Nitric Oxide - Therapeutics, Markets and Companies

Table of Contents

Executive Summary  

1. Introduction

• Role of nitric oxide in atmosphere and biology  
• Historical aspects  
• Free radicals  
• Nitrogen cycle and NO  
• Role of NO in biology and medicine  
• Nitric oxide synthase
• Structure and function NOS
• Inducible nitric oxide synthase
• iNOS gene  
• Regulation of iNOS  
• Regulation of endothelial nitric oxide synthase
• Interaction between eNOS and other proteins
• Tetrahydrobiopterin
• eNOS gene
• NOS-independent NO generation and circulation
• Entero-salivary circulation of nitrate
• Methods of study of NO and NOS
• Colorimetric determination of NO2- using the Greiss reagent
• Chemiluminescence  
• High performance liquid chromatography  
• Bioimaging of NO
• DNA-based fluorescent NOS2probes
• Electrochemical methods using amperometry  
• Method using micro ion electrodes
• Metabolomics approach to study of NO metabolism  

2. Nitric Oxide Pathways  

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

3. Role of NO in Physiology

• Role of NO in homeostasis
• Role of NO in adaptation to high altitude
• NO as a biomarker
• Functions of NO in various systems of the body
• NO and proteins. 
• A proteomic method for identification of cysteine S-nitrosylation sites
• Protein S-nitrosylation and intracellular transport processes
• Cellular inactivation NO by iNOS aggresome formation  
• NO and mitochondria  
• Mitochondrial permeability and reperfusion injury
• Endocrine role of NO  
• Role of NO in the cardiovascular system
• NO and atrial natriuretic peptide
• NOS in the cardiac myocyte
• NO and the autonomic control of the heart rate  
• NO and vascular system  
• NO and vasodilatation
• NO and blood pressure  
• Role of NO in the plasma compartment  
• Measurement of NO as a biomarker of cardiovascular function  
• Hemoglobin, oxygen and nitric oxide  
• Myoglobin and NO
• NO and pulmonary circulation  
• Role of NO in the regulation of hypoxic pulmonary vasoconstriction
• Role of NO in the lymphatic system  
• Role of NO in the nervous system  
• Neurovascular coupling of COX-2 and nNOS
• Neuroglobin
• NO and blood-brain barrier
• NO as a neurotransmitter
• Role of NO in consciousness
• Role of NO in memory and learning
• Role of NO in synaptic plasticity  
• Role of NO in the peripheral nervous system  
• Role of NO in the cochlea  
• NO and neuroendocrine function  
• NO and pregnancy
• Role of NO in penile erection
• Role of NO in immune regulation
• Role of NO in temperature regulation
• Role of NO in gastrointestinal system
• Role of NO in kidney function  
• Role of NO in liver  
• Role of NO in the skin

4. Role of NO in Diseases  

• Introduction  
• Cytotoxicity of reactive nitrogen species
• Peroxynitrite, mitochondria and cell death
• Diseases involving oxidative stress and nitric oxide  
• Stress-related disorders  
• Role of NO in allergic disorders  
• Inflammatory diseases  
• Autoimmune disorders
• Role of NO in rheumatoid arthritis  
• Role of NO in infections
• NO-mediated cytoprotection in bacteria  
• Nanoscale nanoparticle delivery for cutaneous infection  
• Leishmaniasis  
• Malaria and iNOS polymorphism  
• Susceptibility of Mycobacterium leprae to NO  
• Role of NO in the treatment of tuberculosis
• Septic shock  
• Trypanosomiasis  
• Viral infections
• Role of NO in anaphylactic shock
• Role of NO in anemia and hypoxia
• Role of NO in neurological disorders  
• Neurodegenerative diseases  
• NO-induced mitochondrial dysfunction in neurodegeneration  
• White matter disorders  
• Amyotrophic lateral sclerosis  
• Alzheimer's disease
• Role of NO in pathophysiology of Alzheimer's disease  
• Role of ApoE genotype
• Parkinson's disease
• Traumatic brain injury  
• Epilepsy  
• Stroke  
• Pathophysiology of cerebral ischemia  
• Role of NO in cerebral ischemia  
• eNOS gene polymorphisms as predictor of cerebral aneurysm rupture
• Role of NO in assessment of cerebral and retinal blood flow
• Role of NO in cerebral vasospasm after subarachnoid hemorrhage  
• Role of NO in neuroprotection
• Stroke and heart disease
• Role of NO in peripheral neuropathy
• iNOS induction in experimental allergic neuritis. 
• Role of NO in sciatica
• Role of NO in the pathogenesis of muscular dystrophy  
• Role of NO in neurological decompression sickness
• Role of NO in psychiatric disorders  
• NO-dysregulation in schizophrenia
• Role of NO in pathomechanism of cardiovascular disorders
• Oxidative stress as a cause of cardiovascular disease
• Role of NO in pathomechanism of cardiovascular diseases. 
• Role of iNOS in cardiovascular disease
• Role of eNOS in cardiovascular disease  
• Role nNOS in cardiac arrhythmia and sudden death  
• Role of NO in atherosclerosis  
• Therapeutic stimulation of the nitrate-nitrite-NO pathway  
• Role of NO in cardiopulmonary disorders
• Role of NO in disturbances of vasodilation
• Caveolin-1 deficiency impairs NO synthesis and vasodilation  
• Role of NO in hypercholesterolemia  
• NO and systemic hypertension.  
• Coronary artery disease  
• Role of NO in the pathophysiology of angina pectoris  
• Congestive heart failure  
• Calcium overload as a cause of heart failure
• NO/redox disequilibrium in the failing heart  
• Myocardial ischemia/reperfusion injury
• NO pathway in cardiac hypertrophy  
• Role of NO in sickle cell disease
• Role of NO in pulmonary disorders  
• Role of NO in the pathophysiology of asthma
• iNOS gene polymorphisms in asthma
• Role of S-nitrosoglutathione in bronchodilation in asthma  
• Monitoring of exhaled NO  
• Nasal NO as a biomarker of response to rhinosinusitis therapy  
• Elevated urinary NO as a biomarker of improved survival in ARDS
• Pulmonary hypertension
• Role of NO in renal disorders
• Role of NOS in diabetic nephropathy  
• Role of NO in cancer  
• Inflammation, NO and colon cancer  
• Tumor hypoxia and NO
• NO and p53 mutations  
• NO and matrix metalloproteinase
• Role of NO in angiogenesis in cancer  
• Role of NO in diseases of the eye
• Glaucoma
• Role of NO in metabolic disorders  
• Metabolic syndrome
• Obesity
• Diabetes mellitus
• Role of NO in gastrointestinal disorders  
• Role of L-arginine in intestinal adaptation
• Role of NO in irritable bowel syndrome
• Role of NO in inflammatory bowel diseases
• Role of NO in celiac disease
• Role of NO in diabetic gastroparesis
• NO and diseases of the liver  
• Cirrhosis of liver  
• Hepatic encephalopathy  
• Role of NO in skin disorders
• Role of NO and oxidative stress in the aging skin
• Role of NO in wound healing  
• Role of NO in erectile dysfunction  
• Role of NO in pain  
• NO and pain of spinal cord origin
• NO interaction with other receptors in pain
• nNOS and pain  
• Role of NO in various types of pain
• Neuropathic pain
• Role of NO in diabetic neuropathy
• NO in oral and facial pain
• Role of NO in migraine
• Role of NO in osteoarthritis  
• NO and Fibromyalgia syndrome  
• Role of spinal NO in analgesic action
• Role of NO in nicotine addiction
• Role of NO in carbon monoxide poisoning  
• Role of NO in chemically-induced toxicity  
• Peroxynitrite and drug-dependent toxicity.  
• Paraquat neurotoxicity  
• Role of NO in radiation damage

5. Pharmacology of Nitric Oxide

• Introduction  
• Cytoxic vs cytoprotective role of NO  
• Antioxidants  
• Ebselen 
• Nicaraven  
• Nitroxides  
• Antioxidants in relation to NO  
• Nitric oxide as an antioxidant  
• NO-related drugs
• Drugs that activate eNOS production  
• Aspirin
• Dehydroepiandrosterone  
• Drugs that scavenge free radicals/NO
• Peroxynitrite scavengers  
• Ruthenium (III) polyaminocarboxylates
• Nitrones
• Drugs that inhibit NO 
• Ginko biloba
• Epigallocatechin  
• Delivery of nitric oxide
• Targeted delivery of NO donors
• Nitric oxide delivery by encapsulated cells
• NO-lipid combination  
• NO-releasing coating to prevent infection of implanted devices  
• Nanoparticles for controlled/sustained release of NO  
• Hydrogel/glass nanoparticles  
• Delivery of nanoparticles to vascular endothelium for release of NO  
• Functionalized inorganic colloidal nanovehicles for NO delivery
• Release of NO in tissues by extracorporeal shock wave application
• Nitric oxide donors  
• Nitroglycerine/glycerine trinitrate
• Isosorbide dinitrate  
• Sodium nitrite
• Organic nitrites  
• NO-releasing NSAIDs
• COX-inhibiting NO-donors
• Grafting of NO-releasing structures on to existing drugs
• Mesoionic Oxatriazoles
• Cysteine-containing NO donors  
• Sodium nitroprusside 
• Syndnonimines  
• S-Nitrosothiols
• Cavosonstat
• Diazeniumdiolates  
• COX-2 inhibitors  
• NO hydrogels  
• Novel NO donors  
• NO mimetics
• Comparison of classical nitrates, grafted NO donors, and NO mimetics
• NO donors and soluble guanylate cyclase activation
• NO donors for increasing the efficacy of chemotherapy
• Factors that enhance availability of NO
• Modulators of cyclic guanosine-3′,5′-monophosphate-dependent protein kinases
• NOS-modulating drugs. 
• Drugs that activate eNOS  
• Statins
• Angiotensin converting enzyme inhibitors  
• 17 Beta-estradiol  
• C-2431  
• NOS inhibitors
• Rationale of NOS inhibitors
• L-Arginine  
• Design of NOS inhibitors  
• Selective iNOS inhibitors  
• Non-amino acid-based inhibitors
• Aminoguanidine  
• Heme ligands
• Pterin antagonists
• Fused-ring bio-isoteric models of arginine as NOS inhibitors
• nNOS inhibitors  
• Lubeluzole
• Neurotrophic factors  
• Therapies based on action of NOS as a paraquat diaphorase  
• Concluding remarks about NOS inhibiting drugs  
• NO and stem cell-based therapy  
• Nitric oxide and gene therapy  
• NOS gene transfer
• Inhibition of NOS by antisense technology  
• Drugs that modulate NO action on platelets  
• Action of NO and NO donors on platelets
• NOS inhibitors and NO scavengers
• Phosphodiesterase inhibitors
• Activators of soluble guanylate cyclase
• YC-1
• A-350619
• Cinaciguat
• Secondary role of NO in the action of drugs
• Selective serotonin reuptake inhibitors
• P2Y receptors and NO
• Calcium channel blockers and NO. 
• Nitric oxide-based transdermal drug delivery
• Mechanism of resistance of NO-based drugs  
• NO and nutraceuticals
• Diet and endogenous production of NO
• L-arginine as a nutraceutical
• Nitrate and nitrite  
• Oleuropein  
• Role of NO in beneficial effects of chocolate

6. Therapeutic Applications  

• Introduction  
• Management of pulmonary disorders by NO-based methods
• Manufacture of NO gas for inhalation  
• NO gas inhalation systems for pulmonary disorders  
• NO inhalation for acute respiratory distress syndrome  
• NO inhalation for premature children with pulmonary dysplasia  
• NO inhalation for premature children with respiratory failure  
• Management of pulmonary hypertension
• NO-based treatment of pulmonary hypertension
• Pediatric pulmonary hypertension
• Gene therapy for pulmonary hypertension 
• Clinical trials of NO therapies for pulmonary arterial hypertension
• Management of asthma and COPD
• iNOS inhibitors for asthma
• NO for bronchodilation in asthma  
• NO in COPD  
• NO-releasing drugs for the treatment of lung infections  
• Role of NO in acute lung injury after smoke inhalation  
• Cardiovascular disorders
• Role of NO in cardioprotection
• Role of NO in the management of myocardial infarction  
• Role of NO in the management of hypertension
• Role of NO in the management of angina pectoris  
• Role of NO in therapy of coronary heart disease
• NO-releasing aspirin in patients undergoing CABG
• Management of coronary restenosis
• Modified NO donors
• NO-generating stent for coronary restenosis. 
• eNOS gene therapy for restenosis
• NO-based management of cardiac hypertrophy 
• Congestive heart failure  
• Limitation of antioxidant therapy in congestive heart failure
• NO-based therapies for congestive heart failure  
• eNOS gene therapy for congestive heart failure  
• Gene transfer of nNOS in congestive heart failure
• NO-based therapy for management of cardiogenic shock  
• NO-based therapy for cardiac arrhythmias  
• Prophylaxis of cardiovascular disorders
• Prevention of atherosclerosis with aging  
• Role of iNO in cardiac surgery  
• Strategies for increasing NO signaling in cardiovascular disorders  
• Peripheral vascular disorders
• Peripheral atherosclerotic arterial disease  
• Peripheral ischemic disease  
• An eNOS mutant as therapeutic for peripheral vascular ischemia  
• Sodium nitrite therapy for peripheral vascular ischemia
• Raynaud's phenomenon
• Neurological disorders
• Cerebrovascular ischemic disorders  
• Attenuation of NO for neuroprotection in cerebral ischemia  
• Use of NO donors in cerebral ischemia
• Use of NO donors in cerebral reperfusion injury  
• NO-based treatments for cerebral vasospasm due to SAH  
• NOS gene therapy for cerebral vasospasm
• Degenerative CNS disorders  
• Statins for Alzheimer's disease
• NO mimetics for Alzheimer's disease
• iNOS inhibitors for treatment of Alzheimer’s disease  
• NO-NSAIDs for Alzheimer's disease
• Ginko biloba for Alzheimer's disease  
• Personalization of NO-based therapy for Alzheimer's disease  
• Role of NO in the treatment of traumatic brain injury
• Neuroinflammatory disorders  
• Role of NO-releasing sodium nitroprusside in the treatment of schizophrenia
• Antidepressant effect of NOS inhibitors
• Muscular dystrophy  
• Vestibulotoxicity  
• NO for opening the blood-brain barrier
• Cochlear disorders
• Cochlear ischemia  
• Role of NO in sensoryneural hearing loss  
• Ophthalmic disorders  
• Glaucoma  
• Pain
• NO-based therapies for pain  
• Treatment of diabetic neuropathy with isosorbide dinitrate spray
• NO-based therapies for migraine 
• NO-based therapy for fibromyalgia syndrome  
• NO-based therapies for inflammatory disorders  
• NO-based therapies for gastrointestinal disorders. 
• Protection of gastrointestinal injury from NSAIDs
• Role of NO in the treatment of inflammatory bowel disease
• Topical nitroglycerin for chronic anal fissure  
• Cancer
• Mechanism of action of NO in cancer  
• Antineoplastic effect of iNOS-expressing cells  
• Role of NO in drug resistance of cancer
• Role of NO in treatment of brain tumors
• NO-induced apoptosis
• Role of NO in antiangiogenesis therapies in cancer
• NO donors for the treatment of cancer 
• NO-releasing NSAIDs and colon cancer chemoprevention  
• Rationale of combining NO aspirin with cancer vaccines  
• NO-based cancer gene therapy  
• Transdermal nitroglycerine for prostate cancer  
• NO-based therapies for skin disorders
• NO-based therapies for skin infections  
• Role of NO in the treatment of psoriasis  
• NO-based therapy for sickle cell anemia  
• Inhaled NO for acute respiratory distress syndrome in sickle cell disease  
• NO inhalation for pulmonary hypertension in sickle cell anemia 
• Role of NO in disorders associated with pregnancy
• Pre-eclampsia and intra-uterine growth restriction
• Use of NO donors in management of labor  
• Erectile dysfunction
• Selective inhibitors of phosphodiesterase 5
• Erectile dysfunction in diabetes  
• NO-donating substances for treatment of ED
• NOS gene transfer for ED  
• Organ transplant rejection
• Role of NO in the treatment of renal disorders  
• Role of NO in the treatment of hepatic disorders
• Portal hypertension  
• NO inhalation for restoration of liver function following transplantation
• Role of NO in blood transfusion
• Role of NO in the treatment of osteoporosis  
• NO-based wound healing

7. Evaluation of NO-Based Drugs  

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

8. Markets for NO-based Therapies

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

9. Companies  

• Introduction  
• Profiles of companies with focus on NO
• Major pharmaceutical companies with involvement in NO
• Smaller biotech and pharmaceutical companies involved in NO
• Biopharmaceutical companies involved in antioxidant research  
• Companies supplying NO equipment for healthcare
• Academic institutes with commercial collaboration in NO research
• Companies supplying NO products for research
• Collaborations  

10. References  

Tables
Table 1-1: Historical landmarks in the discovery and applications of nitric oxide  
Table 3-1: Important functions of NO in the human body 
Table 4-1: Diseases involving nitric oxide
Table 4-2: Role of nitric oxide in pathogenesis of autoimmune disorders
Table 4-3: Role of nitric oxide in infections  
Table 5-1: Neuroprotective antioxidants
Table 5-2: NO-related drugs
Table 5-3: Methods of delivery of nitric oxide  
Table 5-4: Comparison of classical nitrates, grafted NO donors, and NO mimetics  
Table 5-5: Classification of NOS inhibitors
Table 5-6: Potential clinical applications of gene transfer for NOS overexpression  
Table 6-1: Clinical trials of NO-based therapies for pulmonary hypertension  
Table 6-2: Cardiovascular disorders for which NO-based therapies are used  
Table 6-3: Selected neurological applications of NO-based therapies  
Table 6-4: NO-related therapies for pain
Table 7-1: SWOT of technology − NO donors by grafting of NO-releasing structures
Table 7-2: SWOT of products − NO donors by grafting of NO-releasing structures  
Table 7-3: SWOT of NOS gene manipulation
Table 7-4: SWOT of analgesic development by NOS isoform targeting  
Table 8-1: Share of NO-based therapies in relevant therapeutic areas 2020-2030
Table 8-2: Share of NO-based therapies in cardiovascular diseases 2020-2030
Table 9-1: Classification of companies involved in NO and antioxidant therapies  
Table 9-2: NicOx products in development  
Table 9-3: NO-related products of Sigma Aldrich
Table 9-4: Collaborations of companies relevant to nitric oxide  

Figures
Figure 1-1: Nitrogen cycle in the human body
Figure 1-2: Biosynthesis of nitric oxide (NO)
Figure 1-3: NO synthase pathway  
Figure 2-1: Reactivity of nitric oxide with heme proteins in oxygen or peroxide reaction cycles  
Figure 2-2: NO-cGMP pathway leading to vasorelaxation  
Figure 2-3: The biological pathways toward protein nitration
Figure 2-4: NF-B activation and iNOS induction  
Figure 2-5: Overview of mitochondrial NO-cytochrome c oxidase signaling pathway
Figure 3-1: Role of NO in adaptation to high altitude  
Figure 3-2: NOS in the cardiac myocyte
Figure 3-3: Pathways for generation and inhibition of NO in the vasculature 
Figure 3-4: Interactions of the Mb compounds with O2 and NO  
Figure 3-5: Role of NO in dynamics of lymphatic pumping  
Figure 4-1: Molecular mechanisms of peroxynitrite-mediated cell death  
Figure 4-2: NO neurotoxicity and neuroprotection in relation to Alzheimer's disease. 
Figure 4-3: Some steps in the ischemic cascade and site of action of neuroprotectives
Figure 4-4: Dual role of nitric oxide (NO) in cerebral ischemia
Figure 4-5: Blood cell-endothelial cell interactions induced by hypercholesterolemia. 
Figure 4-6: Effects of NO on the pathophysiology of myocardial ischemia-reperfusion  
Figure 4-7: Nitric oxide: tumor enhancement or inhibition  
Figure 4-8: Role of nitric oxide in angiogenesis  
Figure 4-9: Role of NO in HBO-induced wound healing
Figure 5-1: Nitrogen oxide mimetics − synergy by chemical modification  
Figure 5-2: Factors that enhance availability of NO  
Figure 5-3: Mechanism of resistance to NO-based therapeutics
Figure 5-4:Effect of dietary trigonelline on NO production of NO in vascular endothelium  
Figure 6-1: Mechanism of development of tolerance to glyceryl trinitrate  
Figure 6-2: Vicious circle of vascular occlusion following angioplasty and stenting  
Figure 6-3: PDE5 inhibition and the response to sexual stimulation  
Figure 8-1:  Unfulfilled needs in NO therapeutics

Samples