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Nitric Oxide - Therapeutics, Markets and Companies
Jain PharmaBiotech, Nov 2009, Pages: 272
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
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
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
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 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
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
Role of NO in the treatment of 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
Calcium overload as a cause of heart failure
NO/redox disequilibrium in the failing heart
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
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
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 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 endothelial NO production
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
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
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
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
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
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
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
Role of NO in the treatment of osteoporosis
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: 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: 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 2008-2018
Table 8-2: Share of NO-based therapies in cardiovascular diseases 2008-2018
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-kB 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
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