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Nitric Oxide - Therapeutics, Markets and Companies

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  • 284 Pages
  • November 2021
  • Region: Global
  • Jain PharmaBiotech
  • ID: 4748162

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 2020 and is projected to 2024 and 2030 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 36 companies involved in this area of which 10 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 18 collaborations in this area are tabulated.

There are numerous publications relevant to NO. Selected 500 references are included in the bibliography. The text is supplemented with 26 tables and 30 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.

The report contains information on the following:

  • Introduction to nitric oxide (NO)
  • NO Pathways
  • Role of NO in Physiology
  • Role of NO in Disease
  • Pharmacology
  • Therapeutic Applications
  • Evaluation of NO-based drugs
  • Markets for NO-based Therapies
  • Companies involved in NO therapeutics

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  

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  

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