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Nitric Oxide - Therapeutics, Markets and Companies

  • ID: 4748162
  • Report
  • December 2019
  • Region: Global
  • 280 Pages
  • Jain PharmaBiotech
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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 2018 and is projected to 2023 and 2028 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 35 companies involved in this area of which 9 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
Note: Product cover images may vary from those shown
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0. 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
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  
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  
Role of NO in the management of pulmonary disorders  
Manufacture of NO gas for inhalation
Delivery of NO gas 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  
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
Asthma
iNOS inhibitors for asthma  
NO for bronchodilation in asthma
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 2018-2028  
Table 8-2: Share of NO-based therapies in cardiovascular diseases 2018-2028  
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 

Note: Product cover images may vary from those shown
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