Reportlinker Adds Nitric Oxide - Therapeutics, Markets and Companies

Jun 07, 2010, 13:44 ET from Reportlinker

NEW YORK, June 7 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

Nitric Oxide - Therapeutics, Markets and Companies


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 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.


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


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


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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