 Biologic Agents 102

10.8.1 Etanercept 102

10.8.2 Infliximab 103

10.8.3 Adalimumab 104

10.9 Other Biologic Agents 105

10.9.1 Alefacept 105

10.9.2 Efalizumab 106

10.9.3 Abatacept 106

10.10 Other Potential Treatments 106

10.11 Cost-Effectiveness Analysis 107

10.12 Conclusion 107

References 108

11 Biologic Therapies for Rheumatoid Arthritis Targeting TNF-a and IL-1

P.C.Taylor 111

11.1 Introduction 111

11.2 Biologic Therapies Targeting TNF-a 111

11.2.1 Rationale for TNF Blockade in the Treatment of Rheumatoid Arthritis 111

11.2.2 Clinical Studies of Anti-TNF Therapy 112

11.2.3 Safety of Biologic TNF Inhibitors 114

11.2.4 Infectious Complications 114

11.2.5 Congestive Cardiac Failure 115

11.2.6 Solid Tumours and Lymphoma 116

11.2.7 Other Toxicity Issues 116

11.2.8 Injection Site Reactions or Infusion-Related Reactions 117

11.2.9 Mechanism of Action of TNF Blockade 117

11.3 Targeting IL-1 118

11.4 Combination Anti-cytokine Therapies 119

11.5 Conclusions 120

References 120

12 Biologics in Crohn's Disease and Ulcerative Colitis: Focus on Tumor Necrosis Factor Antagonists

J. Salfeld, P. Rutgeerts 124

12.1 Clinical Features of Crohn's Disease 124

12.2 Pathogenesis of Crohn's Disease 124

12.3 Biologics for Use in Crohn's Disease 126

12.3.1 TNF Antagonists 130

12.3.2 Selective Adhesion Molecule Inhibitors 134

12.3.3 Anti-IL-12/IL-23 Antibodies 135

12.3.4 Anti-IFN-y Antibodies 136

12.3.5 Anti-IL-6 Receptor Monoclonal Antibody 136

12.3.6 Miscellaneous 137

12.4 Biologics in Ulcerative Colitis 137

12.5 Summary and Outlook 137

References 138

13 Multiple Sclerosis: New Immunobiologics

R. Gold, R. Hohlfeld 141

13.1 Introduction 141

13.2 Immunopathogenesis of Multiple Sclerosis 141

13.3 Prominent Failure of TNF-a Targeting 142

13.4 Adverse Reactions in Highly Efficacious Anti- 4-Integrin Therapy with Natalizumab 143

13.5 Currently Investigated Monoclonal Antibodies 144

13.5.1 Anti-CD52 144

13.5.2 Anti-CD25 144

13.5.3 Anti-CD20 145

13.5.4 Other Therapeutic Monoclonal Antibodies 145

13.6 Conclusions and Outlook 145

References 146

14 Biologics in Cutaneous Lymphoma

14.1 Introduction 147

14.2 Cutaneous T-Cell Lymphomas 148

14.2.1 Cutaneous B-Cell Lymphoma 149

14.3 Biologics in the Treatment of CTCL 149

14.3.1 DAB389-Interleukin-2 (DAB389IL-2) 149

14.3.2 Alemtuzumab 150

14.3.3 Rituximab 150

14.3.4 90Y-Ibritumomab Tiuxetan 151

14.3.5 Histone Deacetylase Inhibitors 152

References 152

15 Biologics in Targeted Cancer Therapy

D. Schrama, J.C. Becker 153

15.1 Introduction 153

15.2 Chemoimmunoconjugates 154

15.3 Immunotoxins 156

15.4 Antibody-Cytokine Fusion Proteins 157

15.5 Evolving Approaches 160

15.6 Conclusions 162

References 163

III Safety and Perspectives

16 Safety Aspects of Biologics: Lessons Learnt from Monoclonal Antibodies Ch.K. Schneider, J. Lower 169

16.1 Introduction 169

16.2 Intervention with Pleiotropic Cytokine Pathways 170

16.3 Intervention with Adhesion Molecules 171

16.4 Intervention with Growth Factor Receptors 172

16.5 Conclusion 173

References 173

17 New Biological Therapeutics in the Genome Age

T.N.C. Weils, S. Schnieper-Samec 175

17.1 Introduction 175

17.2 Early Biotechnology Production of Human Cytokines and Hormones .. 176

17.3 Finding New Cytokine Orphans in the Human Genome: Early Excitement from Expressed Sequence Tags 177

17.4 Assembling the Complete Protein Collection: The Serono Secretome .. 177

17.5 Moving from the Protein to the Biological Activity: The Post-Genome

Era 178

17.6 Strategies for Blocking Responses 180

17.6.1 Monoclonal Antibodies 180

17.6.2 Receptor Fusion Proteins 180

17.6.3 Protein Antagonists 180

17.6.4 Small Molecules: The Convenience of an Oral Medicine 180

17.7 Future Directions 180

References 181

18 Evidence Based Medicine's Perspective on Biologics

18.1 What is EBM? 184

18.2 EBM Steps to Treating an Individual Patient 184

18.3 German S3 Guideline for the Treatment of Plaque Psoriasis 185

18.4 EBM and Biologics 185

18.5 Where Do Biologics Stand Among Other Systemic Treatments of Psoriasis? 186

References 186

Subject Index 187

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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