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시장보고서

Nitric Oxide - Therapeutics, Markets and Companies

리서치사	Jain Pharmabiotech
발행일	2012년 04월	상품코드	70925
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한글목차
영문목차
관련자료

영문목차

Abstract

Summary

This report describes the latest concepts of the role of nitric oxide (NO) in health and disease as a basis for therapeutics and development of new drugs. Major segments of the market for nitric oxide-based drugs are described as well as the companies involved in developing them.

Nitric oxide (NO) can generate free radicals as well as scavenge them. It also functions as a signaling molecule and has an important role in the pathogenesis of several diseases. A major focus is delivery of NO by various technologies. Another approach is modulation of nitric oxide synthase (NOS), which converts L-arginine to NO. NOS can be stimulated as well as inhibited by pharmacological and gene therapy approaches.

Important therapeutic areas for NO-based therapies are inflammatory disorders, cardiovascular diseases, erectile dysfunction, inflammation, pain and neuroprotection. The first therapeutic use of NO was by inhaltion for acute respiratory distress syndrome (ARDS). NO-donors, NO-mimics and NOS modulators are described and compared along with developmental status. NO-related mechanisms of action in existing drugs are identified.

Various pharmacological approaches are described along with their therapeutic relevance. Various approaches are compared using SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis. NO-based therapies are compared with conventional approaches and opportunities for combination with modern biotechnology approaches are described.

Share of drugs where NO is involved in the mechanism of action is analyzed in the worldwide pharmaceutical market for 2011 and is projected to 2016 and 2021 as new drugs with NO-based mechanisms are introduced into the market. Various strategies for developing such drugs are discussed.

Several companies have a product or products involving NO and free radicals. The report includes profiles of 39 companies involved in this area of which 12 have a significant interest in NO-based therapeutics. Other players are pharmaceutical and biotechnology companies as well as suppliers of products for NO research. Unfulfilled needs in the development of NO-based therapeutics are identified. Important 19 collaborations in this area are tabulated.

As of the end of 2010, there are over 100,000 publications relevant to NO. Selected 500 references are included in the bibliography. The text is supplemented with 26 tables and 25 figures.It is concluded that the future prospects for NO-based therapies are bright and fit in with biotechnology-based approaches to modern drug discovery and development. It is anticipated that some of these products will help in meeting the unfulfilled needs in human therapeutics.

0. Executive Summary 12

1. Introduction 14

Nitric oxide 14
Historical aspects 14
Free radicals 15
Nitrogen cycle and NO 15
Role of NO in biology and medicine 16
Nitric oxide synthase 17
Structure and function NOS 17
Inducible nitric oxide synthase 18
iNOS gene 18
Regulation of iNOS 18
Regulation of endothelial nitric oxide synthase 19
Interaction between eNOS and other proteins 19
Tetrahydrobiopterin 20
NOS-independent NO generation and circulation 20
Entero-salivary circulation of nitrate 20
Methods of study of NO and NOS 21
Bioimaging of NO 21
Assays of NO in tissues 21
Metabolomics approach to study of NO metabolism 22

2. Nitric Oxide Pathways 24

Introduction 24
Mechanisms action of NO 25
NO-cGMP pathway 25
Nitrate-nitrite-NO pathway 26
Soluble guanylyl cyclase as the NO receptor 26
Oxidative stress pathways 26
NO and oxidative stress 27
Oxidative stress and the NO-cyclic GMP signal transduction pathway 27
NO and platelets 29
Mitochondrial NO-cytochrome c oxidase signaling pathway 29
Nitric oxide and cytochrome c oxidase 30
Dual role of NO as a free radical and a scavenger 31
NO and carbon monoxide 31
NO signaling and apoptosis 32

3. Role of NO in Physiology 34

Homeostasis of NO 34
Role of NO in adaptation to high altitude 34
NO as a biomarker 35
Functions of NO in various systems of the body 35
NO and proteins 36
A proteomic method for identification of cysteine S-nitrosylation sites 36
Protein S-nitrosylation and intracellular transport processes 36
Cellular inactivation NO by iNOS aggresome formation 36
NO and mitochondria 37
Mitochondrial permeability and reperfusion injury 38
Endocrine role of NO 38
Role of NO in the cardiovascular system 38
NO and atrial natriuretic peptide 39
NOS in the cardiac myocyte 39
NO and the autonomic control of the heart rate 40
NO and vasodilatation 41
Role of NO in the plasma compartment 42
Measurement of NO as a biomarker of cardiovascular function 42
Hemoglobin, oxygen and nitric oxide 43
Myoglobin and NO 44
NO and pulmonary circulation 44
Role of NO in the regulation of hypoxic pulmonary vasoconstriction 45
Role of NO in the nervous system 45
Neurovascular coupling of COX-2 and nNOS 46
Neuroglobin 46
Acute actions of NO in the CNS pathways 47
Role of NO in memory and learning 47
Role of NO in synaptic plasticity 47
Role of NO in the peripheral nervous system 48
Role of NO in the cochlea 48
NO and neuroendocrine function 48
NO and pregnancy 48
Role of NO in penile erection 49
Role of NO in immune regulation 49
Role of NO in temperature regulation 50
Role of NO in gastrointestinal system 50
Role of NO in kidney function 50
Role of NO in liver 51
Role of NO in the skin 51

4. Role of NO in Diseases 54

Introduction 54
Cytotoxicity of reactive nitrogen species 54
Peroxynitrite, mitochondria and cell death 54
Diseases involving oxidative stress and nitric oxide 56
Stress-related disorders 57
Role of NO in allergic disorders 57
Inflammatory diseases 57
Autoimmune disorders 58
Role of NO in rheumatoid arthritis 59
Role of NO in infections 59
NO-mediated cytoprotection in bacteria 60
Trypanosomiasis 61
Malaria and iNOS polymorphism 61
Susceptibility of Mycobacterium leprae to NO 61
Role of NO in the treatment of tuberculosis 62
Septic shock 62
Viral infections 63
Role of NO in anaphylactic shock 63
Role of NO in anemia and hypoxia 64
Role of NO in neurological disorders 64
Neurodegenerative diseases 64
NO-induced mitochondrial dysfunction in neurodegeneration 65
White matter disorders 65
Amyotrophic lateral sclerosis 66
Alzheimer's disease 66
Role of NO in pathophysiology of Alzheimer's disease 66
Role of ApoE genotype 69
Parkinson's disease 69
Traumatic brain injury 71
Epilepsy 72
Stroke 72
Pathophysiology of cerebral ischemia 72
Role of NO in cerebral ischemia 73
eNOS gene polymorphisms as predictor of cerebral aneurysm rupture 75
Role of NO in assessment of cerebral and retinal blood flow 75
Role of NO in neuroprotection 75
Stroke and heart disease 75
Role of NO in peripheral neuropathy 76
iNOS induction in experimental allergic neuritis 76
Role of NO in sciatica 76
Role of NO in the pathogenesis of muscular dystrophy 76
Role of NO in psychiatric disorders 77
NO-dysregulation in schizophrenia 77
Role of NO in pathomechanism of cardiovascular disorders 78
Oxidative stress as a cause of cardiovascular disease 78
Role of NO in pathomechanism of cardiovascular diseases 78
Role of iNOS in cardiovascular disease 79
Role of eNOS in cardiovascular disease 79
Role nNOS in cardiac arrhythmia and sudden death 80
NO and atherosclerosis 80
Role of NO in cardiopulmonary disorders 81
Role of NO in disturbances of vasodilation 82
Caveolin-1 deficiency impairs NO synthesis and vasodilation 82
Role of NO in hypercholesterolemia 82
Pulmonary hypertension 83
NO and systemic hypertension. 84
Coronary artery disease 85
Role of NO in the pathophysiology of angina pectoris 85
Congestive heart failure 86
Calcium overload as a cause of heart failure 86
NO/redox disequilibrium in the failing heart 86
Myocardial ischemia/reperfusion injury 86
NO pathway in cardiac hypertrophy 88
Role of NO in sickle cell disease 89
Role of NO in respiratory disorders 89
Role of NO in the pathophysiology of asthma 89
iNOS gene polymorphisms in asthma 90
Role of S-nitrosoglutathione in bronchodilation in asthma 91
Monitoring of exhaled NO 91
Nasal NO as a biomarker of response to rhinosinusitis therapy 92
Elevated urinary NO as a biomarker of improved survival in ARDS 92
Role of NO in renal disorders 93
Role of NOS in diabetic nephropathy 93
Role of NO in cancer 93
Inflammation, NO and colon cancer 94
Tumor hypoxia and NO 95
NO and p53 mutations 95
NO and matrix metalloproteinase 96
Role of NO in angiogenesis in cancer 96
Role of NO in diseases of the eye 97
Glaucoma 97
Role of NO in metabolic disorders 98
Metabolic syndrome 98
Obesity 98
Diabetes mellitus 98
Role of NO in gastrointestinal disorders 99
Role of L-arginine in intestinal adaptation 99
Role of NO in irritable bowel syndrome 99
Role of NO in inflammatory bowel diseases 99
Role of NO in celiac disease 100
Role of NO in diabetic gastroparesis 100
NO and diseases of the liver 100
Cirrhosis of liver 100
Hepatic encephalopathy 101
Role of NO in skin disorders 101
Role of NO and oxidative stress in the aging skin 101
Role of NO in wound healing 102
Role of NO in pain 102
NO and pain of spinal cord origin 102
NO interaction with other receptors in pain 103
nNOS and pain 103
Role of NO in various types of pain 103
Neuropathic pain 103
Role of NO in diabetic neuropathy 103
NO in oral and facial pain 104
Role of NO in migraine 104
Role of NO in osteoarthritis 105
NO and Fibromyalgia syndrome 105
Role of spinal NO in analgesic action 106
Role of NO in nicotine addiction 106
Role of NO in carbon monoxide poisoning 107
Role of NO in chemically-induced toxicity 107
Peroxynitrite and drug-dependent toxicity. 107
Paraquat neurotoxicity 107
Role of NO in radiation damage 108

5. Pharmacology of Nitric Oxide 110

Introduction 110
Cytoxic vs cytoprotective role of NO 110
Antioxidants 110
Ebselen 111
Nicaraven 111
Nitroxides 112
Antioxidants in relation to NO 112
Nitric oxide as an antioxidant 113
NO-related drugs 113
Drugs that activate eNOS production 115
Aspirin 115
Dehydroepiandrosterone 115
Drugs that scavenge free radicals/NO 115
Peroxynitrite scavengers 115
Ruthenium (III) polyaminocarboxylates 116
Nitrones 116
Drugs that inhibit NO 116
Ginko biloba 116
Epigallocatechin 117
Delivery of nitric oxide 117
Targeted delivery of NO donors 118
Nitric oxide delivery by encapsulated cells 118
NO-lipid combination 118
NO-releasing coating to prevent infection of implanted devices 119
Nanoparticles for controlled/sustained release of NO 119
Hydrogel/glass nanoparticles 119
Delivery of nanoparticles to vascular endothelium for release of NO 119
Nitric oxide donors 120
Nitroglycerine/glycerine trinitrate 120
Isosorbide dinitrate 121
Sodium nitrite 121
Organic nitrites 121
NO-releasing NSAIDs 122
COX-inhibiting NO-donors 123
Grafting of NO-releasing structures on to existing drugs 125
Mesoionic Oxatriazoles 126
Adding NO-donating structures to extend life cycle of existing drugs 126
Cysteine-containing NO donors 126
Ferrous nitrosyl complexes 127
Syndnonimines 127
S-Nitrosothiols 127
Diazeniumdiolates 128
COX-2 inhibitors 129
NO hydrogels 129
Novel NO donors 129
NO mimetics 130
Comparison of classical nitrates, grafted NO donors, and NO mimetics 130
NO donors and soluble guanylate cyclase activation 131
NO donors for increasing the efficacy of chemotherapy 131
Factors that enhance availability of NO 131
Modulators of cyclic guanosine-3',5'-monophosphate-dependent protein kinases 132
NOS-modulating drugs 133
Drugs that activate eNOS 133
Statins 133
Angiotensin converting enzyme inhibitors 134
17 Beta-estradiol 134
C-2431 134
NOS inhibitors 134
Rationale of NOS inhibitors 134
L-Arginine 136
Design of NOS inhibitors 136
Selective iNOS inhibitors 137
Non-amino acid-based inhibitors 138
Aminoguanidine 138
Heme ligands 139
Pterin antagonists 139
Fused-ring bio-isoteric models of arginine as NOS inhibitors 139
nNOS inhibitors 139
Lubeluzole 141
Neurotrophic factors 141
Therapies based on action of NOS as a paraquat diaphorase 141
Concluding remarks about NOS inhibiting drugs 142
NO and stem cell-based therapy 142
Nitric oxide and gene therapy 143
NOS gene transfer 143
Inhibition of NOS by antisense technology 144
Drugs that modulate NO action on platelets 145
Action of NO and NO donors on platelets 145
NOS inhibitors and NO scavengers 145
Phosphodiesterase inhibitors 145
Activators of soluble guanylate cyclase 146
YC-1 146
A-350619 146
Cinaciguat 146
Secondary role of NO in the action of drugs 146
Selective serotonin reuptake inhibitors 147
P2Y receptors and NO 147
Calcium channel blockers and NO 147
Nitric oxide-based transdermal drug delivery 147
Mechanism of resistance of NO-based drugs 148
NO and nutraceuticals 148
L-arginine as a nutraceutical 148
Oleuropein 149
Role of NO in beneficial effects of chocolate 149

6. Therapeutic Applications 150

Introduction 150
Role of NO in the management of pulmonary disorders 150
Manufacture of NO gas for inhalation 150
NO inhalation for acute respiratory distress syndrome 150
NO inhalation for premature children with pulmonary dysplasia 151
NO inhalation for premature children with respiratory failure 151
Pulmonary hypertension 152
NO-based treatment of pulmonary hypertension 152
Inhaled nebulized nitrite for neonatal pulmonary hypertension 153
Gene therapy for pulmonary hypertension 153
Asthma 154
iNOS inhibitors for asthma 154
NO for bronchodilation in asthma 154
Role of NO in acute lung injury after smoke inhalation 154
Cardiovascular disorders 155
Role of NO in cardioprotection 155
Role of NO in the management of angina pectoris 156
Role of NO in therapy of coronary heart disease 157
NO-releasing aspirin in patients undergoing CABG 157
Management of coronary restenosis 158
Modified NO donors 158
NO-generating stent for coronary restenosis 158
eNOS gene therapy for restenosis 159
NO-based management of cardiac hypertrophy 160
Congestive heart failure 160
Limitation of antioxidant therapy in congestive heart failure 160
NO-based therapies for congestive heart failure 161
eNOS gene therapy for congestive heart failure 161
Gene transfer of nNOS in congestive heart failure 161
NO-based therapy for management of cardiogenic shock 162
NO-based therapy for cardiac arrhythmias 162
Prophylaxis of cardiovascular disorders 162
Prevention of atherosclerosis with aging 163
Peripheral vascular disorders 163
Peripheral atherosclerotic arterial disease 163
Peripheral ischemic disease 163
An eNOS mutant as therapeutic for peripheral vascular ischemia 164
Sodium nitrite therapy for peripheral vascular ischemia 164
Raynaud's phenomenon 165
Neurological disorders 165
Cerebrovascular ischemic disorders 165
Attenuation of NO for neuroprotection in cerebral ischemia 166
Use of NO donors in cerebral ischemia 166
Use of NO donors in cerebral reperfusion injury 167
Cerebral vasospasm and NO 167
NOS gene therapy for cerebral vasospasm 168
Degenerative CNS disorders 168
Statins for Alzheimer's disease 169
NO mimetics for Alzheimer's disease 169
iNOS inhibitors for treatment of Alzheimer's disease 169
NO-NSAIDs for Alzheimer's disease 170
Ginko biloba for Alzheimer's disease 170
Personalization of NO-based therapy for Alzheimer's disease 170
Role of NO in the treatment of traumatic brain injury 170
Neuroinflammatory disorders 171
Muscular dystrophy 171
Vestibulotoxicity 172
NO for opening the blood-brain barrier 172
Cochlear disorders 172
Cochlear ischemia 172
Role of NO in sensoryneural hearing loss 173
Pain 173
NO-based therapies for pain 173
Treatment of diabetic neuropathy with isosorbide dinitrate spray 173
NO-based therapies for migraine 174
NO-based therapy for fibromyalgia syndrome 174
NO-based therapies for inflammatory disorders 174
NO-based therapies for gastrointestinal disorders 175
Protection of gastrointestinal injury from NSAIDs 175
Role of NO in the treatment of inflammatory bowel disease 175
Topical nitroglycerin for chronic anal fissure 175
Cancer 176
Mechanism of action of NO in cancer 176
Antineoplastic effect of iNOS-expressing cells 176
Role of NO in drug resistance of cancer 176
Role of NO in treatment of brain tumors 177
NO-induced apoptosis 177
Role of NO in antiangiogenesis therapies in cancer 178
NO donors for the treatment of cancer 178
NO-releasing NSAIDs and colon cancer chemoprevention 178
Rationale of combining NO aspirin with cancer vaccines 179
NO-based cancer gene therapy 179
Transdermal nitroglycerine for prostate cancer 180
NO-based therapies for skin disorders 180
NO-based therapies for skin infections 180
Role of NO in the treatment of psoriasis 181
NO-based therapy for sickle cell anemia 181
Inhaled NO for acute respiratory distress syndrome in sickle cell disease 182
NO inhalation for pulmonary hypertension in sickle cell anemia 182
Role of NO in disorders associated with pregnancy 182
Use of NO donors in management of labor 182
Eclampsia 183
Erectile dysfunction 183
Selective inhibitors of phosphodiesterase 5 183
Erectile dysfunction in diabetes 184
NO-donating substances for treatment of ED 185
NOS gene transfer for ED 185
Organ transplant rejection 185
Role of NO in the treatment of renal disorders 186
Role of NO in the treatment of hepatic disorders 187
Portal hypertension 187
NO inhalation for restoration of liver function following transplantation 187
Role of NO in blood transfusion 188
Role of NO in the treatment of osteoporosis 188
NO-based wound healing 188

7. Evaluation of NO-Based Drugs 190

Current status 190
Antioxidant vs. NO-based approaches 190
SWOT analysis of selected approaches for NO modulation 190
NO donors by grafting of NO-releasing structures 190
NOS modulation 191
Challenges of developing NO-based therapies 192
Concluding remarks and future prospects 192

8. Markets for NO-based Therapies 194

Introduction 194
Impact of NO-based therapies on international markets 194
Share of NO-based therapies in major therapeutic areas 194
Share of NO-based therapies in cardiovascular disorders 195
Hypercholesterolemia 195
Myocardial infarction 196
Angina pectoris 196
Heart failure 196
Coronary restenosis and stenting 196
Strategies for developing NO-based therapy markets 197
Addressing the unfulfilled needs 197
Multidisciplinary approaches 197
Collaboration between the academia and the industry 198
Education of the public 198

9. Companies 200

Introduction 200
Profiles of companies with focus on NO 202
Major pharmaceutical companies with involvement in NO 217
Smaller biotech and pharmaceutical companies involved in NO 223
Biopharmaceutical companies involved in antioxidant research 232
Companies supplying NO equipment for healthcare 236
Academic institutes with commercial collaboration in NO research 240
Companies supplying NO products for research 241
Collaborations 245

10. References 246

Tables

Table 1-1: Historical landmarks in the discovery and applications of nitric oxide 14
Table 3-1: Important functions of NO in the human body 35
Table 4-1: Diseases involving nitric oxide 56
Table 4-2: Role of nitric oxide in pathogenesis of autoimmune disorders 58
Table 4-3: Role of nitric oxide in infections 60
Table 5-1: Neuroprotective antioxidants 110
Table 5-2: NO-related drugs 113
Table 5-3: Methods of delivery of nitric oxide 117
Table 5-4: Comparison of classical nitrates, grafted NO donors, and NO mimetics 130
Table 5-5: Classification of NOS inhibitors 135
Table 5-6: Potential clinical applications of gene transfer for NOS overexpression 143
Table 6-1: Cardiovascular disorders for which NO-based therapies are used 155
Table 6-2: Selected neurological applications of NO-based therapies 165
Table 6-3: NO-related therapies for pain 173
Table 7-1: SWOT of technology - NO donors by grafting of NO-releasing structures 191
Table 7-2: SWOT of products - NO donors by grafting of NO-releasing structures 191
Table 7-3: SWOT of NOS gene manipulation 191
Table 7-4: SWOT of analgesic development by NOS isoform targeting 192
Table 8-1: Share of NO-based therapies in major therapeutic areas 2011-2021 195
Table 8-2: Share of NO-based therapies in cardiovascular diseases 2011-2021 195
Table 9-1: Classification of companies involved in NO and antioxidant therapies 201
Table 9-2: NicOx products in development 206
Table 9-3: Product pipeline of Nitrox LLC 211
Table 9-4: NO-related products of Sigma Aldrich 243
Table 9-5: Collaborations of companies relevant to nitric oxide 245

Figures

Figure 1-1: Nitrogen cycle in the human body 16
Figure 1-2: Biosynthesis of nitric oxide (NO) 17
Figure 1-3: NO synthase pathway 18
Figure 2-1: Reactivity of nitric oxide with heme proteins in oxygen or peroxide reaction cycles 24
Figure 2-2: NO-cGMP pathway leading to vasorelaxation 25
Figure 2-3: The biological pathways toward protein nitration 27
Figure 2-4: NF-kΒ activation and iNOS induction 28
Figure 2-5: Overview of mitochondrial NO-cytochrome c oxidase signaling pathway 30
Figure 3-1: Role of NO in adaptation to high altitude 34
Figure 3-2: NOS in the cardiac myocyte 40
Figure 3-3: Interactions of the Mb compounds with O2 and NO 44
Figure 4-1: Molecular mechanisms of peroxynitrite-mediated cell death 55
Figure 4-2: NO neurotoxicity and neuroprotection in relation to Alzheimer's disease 68
Figure 4-3: Some steps in the ischemic cascade and site of action of neuroprotectives 73
Figure 4-4: Dual role of nitric oxide (NO) in cerebral ischemia 74
Figure 4-5: Blood cell-endothelial cell interactions induced by hypercholesterolemia 83
Figure 4-6: Effects of NO on the pathophysiology of myocardial ischemia-reperfusion 88
Figure 4-7: Nitric oxide: tumor enhancement or inhibition 94
Figure 4-8: Role of nitric oxide in angiogenesis 97
Figure 5-1: Nitrogen oxide mimetics - synergy by chemical modification 130
Figure 5-2: Factors that enhance availability of NO 132
Figure 5-3: Mechanism of resistance to NO-based therapeutics 148
Figure 6-1: Vicious circle of vascular occlusion following angioplasty and stenting 159
Figure 6-2: PDE5 inhibition and the response to sexual stimulation 184
Figure 8-1: Unfulfilled needs in NO therapeutics 197