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Nitric Oxide - Therapeutics, Markets and Companies
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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.
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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 inhalation 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 2009 and is projected to 2014 and 2019 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 41 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 2009, 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 23 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
NO signaling and apoptosis 33
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 70
Stroke 70
Pathophysiology of cerebral ischemia 70
Role of NO in cerebral ischemia 71
eNOS gene polymorphisms as predictor of cerebral aneurysm rupture 73
Role of NO in assessment of cerebral and retinal blood flow 73
Role of NO in neuroprotection 73
Stroke and heart disease 73
Role of NO in peripheral neuropathy 74
iNOS induction in experimental allergic neuritis 74
Role of NO in sciatica 74
Role of NO in the pathogenesis of muscular dystrophy 74
Role of NO in psychiatric disorders 75
NO-dysregulation in schizophrenia 75
Role of NO in pathomechanism of cardiovascular disorders 76
Oxidative stress as a cause of cardiovascular disease 76
Role of NO in pathomechanism of cardiovascular diseases 76
Role of iNOS in cardiovascular disease 77
Role of eNOS in cardiovascular disease 77
Role nNOS in cardiac arrhythmia and sudden death 78
NO and atherosclerosis 78
Role of NO in cardiopulmonary disorders 79
Role of NO in disturbances of vasodilation 79
Role of NO in hypercholesterolemia 80
Pulmonary hypertension 81
NO and systemic hypertension. 81
Coronary artery disease 82
Role of NO in the pathophysiology of angina pectoris 83
Congestive heart failure 83
Calcium overload as a cause of heart failure 83
NO/redox disequilibrium in the failing heart 84
Myocardial ischemia/reperfusion injury 84
Role of NO in sickle cell disease 85
Role of NO in respiratory disorders 86
Role of NO in the pathophysiology of asthma 86
iNOS gene polymorphisms in asthma 87
Role of S-nitrosoglutathione in bronchodilation in asthma 87
Monitoring of exhaled NO 88
Nasal NO as a biomarker of response to rhinosinusitis therapy 89
Elevated urinary NO as a biomarker of improved survival in ARDS 89
Role of NO in renal disorders 90
Role of NOS in diabetic nephropathy 90
Role of NO in cancer 90
Inflammation, NO and colon cancer 91
Tumor hypoxia and NO 92
NO and p53 mutations 92
NO and matrix metalloproteinase 93
Role of NO in angiogenesis in cancer 93
Role of NO in diseases of the eye 94
Glaucoma 94
Role of NO in metabolic disorders 95
Obesity 95
Diabetes mellitus 95
Role of NO in gastrointestinal disorders 95
Role of L-arginine in intestinal adaptation 96
Role of NO in irritable bowel syndrome 96
Role of NO in inflammatory bowel diseases 96
Role of NO in celiac disease 96
Role of NO in diabetic gastroparesis 97
NO and diseases of the liver 97
Cirrhosis of liver 97
Hepatic encephalopathy 97
Role of NO in skin disorders 98
Role of NO and oxidative stress in the aging skin 98
Role of NO in wound healing 98
Role of NO in pain 99
NO and pain of spinal cord origin 99
NO interaction with other receptors in pain 99
nNOS and pain 99
Role of NO in various types of pain 100
Neuropathic pain 100
Role of NO in diabetic neuropathy 100
NO in oral and facial pain 100
Role of NO in migraine 101
Role of NO in osteoarthritis 101
NO and Fibromyalgia syndrome 102
Role of spinal NO in analgesic action 102
Role of NO in nicotine addiction 103
Role of NO in carbon monoxide poisoning 103
Role of NO in chemically-induced toxicity 103
Peroxynitrite and drug-dependent toxicity. 103
Paraquat neurotoxicity 104
Role of NO in radiation damage 104
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
Nitric oxide as an antioxidant 108
NO-related drugs 108
Drugs that activate endothelial NO production 110
Dehydroepiandrosterone 110
Drugs that scavenge free radicals/NO 110
Peroxynitrite scavengers 110
Ruthenium (III) polyaminocarboxylates 110
Nitrones 111
Drugs that inhibit NO 111
Ginko biloba 111
Epigallocatechin 112
Delivery of nitric oxide 112
Targeted delivery of NO donors 112
Nitric oxide delivery by encapsulated cells 113
NO-lipid combination 113
NO-releasing coating to prevent infection of implanted devices 113
Nanoparticles for controlled/sustained release of NO 114
Hydrogel/glass nanoparticles 114
Delivery of nanoparticles to vascular endothelium for release of NO 114
Nitric oxide donors 114
Nitroglycerine/glycerine trinitrate 115
Isosorbide dinitrate 115
Sodium nitrite 116
Organic nitrites 116
NO-releasing NSAIDs 116
COX-inhibiting NO-donors 118
Grafting of NO-releasing structures on to existing drugs 119
Mesoionic Oxatriazoles 121
Adding NO-donating structures to extend life cycle of existing drugs 121
Cysteine-containing NO donors 121
Ferrous nitrosyl complexes 121
Syndnonimines 122
S-Nitrosothiols 122
Diazeniumdiolates 123
COX-2 inhibitors 123
NO hydrogels 124
Novel NO donors 124
NO mimetics 124
Comparison of classical nitrates, grafted NO donors, and NO mimetics 125
NO donors and soluble guanylate cyclase activation 125
NO donors for increasing the efficacy of chemotherapy 126
Factors that enhance availability of NO 126
Modulators of cyclic guanosine-3?,5?-monophosphate-dependent protein kinases 127
NOS-modulating drugs 128
Drugs that activate eNOS 128
Statins 128
Angiotensin converting enzyme inhibitors 129
17 Beta-estradiol 129
C-2431 129
NOS inhibitors 129
Rationale of NOS inhibitors 129
L-Arginine 131
Design of NOS inhibitors 131
Selective iNOS inhibitors 132
Non-amino acid-based inhibitors 133
Aminoguanidine 133
Heme ligands 134
Pterin antagonists 134
Fused-ring bio-isoteric models of arginine as NOS inhibitors 134
nNOS inhibitors 134
Lubeluzole 136
Neurotrophic factors 136
Therapies based on action of NOS as a paraquat diaphorase 136
Concluding remarks about NOS inhibiting drugs 137
NO and stem cell-based therapy 137
Nitric oxide and gene therapy 138
NOS gene transfer 138
Inhibition of NOS by antisense technology 139
Drugs that modulate NO action on platelets 140
Action of NO and NO donors on platelets 140
NOS inhibitors and NO scavengers 140
Phosphodiesterase inhibitors 140
Activators of soluble guanylate cyclase 141
YC-1 141
A-350619 141
Cinaciguat 141
Secondary role of NO in the action of drugs 141
Selective serotonin reuptake inhibitors 142
P2Y receptors and NO 142
Calcium channel blockers and NO 142
Nitric oxide-based transdermal drug delivery 142
Mechanism of resistance of NO-based drugs 143
NO and nutraceuticals 143
L-arginine as a nutraceutical 143
Oleuropein 144
Role of NO in beneficial effects of chocolate 144
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
Limitation of antioxidant therapy in congestive heart failure 155
NO-based therapies for congestive heart failure 155
eNOS gene therapy for congestive heart failure 156
Gene transfer of nNOS in congestive heart failure 156
NO-based therapy for management of cardiogenic shock 156
NO-based therapy for cardiac arrhythmias 157
Prophylaxis of cardiovascular disorders 157
Prevention of atherosclerosis with aging 157
Peripheral vascular disorders 158
Peripheral atherosclerotic arterial disease 158
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 160
Cerebrovascular ischemic disorders 160
Attenuation of NO for neuroprotection in cerebral ischemia 160
Use of NO donors in cerebral ischemia 161
Use of NO donors in cerebral reperfusion injury 161
Cerebral vasospasm and NO 162
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 164
NO-NSAIDs for Alzheimer's disease 164
Ginko biloba for Alzheimer's disease 165
Personalization of NO-based therapy for Alzheimer's disease 165
Role of NO in the treatment of traumatic brain injury 165
Neuroinflammatory disorders 165
Muscular dystrophy 166
Vestibulotoxicity 166
NO for opening the blood-brain barrier 167
Cochlear disorders 167
Cochlear ischemia 167
Role of NO in sensoryneural hearing loss 167
Pain 167
NO-based therapies for pain 168
Treatment of diabetic neuropathy with isosorbide dinitrate spray 168
NO-based therapies for migraine 168
NO-based therapy for fibromyalgia syndrome 169
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 170
Topical nitroglycerin for chronic anal fissure 170
Cancer 170
Mechanism of action of NO in cancer 170
Antineoplastic effect of iNOS-expressing cells 171
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 173
NO-releasing NSAIDs and colon cancer chemoprevention 173
Rationale of combining NO aspirin with cancer vaccines 174
NO-based cancer gene therapy 174
Transdermal nitroglycerine for prostate cancer 175
NO-based therapies for skin disorders 175
NO-based therapies for skin infections 175
Role of NO in the treatment of psoriasis 175
NO-based therapy for sickle cell anemia 176
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 177
Use of NO donors in management of labor 177
Eclampsia 177
Erectile dysfunction 178
Selective inhibitors of phosphodiesterase 5 178
Erectile dysfunction in diabetes 179
NO-donating substances for treatment of ED 179
NOS gene transfer for ED 180
Organ transplant rejection 180
Role of NO in the treatment of renal disorders 181
Role of NO in the treatment of hepatic disorders 182
Portal hypertension 182
NO inhalation for restoration of liver function following transplantation 182
Role of NO in blood transfusion 182
Role of NO in the treatment of osteoporosis 183
7. Evaluation of NO-Based Drugs 185
Current status 185
Antioxidant vs. NO-based approaches 185
SWOT analysis of selected approaches for NO modulation 185
NO donors by grafting of NO-releasing structures 185
NOS modulation 186
Challenges of developing NO-based therapies 187
Concluding remarks and future prospects 187
8. Markets for NO-based Therapies 189
Introduction 189
Impact of NO-based therapies on international markets 189
Share of NO-based therapies in major therapeutic areas 189
Share of NO-based therapies in cardiovascular disorders 190
Hypercholesterolemia 190
Myocardial infarction 191
Angina pectoris 191
Heart failure 191
Coronary restenosis and stenting 191
Strategies for developing NO-based therapy markets 192
Addressing the unfulfilled needs 192
Multidisciplinary approaches 192
Collaboration between the academia and the industry 193
Education of the public 193
9. Companies 195
Introduction 195
Profiles of companies with focus on NO 197
Major pharmaceutical companies with involvement in NO 212
Smaller biotech and pharmaceutical companies involved in NO 218
Biopharmaceutical companies involved in antioxidant research 229
Companies supplying NO equipment for healthcare 233
Academic institutes with commercial collaboration in NO research 237
Companies supplying NO products for research 238
Collaborations 242
10. References 243
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: Methods of delivery of nitric oxide 112
Table 5 4: Comparison of classical nitrates, grafted NO donors, and NO mimetics 125
Table 5 5: Classification of NOS inhibitors 130
Table 5 6: 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 160
Table 6 3: NO-related therapies for pain 168
Table 7 1: SWOT of technology ? NO donors by grafting of NO-releasing structures 186
Table 7 2: SWOT of products ? NO donors by grafting of NO-releasing structures 186
Table 7 3: SWOT of NOS gene manipulation 186
Table 7 4: SWOT of analgesic development by NOS isoform targeting 187
Table 8 1: Share of NO-based therapies in major therapeutic areas 2009-2019 190
Table 8 2: Share of NO-based therapies in cardiovascular diseases 2009-2019 190
Table 9 1: Classification of companies involved in NO and antioxidant therapies 196
Table 9 2: NicOx products in development 201
Table 9 3: Product pipeline of Nitrox LLC 206
Table 9 4: NO-related products of Sigma Aldrich 240
Table 9 5: Collaborations of companies relevant to nitric oxide 242
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-?B 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 71
Figure 4 4: Dual role of nitric oxide (NO) in cerebral ischemia 72
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 85
Figure 4 7: Nitric oxide: tumor enhancement or inhibition 91
Figure 4 8: Role of nitric oxide in angiogenesis 94
Figure 5 1: Nitrogen oxide mimetics ? synergy by chemical modification 125
Figure 5 2: Factors that enhance availability of NO 127
Figure 5 3: Mechanism of resistance to NO-based therapeutics 143
Figure 6 1: Vicious circle of vascular occlusion following angioplasty and stenting 153
Figure 6 2: PDE5 inhibition and the response to sexual stimulation 179
Figure 8 1: Unfulfilled needs in NO therapeutics 192
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