Nitric Oxide - Therapeutics, Markets and Companies

• Publication date: February 2012

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 ...

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.

Pathology Industry

TABLE OF CONTENTS

0. Executive Summary 13
1. Introduction 15
Nitric oxide 15
Historical aspects 15
Free radicals 16
Nitrogen cycle and NO 16
Role of NO in biology and medicine 17
Nitric oxide synthase 18
Structure and function NOS 18
Inducible nitric oxide synthase 19
iNOS gene 19
Regulation of iNOS 19
Regulation of endothelial nitric oxide synthase 20
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
Nitrate-nitrite-NO pathway 27
Soluble guanylyl cyclase as the NO receptor 27
Oxidative stress pathways 27
NO and oxidative stress 28
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
NO signaling and apoptosis 33
3. Role of NO in Physiology 35
Homeostasis of NO 35
Role of NO in adaptation to high altitude 35
NO as a biomarker 36
Functions of NO in various systems of the body 36
NO and proteins 37
A proteomic method for identification of cysteine S-nitrosylation sites 37
Protein S-nitrosylation and intracellular transport processes 37
Cellular inactivation NO by iNOS aggresome formation 37
NO and mitochondria 38
Mitochondrial permeability and reperfusion injury 39
Endocrine role of NO 39
Role of NO in the cardiovascular system 39
NO and atrial natriuretic peptide 40
NOS in the cardiac myocyte 40
NO and the autonomic control of the heart rate 41
NO and vasodilatation 42
Role of NO in the plasma compartment 43
Measurement of NO as a biomarker of cardiovascular function 43
Hemoglobin, oxygen and nitric oxide 44
Myoglobin and NO 45
NO and pulmonary circulation 45
Role of NO in the regulation of hypoxic pulmonary vasoconstriction 46
Role of NO in the nervous system 46
Neurovascular coupling of COX-2 and nNOS 47
Neuroglobin 47
Acute actions of NO in the CNS pathways 48
Role of NO in memory and learning 48
Role of NO in synaptic plasticity 48
Role of NO in the peripheral nervous system 49
Role of NO in the cochlea 49
NO and neuroendocrine function 49
NO and pregnancy 49
Role of NO in penile erection 50
Role of NO in immune regulation 50
Role of NO in temperature regulation 51
Role of NO in gastrointestinal system 51
Role of NO in kidney function 51
Role of NO in liver 52
Role of NO in the skin 52
4. Role of NO in Diseases 55
Introduction 55
Cytotoxicity of reactive nitrogen species 55
Peroxynitrite, mitochondria and cell death 55
Diseases involving oxidative stress and nitric oxide 57
Stress-related disorders 58
Role of NO in allergic disorders 58
Inflammatory diseases 58
Autoimmune disorders 59
Role of NO in rheumatoid arthritis 60
Role of NO in infections 60
NO-mediated cytoprotection in bacteria 61
Trypanosomiasis 62
Malaria and iNOS polymorphism 62
Susceptibility of Mycobacterium leprae to NO 62
Role of NO in the treatment of tuberculosis 63
Septic shock 63
Viral infections 64
Role of NO in anaphylactic shock 64
Role of NO in anemia and hypoxia 65
Role of NO in neurological disorders 65
Neurodegenerative diseases 65
NO-induced mitochondrial dysfunction in neurodegeneration 66
White matter disorders 66
Amyotrophic lateral sclerosis 67
Alzheimer's disease 67
Role of NO in pathophysiology of Alzheimer's disease 67
Role of ApoE genotype 70
Parkinson's disease 70
Traumatic brain injury 72
Epilepsy 73
Stroke 73
Pathophysiology of cerebral ischemia 73
Role of NO in cerebral ischemia 74
eNOS gene polymorphisms as predictor of cerebral aneurysm rupture 76
Role of NO in assessment of cerebral and retinal blood flow 76
Role of NO in neuroprotection 76
Stroke and heart disease 76
Role of NO in peripheral neuropathy 77
iNOS induction in experimental allergic neuritis 77
Role of NO in sciatica 77
Role of NO in the pathogenesis of muscular dystrophy 77
Role of NO in psychiatric disorders 78
NO-dysregulation in schizophrenia 78
Role of NO in pathomechanism of cardiovascular disorders 79
Oxidative stress as a cause of cardiovascular disease 79
Role of NO in pathomechanism of cardiovascular diseases 79
Role of iNOS in cardiovascular disease 80
Role of eNOS in cardiovascular disease 80
Role nNOS in cardiac arrhythmia and sudden death 81
NO and atherosclerosis 81
Role of NO in cardiopulmonary disorders 82
Role of NO in disturbances of vasodilation 83
Caveolin-1 deficiency impairs NO synthesis and vasodilation 83
Role of NO in hypercholesterolemia 83
Pulmonary hypertension 84
NO and systemic hypertension. 85
Coronary artery disease 86
Role of NO in the pathophysiology of angina pectoris 86
Congestive heart failure 87
Calcium overload as a cause of heart failure 87
NO/redox disequilibrium in the failing heart 87
Myocardial ischemia/reperfusion injury 87
NO pathway in cardiac hypertrophy 89
Role of NO in sickle cell disease 90
Role of NO in respiratory disorders 90
Role of NO in the pathophysiology of asthma 90
iNOS gene polymorphisms in asthma 91
Role of S-nitrosoglutathione in bronchodilation in asthma 92
Monitoring of exhaled NO 92
Nasal NO as a biomarker of response to rhinosinusitis therapy 93
Elevated urinary NO as a biomarker of improved survival in ARDS 93
Role of NO in renal disorders 94
Role of NOS in diabetic nephropathy 94
Role of NO in cancer 94
Inflammation, NO and colon cancer 95
Tumor hypoxia and NO 96
NO and p53 mutations 96
NO and matrix metalloproteinase 97
Role of NO in angiogenesis in cancer 97
Role of NO in diseases of the eye 98
Glaucoma 98
Role of NO in metabolic disorders 99
Metabolic syndrome 99
Obesity 99
Diabetes mellitus 99
Role of NO in gastrointestinal disorders 100
Role of L-arginine in intestinal adaptation 100
Role of NO in irritable bowel syndrome 100
Role of NO in inflammatory bowel diseases 100
Role of NO in celiac disease 101
Role of NO in diabetic gastroparesis 101
NO and diseases of the liver 101
Cirrhosis of liver 101
Hepatic encephalopathy 102
Role of NO in skin disorders 102
Role of NO and oxidative stress in the aging skin 102
Role of NO in wound healing 103
Role of NO in pain 103
NO and pain of spinal cord origin 103
NO interaction with other receptors in pain 104
nNOS and pain 104
Role of NO in various types of pain 104
Neuropathic pain 104
Role of NO in diabetic neuropathy 104
NO in oral and facial pain 105
Role of NO in migraine 105
Role of NO in osteoarthritis 106
NO and Fibromyalgia syndrome 106
Role of spinal NO in analgesic action 107
Role of NO in nicotine addiction 107
Role of NO in carbon monoxide poisoning 108
Role of NO in chemically-induced toxicity 108
Peroxynitrite and drug-dependent toxicity. 108
Paraquat neurotoxicity 108
Role of NO in radiation damage 109
5. Pharmacology of Nitric Oxide 111
Introduction 111
Cytoxic vs cytoprotective role of NO 111
Antioxidants 111
Ebselen 112
Nicaraven 112
Nitroxides 113
Antioxidants in relation to NO 113
Nitric oxide as an antioxidant 114
NO-related drugs 114
Drugs that activate eNOS production 116
Aspirin 116
Dehydroepiandrosterone 116
Drugs that scavenge free radicals/NO 116
Peroxynitrite scavengers 116
Ruthenium (III) polyaminocarboxylates 117
Nitrones 117
Drugs that inhibit NO 117
Ginko biloba 117
Epigallocatechin 118
Delivery of nitric oxide 118
Targeted delivery of NO donors 119
Nitric oxide delivery by encapsulated cells 119
NO-lipid combination 119
NO-releasing coating to prevent infection of implanted devices 120
Nanoparticles for controlled/sustained release of NO 120
Hydrogel/glass nanoparticles 120
Delivery of nanoparticles to vascular endothelium for release of NO 120
Nitric oxide donors 121
Nitroglycerine/glycerine trinitrate 121
Isosorbide dinitrate 122
Sodium nitrite 122
Organic nitrites 122
NO-releasing NSAIDs 123
COX-inhibiting NO-donors 124
Grafting of NO-releasing structures on to existing drugs 126
Mesoionic Oxatriazoles 127
Adding NO-donating structures to extend life cycle of existing drugs 127
Cysteine-containing NO donors 127
Ferrous nitrosyl complexes 128
Syndnonimines 128
S-Nitrosothiols 128
Diazeniumdiolates 129
COX-2 inhibitors 130
NO hydrogels 130
Novel NO donors 130
NO mimetics 131
Comparison of classical nitrates, grafted NO donors, and NO mimetics 131
NO donors and soluble guanylate cyclase activation 132
NO donors for increasing the efficacy of chemotherapy 132
Factors that enhance availability of NO 132
Modulators of cyclic guanosine-3?,5?-monophosphate-dependent protein kinases 133
NOS-modulating drugs 134
Drugs that activate eNOS 134
Statins 134
Angiotensin converting enzyme inhibitors 135
17 Beta-estradiol 135
C-2431 135
NOS inhibitors 135
Rationale of NOS inhibitors 135
L-Arginine 137
Design of NOS inhibitors 137
Selective iNOS inhibitors 138
Non-amino acid-based inhibitors 139
Aminoguanidine 139
Heme ligands 140
Pterin antagonists 140
Fused-ring bio-isoteric models of arginine as NOS inhibitors 140
nNOS inhibitors 140
Lubeluzole 142
Neurotrophic factors 142
Therapies based on action of NOS as a paraquat diaphorase 142
Concluding remarks about NOS inhibiting drugs 143
NO and stem cell-based therapy 143
Nitric oxide and gene therapy 144
NOS gene transfer 144
Inhibition of NOS by antisense technology 145
Drugs that modulate NO action on platelets 146
Action of NO and NO donors on platelets 146
NOS inhibitors and NO scavengers 146
Phosphodiesterase inhibitors 146
Activators of soluble guanylate cyclase 147
YC-1 147
A-350619 147
Cinaciguat 147
Secondary role of NO in the action of drugs 147
Selective serotonin reuptake inhibitors 148
P2Y receptors and NO 148
Calcium channel blockers and NO 148
Nitric oxide-based transdermal drug delivery 148
Mechanism of resistance of NO-based drugs 149
NO and nutraceuticals 149
L-arginine as a nutraceutical 149
Oleuropein 150
Role of NO in beneficial effects of chocolate 150
6. Therapeutic Applications 151
Introduction 151
Role of NO in the management of pulmonary disorders 151
Manufacture of NO gas for inhalation 151
NO inhalation for acute respiratory distress syndrome 151
NO inhalation for premature children with pulmonary dysplasia 152
NO inhalation for premature children with respiratory failure 152
Pulmonary hypertension 153
NO-based treatment of pulmonary hypertension 153
Inhaled nebulized nitrite for neonatal pulmonary hypertension 154
Gene therapy for pulmonary hypertension 154
Asthma 155
iNOS inhibitors for asthma 155
NO for bronchodilation in asthma 155
Role of NO in acute lung injury after smoke inhalation 155
Cardiovascular disorders 156
Role of NO in cardioprotection 156
Role of NO in the management of angina pectoris 157
Role of NO in therapy of coronary heart disease 158
NO-releasing aspirin in patients undergoing CABG 158
Management of coronary restenosis 159
Modified NO donors 159
NO-generating stent for coronary restenosis 159
eNOS gene therapy for restenosis 160
NO-based management of cardiac hypertrophy 161
Congestive heart failure 161
Limitation of antioxidant therapy in congestive heart failure 161
NO-based therapies for congestive heart failure 162
eNOS gene therapy for congestive heart failure 162
Gene transfer of nNOS in congestive heart failure 162
NO-based therapy for management of cardiogenic shock 163
NO-based therapy for cardiac arrhythmias 163
Prophylaxis of cardiovascular disorders 163
Prevention of atherosclerosis with aging 164
Peripheral vascular disorders 164
Peripheral atherosclerotic arterial disease 164
Peripheral ischemic disease 164
An eNOS mutant as therapeutic for peripheral vascular ischemia 165
Sodium nitrite therapy for peripheral vascular ischemia 165
Raynaud's phenomenon 166
Neurological disorders 166
Cerebrovascular ischemic disorders 166
Attenuation of NO for neuroprotection in cerebral ischemia 167
Use of NO donors in cerebral ischemia 167
Use of NO donors in cerebral reperfusion injury 168
Cerebral vasospasm and NO 168
NOS gene therapy for cerebral vasospasm 169
Degenerative CNS disorders 169
Statins for Alzheimer's disease 170
NO mimetics for Alzheimer's disease 170
iNOS inhibitors for treatment of Alzheimer’s disease 170
NO-NSAIDs for Alzheimer's disease 171
Ginko biloba for Alzheimer's disease 171
Personalization of NO-based therapy for Alzheimer's disease 171
Role of NO in the treatment of traumatic brain injury 171
Neuroinflammatory disorders 172
Muscular dystrophy 172
Vestibulotoxicity 173
NO for opening the blood-brain barrier 173
Cochlear disorders 173
Cochlear ischemia 173
Role of NO in sensoryneural hearing loss 174
Pain 174
NO-based therapies for pain 174
Treatment of diabetic neuropathy with isosorbide dinitrate spray 174
NO-based therapies for migraine 175
NO-based therapy for fibromyalgia syndrome 175
NO-based therapies for inflammatory disorders 175
NO-based therapies for gastrointestinal disorders 176
Protection of gastrointestinal injury from NSAIDs 176
Role of NO in the treatment of inflammatory bowel disease 176
Topical nitroglycerin for chronic anal fissure 176
Cancer 177
Mechanism of action of NO in cancer 177
Antineoplastic effect of iNOS-expressing cells 177
Role of NO in drug resistance of cancer 177
Role of NO in treatment of brain tumors 178
NO-induced apoptosis 178
Role of NO in antiangiogenesis therapies in cancer 179
NO donors for the treatment of cancer 179
NO-releasing NSAIDs and colon cancer chemoprevention 179
Rationale of combining NO aspirin with cancer vaccines 180
NO-based cancer gene therapy 180
Transdermal nitroglycerine for prostate cancer 181
NO-based therapies for skin disorders 181
NO-based therapies for skin infections 181
Role of NO in the treatment of psoriasis 182
NO-based therapy for sickle cell anemia 182
Inhaled NO for acute respiratory distress syndrome in sickle cell disease 183
NO inhalation for pulmonary hypertension in sickle cell anemia 183
Role of NO in disorders associated with pregnancy 183
Use of NO donors in management of labor 183
Eclampsia 184
Erectile dysfunction 184
Selective inhibitors of phosphodiesterase 5 184
Erectile dysfunction in diabetes 185
NO-donating substances for treatment of ED 186
NOS gene transfer for ED 186
Organ transplant rejection 186
Role of NO in the treatment of renal disorders 187
Role of NO in the treatment of hepatic disorders 188
Portal hypertension 188
NO inhalation for restoration of liver function following transplantation 188
Role of NO in blood transfusion 189
Role of NO in the treatment of osteoporosis 189
NO-based wound healing 189
7. Evaluation of NO-Based Drugs 191
Current status 191
Antioxidant vs. NO-based approaches 191
SWOT analysis of selected approaches for NO modulation 191
NO donors by grafting of NO-releasing structures 191
NOS modulation 192
Challenges of developing NO-based therapies 193
Concluding remarks and future prospects 193
8. Markets for NO-based Therapies 195
Introduction 195
Impact of NO-based therapies on international markets 195
Share of NO-based therapies in major therapeutic areas 195
Share of NO-based therapies in cardiovascular disorders 196
Hypercholesterolemia 196
Myocardial infarction 197
Angina pectoris 197
Heart failure 197
Coronary restenosis and stenting 197
Strategies for developing NO-based therapy markets 198
Addressing the unfulfilled needs 198
Multidisciplinary approaches 198
Collaboration between the academia and the industry 199
Education of the public 199
9. Companies 201
Introduction 201
Profiles of companies with focus on NO 203
Major pharmaceutical companies with involvement in NO 218
Smaller biotech and pharmaceutical companies involved in NO 224
Biopharmaceutical companies involved in antioxidant research 233
Companies supplying NO equipment for healthcare 237
Academic institutes with commercial collaboration in NO research 241
Companies supplying NO products for research 242
Collaborations 246
10. References 247

List of Tables
Table 1 1: Historical landmarks in the discovery and applications of nitric oxide 15
Table 3 1: Important functions of NO in the human body 36
Table 4 1: Diseases involving nitric oxide 57
Table 4 2: Role of nitric oxide in pathogenesis of autoimmune disorders 59
Table 4 3: Role of nitric oxide in infections 61
Table 5 1: Neuroprotective antioxidants 111
Table 5 2: NO-related drugs 114
Table 5 3: Methods of delivery of nitric oxide 118
Table 5 4: Comparison of classical nitrates, grafted NO donors, and NO mimetics 131
Table 5 5: Classification of NOS inhibitors 136
Table 5 6: Potential clinical applications of gene transfer for NOS overexpression 144
Table 6 1: Cardiovascular disorders for which NO-based therapies are used 156
Table 6 2: Selected neurological applications of NO-based therapies 166
Table 6 3: NO-related therapies for pain 174
Table 7 1: SWOT of technology ? NO donors by grafting of NO-releasing structures 192
Table 7 2: SWOT of products ? NO donors by grafting of NO-releasing structures 192
Table 7 3: SWOT of NOS gene manipulation 192
Table 7 4: SWOT of analgesic development by NOS isoform targeting 193
Table 8 1: Share of NO-based therapies in major therapeutic areas 2011-2021 196
Table 8 2: Share of NO-based therapies in cardiovascular diseases 2011-2021 196
Table 9 1: Classification of companies involved in NO and antioxidant therapies 202
Table 9 2: NicOx products in development 207
Table 9 3: Product pipeline of Nitrox LLC 212
Table 9 4: NO-related products of Sigma Aldrich 244
Table 9 5: Collaborations of companies relevant to nitric oxide 246

List of Figures
Figure 1 1: Nitrogen cycle in the human body 17
Figure 1 2: Biosynthesis of nitric oxide (NO) 18
Figure 1 3: 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-?B activation and iNOS induction 29
Figure 2 5: Overview of mitochondrial NO-cytochrome c oxidase signaling pathway 31
Figure 3 1: Role of NO in adaptation to high altitude 35
Figure 3 2: NOS in the cardiac myocyte 41
Figure 3 3: Interactions of the Mb compounds with O2 and NO 45
Figure 4 1: Molecular mechanisms of peroxynitrite-mediated cell death 56
Figure 4 2: NO neurotoxicity and neuroprotection in relation to Alzheimer's disease 69
Figure 4 3: Some steps in the ischemic cascade and site of action of neuroprotectives 74
Figure 4 4: Dual role of nitric oxide (NO) in cerebral ischemia 75
Figure 4 5: Blood cell-endothelial cell interactions induced by hypercholesterolemia 84
Figure 4 6: Effects of NO on the pathophysiology of myocardial ischemia-reperfusion 89
Figure 4 7: Nitric oxide: tumor enhancement or inhibition 95
Figure 4 8: Role of nitric oxide in angiogenesis 98
Figure 5 1: Nitrogen oxide mimetics ? synergy by chemical modification 131
Figure 5 2: Factors that enhance availability of NO 133
Figure 5 3: Mechanism of resistance to NO-based therapeutics 149
Figure 6 1: Vicious circle of vascular occlusion following angioplasty and stenting 160
Figure 6 2: PDE5 inhibition and the response to sexual stimulation 185
Figure 8 1: Unfulfilled needs in NO therapeutics 198