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Nitric Oxide - Therapeutics, Markets and Companies

  • ID: 4748162
  • Report
  • 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 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 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:

  • 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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