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Nitric Oxide

Therapeutics, Markets and Companies

Publication Date   March 2008
Publisher   Jain PharmaBiotech
Product Type   Strategic Report
Pages   260
ISBN Number   not applicable
Product Code   JAI017
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Summary


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. The text is supplemented with 25 tables and 22 figures.

Share of drugs where NO is involved in the mechanism of action is analyzed in the worldwide pharmaceutical market for 2007 and is projected to 2012 and 2017 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 38 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 collaborations in this area are tabulated.

As of the end of 2007, there are over 85,000 publications relevant to NO. Selected 500 references are included in the bibliography. The text is supplemented with 24 tables and 22 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.

Content


  • 0. Executive Summary
  • 1. Introduction
    • Free radicals
    • Nitric oxide
    • Historical aspects
    • 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
    • NOS-independent NO generation and circulation
    • Entero-salivary circulation of nitrate
    • Methods of study of NO and NOS
    • Bioimaging of NO
    • Assays of NO in tissues
    • Metabolomics approach to study of NO metabolism
  • 2. Nitric Oxide Pathways
    • Introduction
    • Mechanisms action of NO
    • NO-cGMP 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
    • Dual role of NO as a free radical and a scavenger
    • NO and carbon monoxide
  • 3. Role of NO in Physiology
    • Homeostasis of NO
    • 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
    • NO and mitochondria
    • Mitochondrial permeability and reperfusion injury
    • 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 vasodilatation
    • 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 nervous system
    • Neurovascular coupling of COX-2 and nNOS
    • Neuroglobin
    • Acute actions of NO in the CNS pathways
    • 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
    • NO and hypertension
    • 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
    • Trypanosomiasis
    • Malaria and iNOS polymorphism
    • Susceptibility of Mycobacterium leprae to NO
    • Inhaled NO for tuberculosis
    • Septic shock
    • Viral infections
    • Role of NO in anaphylactic shock
    • 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 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 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
    • NO and atherosclerosis
    • Role of NO in cardiopulmonary disorders
    • Role of NO in disturbances of vasodilation
    • Role of NO in hypercholesterolemia
    • Pulmonary hypertension
    • NO and systemic hypertension
    • Coronary artery disease
    • Role of NO in the pathophysiology of angina pectoris
    • Congestive heart failure
    • Myocardial ischemia/reperfusion injury
    • Role of NO in sickle cell disease
    • Role of NO in respiratory 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
    • Role of NO in renal disorders
    • Role of NOS in diabetic nephropathy
    • Role of NO in 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
    • 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 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 radiation damage
  • 5. Pharmacology of Nitric Oxide
    • Introduction
    • Cytoxic vs cytoprotective role of NO
    • Antioxidants
    • Ebselen
    • Nicaraven
    • Nitroxides
    • Antioxidants in relation to NO
    • Limitation of antioxidant therapy in congestive heart failure
    • NO-related drugs
    • Drugs that activate endothelial NO production
    • Dehydroepiandrosterone
    • Drugs that scavenge free radicals/NO
    • Peroxynitrite scavengers
    • Ruthenium (III) polyaminocarboxylates
    • Nitrones
    • Drugs that inhibit NO
    • Ginko biloba
    • Epigallocatechin
    • NO Therapeutics
    • Nitric oxide as an antioxidant
    • 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
    • Adding NO-donating structures to extend life cycle of existing drugs
    • Cysteine-containing NO donors
    • Ferrous nitrosyl complexes
    • Syndnonimines
    • S-Nitrosothiols
    • 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
    • Modulators of cyclic guanosine-3',5'-monophosphate-dependent protein kinases
    • L-Arginine
    • 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
    • Factors that enhance availability of NO
    • NOS-modulating drugs
    • Drugs that activate eNOS
    • Statins
    • Angiotensin converting enzyme inhibitors
  • 17 Beta-estradiol
    • C-2431
    • NOS inhibitors
    • Rationale of NOS inhibitors
    • 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
    • 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
    • Bay 41-2272
    • 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
    • NO and nutraceuticals
    • L-arginine as a nutraceutical
    • 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
    • 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
    • Inhaled nebulized nitrite for neonatal pulmonary hypertension
    • Gene therapy for pulmonary 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 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
    • Congestive heart failure
    • NO-based therapy 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
    • Prophylaxis of cardiovascular disorders
    • Prevention of atherosclerosis with aging
    • Peripheral vascular disorders
    • Peripheral atherosclerotic arterial disease
    • Peripheral ischemic disease
    • An eNOS mutant as therapeutic 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
    • Cerebral vasospasm and NO
    • 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
    • Muscular dystrophy
    • Vestibulotoxicity
    • NO for opening the blood-brain barrier
    • Cochlear disorders
    • Cochlear ischemia
    • Role of NO in sensoryneural hearing loss
    • 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
    • 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
    • Use of NO donors in management of labor
    • Eclampsia
    • 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
  • 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
    • 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: Comparison of classical nitrates, grafted NO donors, and NO mimetics
    • Table 5 4: Classification of NOS inhibitors
    • Table 5 5: Potential clinical applications of gene transfer for NOS overexpression
    • Table 6 1: Cardiovascular disorders for which NO-based therapies are used
    • Table 6 2: Selected neurological applications of NO-based therapies
    • Table 6 3: 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 major therapeutic areas 2007-2017
    • Table 8 2: Share of NO-based therapies in cardiovascular diseases 2007-2017
    • Table 9 1: Classification of companies involved in NO and antioxidant therapies
    • Table 9 2: NicOx products in development
    • Table 9 3: Product pipeline of Nitrox LLC
    • Table 9 4: NO-related products of Sigma Aldrich
    • Table 9 5: Collaborations of companies relevant to nitric oxide
  • Figures
    • Figure 1 1: Biosynthesis of nitric oxide (NO)
    • Figure 1 2: 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: NOS in the cardiac myocyte
    • Figure 3 2: Interactions of the Mb compounds with O2 and NO
    • 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 5 1: Nitrogen oxide mimetics ? synergy by chemical modification
    • Figure 5 2: Factors that enhance availability of NO
    • Figure 6 1: Vicious circle of vascular occlusion following angioplasty and stenting
    • Figure 6 2: PDE5 inhibition and the response to sexual stimulation
    • Figure 8 1: Unfulfilled needs in NO therapeutics"