一氧化氮：治療・市場・企業

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 2008 and is projected to 2013 and 2018 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 40 companies involved in this area of which 11 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 2008, there are over 92,000 publications relevant to NO. Selected 500 references are included in the bibliography. The text is supplemented with 25 tables and 22 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.

Table of Contents

0. Executive Summary 13

1. Introduction 15

• Free radicals 15
• Nitric oxide 15
• Historical aspects 15
• Role of NO in biology and medicine 16
• Nitric oxide synthase 17
• Structure and function NOS 17
• Inducible nitric oxide synthase 19
• iNOS gene 19
• Regulation of iNOS 19
• Regulation of endothelial nitric oxide synthase 19
• Interaction between eNOS and other proteins 20
• Tetrahydrobiopterin 21
• NOS-independent NO generation and circulation 21
• Entero-salivary circulation of nitrate 21
• Methods of study of NO and NOS 22
• Bioimaging of NO 22
• Assays of NO in tissues 22
• Metabolomics approach to study of NO metabolism 23

2. Nitric Oxide Pathways 25

• Introduction 25
• Mechanisms action of NO 26
• NO-cGMP pathway 26
• Soluble guanylyl cyclase as the NO receptor 27
• Oxidative stress pathways 27
• NO and oxidative stress 27
• Oxidative stress and the NO-cyclic GMP signal transduction pathway 28
• NO and platelets 30
• Mitochondrial NO-cytochrome c oxidase signaling pathway 30
• Nitric oxide and cytochrome c oxidase 31
• Dual role of NO as a free radical and a scavenger 32
• NO and carbon monoxide 32

3. Role of NO in Physiology 35

• Homeostasis of NO 35
• 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 37
• Cellular inactivation NO by iNOS aggresome formation 37
• NO and mitochondria 37
• Mitochondrial permeability and reperfusion injury 38
• Endocrine role of NO 38
• Role of NO in the cardiovascular system 39
• NO and atrial natriuretic peptide 39
• NOS in the cardiac myocyte 39
• NO and the autonomic control of the heart rate 41
• 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 45
• 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 50
• Role of NO in temperature regulation 50
• Role of NO in gastrointestinal system 50
• Role of NO in kidney function 51
• Role of NO in liver 51
• Role of NO in the skin 51

4. Role of NO in Diseases 53

• Introduction 53
• Cytotoxicity of reactive nitrogen species 53
• Peroxynitrite, mitochondria and cell death 53
• Diseases involving oxidative stress and nitric oxide 55
• Stress-related disorders 56
• Role of NO in allergic disorders 56
• Inflammatory diseases 56
• Autoimmune disorders 57
• Role of NO in rheumatoid arthritis 58
• Role of NO in infections 58
• NO-mediated cytoprotection in bacteria 59
• Trypanosomiasis 60
• Malaria and iNOS polymorphism 60
• Susceptibility of Mycobacterium leprae to NO 60
• Role of NO in the treatment of tuberculosis 61
• Septic shock 61
• Viral infections 62
• Role of NO in anaphylactic shock 62
• Role of NO in neurological disorders 63
• Neurodegenerative diseases 63
• NO-induced mitochondrial dysfunction in neurodegeneration 63
• White matter disorders 63
• Amyotrophic lateral sclerosis 64
• Alzheimer' s disease 64
• Role of NO in pathophysiology of Alzheimer' s disease 65
• Role of ApoE genotype 67
• Parkinson' s disease 67
• Traumatic brain injury 69
• Epilepsy 69
• Stroke 70
• Pathophysiology of cerebral ischemia 70
• Role of NO in cerebral ischemia 71
• eNOS gene polymorphisms as predictor of cerebral aneurysm rupture 72
• Role of NO in assessment of cerebral and retinal blood flow 72
• Role of NO in neuroprotection 73
• Stroke and heart disease 73
• Role of NO in peripheral neuropathy 73
• iNOS induction in experimental allergic neuritis 73
• Role of NO in sciatica 73
• Role of NO in the pathogenesis of muscular dystrophy 74
• Role of NO in psychiatric disorders 74
• NO-dysregulation in schizophrenia 74
• Role of NO in pathomechanism of cardiovascular disorders 75
• Oxidative stress as a cause of cardiovascular disease 75
• Role of NO in pathomechanism of cardiovascular diseases 75
• Role of iNOS in cardiovascular disease 76
• Role of eNOS in cardiovascular disease 76
• Role nNOS in cardiac arrhythmia and sudden death 77
• NO and atherosclerosis 77
• Role of NO in cardiopulmonary disorders 78
• Role of NO in disturbances of vasodilation 79
• Role of NO in hypercholesterolemia 79
• Pulmonary hypertension 80
• NO and systemic hypertension. 81
• Coronary artery disease 82
• Role of NO in the pathophysiology of angina pectoris 82
• Congestive heart failure 82
• Calcium overload as a cause of heart failure 83
• NO/redox disequilibrium in the failing heart 83
• Myocardial ischemia/reperfusion injury 83
• Role of NO in sickle cell disease 85
• Role of NO in respiratory disorders 85
• Role of NO in the pathophysiology of asthma 85
• iNOS gene polymorphisms in asthma 86
• Role of S-nitrosoglutathione in bronchodilation in asthma 87
• Monitoring of exhaled NO 87
• Nasal NO as a biomarker of response to rhinosinusitis therapy 88
• Elevated urinary NO as a biomarker of improved survival in ARDS 89
• Role of NO in renal disorders 89
• Role of NOS in diabetic nephropathy 89
• Role of NO in cancer 89
• Inflammation, NO and colon cancer 90
• Tumor hypoxia and NO 91
• NO and p53 mutations 91
• NO and matrix metalloproteinase 92
• Role of NO in angiogenesis in cancer 92
• Role of NO in diseases of the eye 93
• Glaucoma 93
• Role of NO in metabolic disorders 94
• Obesity 94
• Diabetes mellitus 94
• Role of NO in gastrointestinal disorders 94
• Role of L-arginine in intestinal adaptation 95
• Role of NO in irritable bowel syndrome 95
• Role of NO in inflammatory bowel diseases 95
• Role of NO in celiac disease 95
• Role of NO in diabetic gastroparesis 96
• NO and diseases of the liver 96
• Cirrhosis of liver 96
• Hepatic encephalopathy 96
• Role of NO in skin disorders 97
• Role of NO and oxidative stress in the aging skin 97
• Role of NO in wound healing 97
• Role of NO in pain 98
• NO and pain of spinal cord origin 98
• NO interaction with other receptors in pain 98
• nNOS and pain 98
• Role of NO in various types of pain 99
• Neuropathic pain 99
• Role of NO in diabetic neuropathy 99
• NO in oral and facial pain 99
• Role of NO in migraine 100
• Role of NO in osteoarthritis 100
• NO and Fibromyalgia syndrome 101
• Role of spinal NO in analgesic action 101
• Role of NO in nicotine addiction 102
• Role of NO in carbon monoxide poisoning 102
• Role of NO in chemically-induced toxicity 102
• Peroxynitrite and drug-dependent toxicity. 102
• Paraquat neurotoxicity 103
• Role of NO in radiation damage 103

5. Pharmacology of Nitric Oxide 105

• Introduction 105
• Cytoxic vs cytoprotective role of NO 105
• Antioxidants 105
• Ebselen 106
• Nicaraven 106
• Nitroxides 107
• Antioxidants in relation to NO 107
• Limitation of antioxidant therapy in congestive heart failure 108
• NO-related drugs 108
• Drugs that activate endothelial NO production 109
• Dehydroepiandrosterone 109
• Drugs that scavenge free radicals/NO 110
• Peroxynitrite scavengers 110
• Ruthenium (III) polyaminocarboxylates 110
• Nitrones 110
• Drugs that inhibit NO 111
• Ginko biloba 111
• Epigallocatechin 111
• NO Therapeutics 111
• Nitric oxide as an antioxidant 111
• Nitric oxide donors 112
• Nitroglycerine/glycerine trinitrate 113
• Isosorbide dinitrate 113
• Sodium nitrite 113
• Organic nitrites 114
• NO-releasing NSAIDs 114
• COX-inhibiting NO-donors 115
• Grafting of NO-releasing structures on to existing drugs 117
• Mesoionic Oxatriazoles 118
• Adding NO-donating structures to extend life cycle of existing drugs 119
• Cysteine-containing NO donors 119
• Ferrous nitrosyl complexes 119
• Syndnonimines 119
• S-Nitrosothiols 120
• Diazeniumdiolates 121
• COX-2 inhibitors 121
• NO hydrogels 122
• Novel NO donors 122
• NO mimetics 122
• Comparison of classical nitrates, grafted NO donors, and NO mimetics 123
• NO donors and soluble guanylate cyclase activation 123
• NO donors for increasing the efficacy of chemotherapy 124
• Modulators of cyclic guanosine-3' ,5' -monophosphate-dependent protein kinases 124
• L-Arginine 124
• Delivery of nitric oxide 125
• Targeted delivery of NO donors 125
• Nitric oxide delivery by encapsulated cells 125
• NO-lipid combination 126
• NO-releasing coating to prevent infection of implanted devices 126
• Factors that enhance availability of NO 126
• NOS-modulating drugs 127
• Drugs that activate eNOS 127
• Statins 127
• Angiotensin converting enzyme inhibitors 128
• 17 Beta-estradiol 128
• C-2431 129
• NOS inhibitors 129
• Rationale of NOS inhibitors 129
• Design of NOS inhibitors 130
• Selective iNOS inhibitors 131
• Non-amino acid-based inhibitors 132
• Aminoguanidine 132
• Heme ligands 133
• Pterin antagonists 133
• Fused-ring bio-isoteric models of arginine as NOS inhibitors 133
• nNOS inhibitors 133
• Lubeluzole 135
• Neurotrophic factors 135
• Therapies based on action of NOS as a paraquat diaphorase 135
• Concluding remarks about NOS inhibiting drugs 136
• NO and stem cell-based therapy 136
• Nitric oxide and gene therapy 137
• NOS gene transfer 137
• Inhibition of NOS by antisense technology 138
• Drugs that modulate NO action on platelets 139
• Action of NO and NO donors on platelets 139
• NOS inhibitors and NO scavengers 139
• Phosphodiesterase inhibitors 139
• Activators of soluble guanylate cyclase 140
• YC-1 140
• A-350619 140
• Bay 41-2272 140
• Secondary role of NO in the action of drugs 141
• Selective serotonin reuptake inhibitors 141
• P2Y receptors and NO 141
• Calcium channel blockers and NO 141
• Nitric oxide-based transdermal drug delivery 141
• NO and nutraceuticals 142
• L-arginine as a nutraceutical 142
• Oleuropein 143
• Role of NO in beneficial effects of chocolate 143

6. Therapeutic Applications 145

• Introduction 145
• Role of NO in the management of pulmonary disorders 145
• Manufacture of NO gas for inhalation 145
• NO inhalation for acute respiratory distress syndrome 145
• NO inhalation for premature children with pulmonary dysplasia 146
• NO inhalation for premature children with respiratory failure 146
• Pulmonary hypertension 147
• NO-based treatment of pulmonary hypertension 147
• Inhaled nebulized nitrite for neonatal pulmonary hypertension 148
• Gene therapy for pulmonary hypertension 148
• Asthma 149
• iNOS inhibitors for asthma 149
• NO for bronchodilation in asthma 149
• Role of NO in acute lung injury after smoke inhalation 150
• Cardiovascular disorders 150
• Role of NO in cardioprotection 150
• Role of NO in the management of angina pectoris 151
• Role of NO in therapy of coronary heart disease 151
• NO-releasing aspirin in patients undergoing CABG 152
• Management of coronary restenosis 152
• Modified NO donors 153
• NO-generating stent for coronary restenosis 153
• eNOS gene therapy for restenosis 154
• Congestive heart failure 155
• NO-based therapies for congestive heart failure 155
• eNOS gene therapy for congestive heart failure 155
• Gene transfer of nNOS in congestive heart failure 156
• NO-based therapy for management of cardiogenic shock 156
• NO-based therapy for cardiac arrhythmias 156
• Prophylaxis of cardiovascular disorders 157
• Prevention of atherosclerosis with aging 157
• Peripheral vascular disorders 157
• Peripheral atherosclerotic arterial disease 157
• Peripheral ischemic disease 158
• An eNOS mutant as therapeutic for peripheral vascular ischemia 158
• Sodium nitrite therapy for peripheral vascular ischemia 159
• Raynaud' s phenomenon 159
• Neurological disorders 159
• Cerebrovascular ischemic disorders 160
• Attenuation of NO for neuroprotection in cerebral ischemia 160
• Use of NO donors in cerebral ischemia 160
• Use of NO donors in cerebral reperfusion injury 161
• Cerebral vasospasm and NO 161
• NOS gene therapy for cerebral vasospasm 162
• Degenerative CNS disorders 163
• Statins for Alzheimer' s disease 163
• NO mimetics for Alzheimer' s disease 163
• iNOS inhibitors for treatment of Alzheimer' s disease 163
• NO-NSAIDs for Alzheimer' s disease 164
• Ginko biloba for Alzheimer' s disease 164
• Personalization of NO-based therapy for Alzheimer' s disease 164
• Role of NO in the treatment of traumatic brain injury 165
• Neuroinflammatory disorders 165
• Muscular dystrophy 165
• Vestibulotoxicity 166
• NO for opening the blood-brain barrier 166
• Cochlear disorders 167
• Cochlear ischemia 167
• Role of NO in sensoryneural hearing loss 167
• Pain 167
• NO-based therapies for pain 167
• Treatment of diabetic neuropathy with isosorbide dinitrate spray 168
• NO-based therapies for migraine 168
• NO-based therapy for fibromyalgia syndrome 168
• NO-based therapies for inflammatory disorders 169
• NO-based therapies for gastrointestinal disorders 169
• Protection of gastrointestinal injury from NSAIDs 169
• Role of NO in the treatment of inflammatory bowel disease 169
• Topical nitroglycerin for chronic anal fissure 170
• Cancer 170
• Mechanism of action of NO in cancer 170
• Antineoplastic effect of iNOS-expressing cells 170
• Role of NO in drug resistance of cancer 171
• Role of NO in treatment of brain tumors 171
• NO-induced apoptosis 172
• Role of NO in antiangiogenesis therapies in cancer 172
• NO donors for the treatment of cancer 172
• NO-releasing NSAIDs and colon cancer chemoprevention 173
• Rationale of combining NO aspirin with cancer vaccines 173
• NO-based cancer gene therapy 173
• NO-based therapies for skin disorders 174
• NO-based therapies for skin infections 174
• Role of NO in the treatment of psoriasis 175
• NO-based therapy for sickle cell anemia 175
• Inhaled NO for acute respiratory distress syndrome in sickle cell disease 176
• NO inhalation for pulmonary hypertension in sickle cell anemia 176
• Role of NO in disorders associated with pregnancy 176
• Use of NO donors in management of labor 176
• Eclampsia 177
• Erectile dysfunction 177
• Selective inhibitors of phosphodiesterase 5 177
• Erectile dysfunction in diabetes 178
• NO-donating substances for treatment of ED 178
• NOS gene transfer for ED 179
• Organ transplant rejection 179
• Role of NO in the treatment of renal disorders 180
• Role of NO in the treatment of hepatic disorders 181
• Portal hypertension 181
• NO inhalation for restoration of liver function following transplantation 181
• Role of NO in blood transfusion 181
• Role of NO in the treatment of osteoporosis 182

7. Evaluation of NO-Based Drugs 183

• Current status 183
• Antioxidant vs. NO-based approaches 183
• SWOT analysis of selected approaches for NO modulation 183
• NO donors by grafting of NO-releasing structures 183
• NOS modulation 184
• Challenges of developing NO-based therapies 185
• Concluding remarks and future prospects 185

8. Markets for NO-based Therapies 187

• Introduction 187
• Impact of NO-based therapies on international markets 187
• Share of NO-based therapies in major therapeutic areas 187
• Share of NO-based therapies in cardiovascular disorders 188
• Hypercholesterolemia 188
• Myocardial infarction 189
• Angina pectoris 189
• Heart failure 189
• Coronary restenosis and stenting 189
• Strategies for developing NO-based therapy markets 190
• Addressing the unfulfilled needs 190
• Multidisciplinary approaches 190
• Collaboration between the academia and the industry 191
• Education of the public 191

9. Companies 193

• Introduction 193
• Profiles of companies with focus on NO 195
• Major pharmaceutical companies with involvement in NO 209
• Smaller biotech and pharmaceutical companies involved in NO 215
• Biopharmaceutical companies involved in antioxidant research 226
• Companies supplying NO equipment for healthcare 230
• Academic institutes with commercial collaboration in NO research 234
• Companies supplying NO products for research 235
• Collaborations 239

10. References 241

Tables

• Table 1 1: Historical landmarks in the discovery and applications of nitric oxide 16
• Table 3 1: Important functions of NO in the human body 36
• Table 4 1: Diseases involving nitric oxide 55
• Table 4 2: Role of nitric oxide in pathogenesis of autoimmune disorders 57
• Table 4 3: Role of nitric oxide in infections 59
• Table 5 1: Neuroprotective antioxidants 105
• Table 5 2: NO-related drugs 108
• Table 5 3: Comparison of classical nitrates, grafted NO donors, and NO mimetics 123
• Table 5 4: Classification of NOS inhibitors 129
• Table 5 5: Potential clinical applications of gene transfer for NOS overexpression 138
• Table 6 1: Cardiovascular disorders for which NO-based therapies are used 150
• Table 6 2: Selected neurological applications of NO-based therapies 159
• Table 6 3: NO-related therapies for pain 167
• Table 7 1: SWOT of technology - NO donors by grafting of NO-releasing structures 184
• Table 7 2: SWOT of products - NO donors by grafting of NO-releasing structures 184
• Table 7 3: SWOT of NOS gene manipulation 184
• Table 7 4: SWOT of analgesic development by NOS isoform targeting 185
• Table 8 1: Share of NO-based therapies in major therapeutic areas 2008-2018 188
• Table 8 2: Share of NO-based therapies in cardiovascular diseases 2008-2018 188
• Table 9 1: Classification of companies involved in NO and antioxidant therapies 194
• Table 9 2: NicOx products in development 199
• Table 9 3: Product pipeline of Nitrox LLC 204
• Table 9 4: NO-related products of Sigma Aldrich 237
• Table 9 5: Collaborations of companies relevant to nitric oxide 239

Figures

• Figure 1 1: Biosynthesis of nitric oxide (NO) 18
• Figure 1 2: NO synthase pathway 19
• Figure 2 1: Reactivity of nitric oxide with heme proteins in oxygen or peroxide reaction cycles 25
• Figure 2 2: NO-cGMP pathway leading to vasorelaxation 26
• Figure 2 3: The biological pathways toward protein nitration 28
• Figure 2 4: NF-kβ activation and iNOS induction 29
• Figure 2 5: Overview of mitochondrial NO-cytochrome c oxidase signaling pathway 31
• Figure 3 1: NOS in the cardiac myocyte 40
• Figure 3 2: Interactions of the Mb compounds with O2 and NO 44
• Figure 4 1: Molecular mechanisms of peroxynitrite-mediated cell death 54
• Figure 4 2: NO neurotoxicity and neuroprotection in relation to Alzheimer' s disease 66
• Figure 4 3: Some steps in the ischemic cascade and site of action of neuroprotectives 70
• Figure 4 4: Dual role of nitric oxide (NO) in cerebral ischemia 71
• Figure 4 5: Blood cell-endothelial cell interactions induced by hypercholesterolemia 80
• Figure 4 6: Effects of NO on the pathophysiology of myocardial ischemia-reperfusion 84
• Figure 4 7: Nitric oxide: tumor enhancement or inhibition 90
• Figure 4 8: Role of nitric oxide in angiogenesis 93
• Figure 5 1: Nitrogen oxide mimetics - synergy by chemical modification 122
• Figure 5 2: Factors that enhance availability of NO 127
• Figure 6 1: Vicious circle of vascular occlusion following angioplasty and stenting 153
• Figure 6 2: PDE5 inhibition and the response to sexual stimulation 178
• Figure 8 1: Unfulfilled needs in NO therapeutics 190