Nitric Oxide - Therapeutics, Markets and Companies |
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0. Executive Summary ................. 11 1. Introduction ....... 13 Free radicals ............... 13 Nitric oxide ................. 13 Historical aspects .......13 Role of NO in biology and medicine...14 Nitric oxide synthase .. 15 Structure and function of NOS .........15 Inducible nitric oxide synthase.........17 iNOS gene............17 Regulation of iNOS 17 Regulation of endothelial nitric oxide synthase ........17 Interaction between eNOS and other proteins....18 Tetrahydrobiopterin...................18 Methods of study of NO and NOS .....19 Bioimaging of NO ..19 Assays of NO in tissues ..............19 Metabolomics approach to study of NO metabolism ................20 2. Nitric Oxide Pathways ............. 21 Introduction............... 21 Mechanisms action of NO ................ 22 NO-cGMP pathway ...... 22 Soluble guanylyl cyclase as the NO receptor ...........23 Oxidative stress pathways .............. 23 NO and oxidative stress ..................23 Oxidative stress and the NO-cyclic GMP signal transduction pathway ..................24 NO and platelets ........26 Mitochondrial NO-cytochrome c oxidase signaling pathway...........26 Dual role of NO as a free radical and a scavenger....27 NO and carbon monoxide ................ 28 3. Role of NO in Physiology.......... 31 Homeostasis of NO...... 31 NO as a biomarker ...... 31 Functions of NO in various systems of the body... 31 NO and proteins.........32 A proteomic method for identification of cysteine S-nitrosylation sites ...........32 Protein S-nitrosylation and intracellular transport processes ....33 NO and mitochondria..33 Mitochondrial permeability and reperfusion injury...................34 Role of NO in the cardiovascular system.................34 NO and atrial natriuretic peptide .35 NOS in the cardiac myocyte........35 NO and the autonomic control of the heart rate .36 NO and vasodilatation................37 Role of NO in the plasma compartment .............38 Measurement of NO as a biomarker of cardiovascular function.38 Hemoglobin, oxygen and nitric oxide 38 Myoglobin and NO .40 NO and pulmonary circulation..........40 Role of NO in the regulation of hypoxic pulmonary vasoconstriction...............41 Role of NO in the nervous system ....41 Neurovascular coupling of COX-2 and nNOS ......42 Neuroglobin..........42 Acute actions of NO in the CNS pathways..........43 Role of NO in memory and learning ..................43 Role of NO in synaptic plasticity ..43 Role of NO in the peripheral nervous system .....43 Role of NO in the cochlea ................44 NO and neuroendocrine function ......44 NO and pregnancy......44 Role of NO in penile erection............44 Role of NO in immune regulation......45 Role of NO in temperature regulation46 Role of NO in gastrointestinal system46 Role of NO in kidney function...........46 - 4 - Role of NO in liver ......47 NO and hypertension .................47 Role of NO in the skin .47 4. Role of NO in Diseases............. 49 Introduction............... 49 Cytotoxicity of reactive nitrogen species.................49 Peroxynitrite, mitochondria and cell death..............49 Diseases involving oxidative stress and nitric oxide ................ 51 Stress-related disorders.................. 52 Role of NO in allergic disorders....... 52 Inflammatory diseases ................... 52 Autoimmune disorders 53 Role of NO in rheumatoid arthritis ....54 Role of NO in infections................... 54 NO-mediated cytoprotection in bacteria .................55 Trypanosomiasis ........55 Malaria and iNOS polymorphism.......56 Susceptibility of Mycobacterium leprae to NO..........56Inhaled NO for tuberculosis .............56 Septic shock ..............57 Viral infections...........57 Role of NO in anaphylactic shock .... 58 Role of NO in neurological disorders 59 Neurodegenerative diseases ............59 NO-induced mitochondrial dysfunction in neurodegeneration ...59 White matter disorders ..............59 Amyotrophic lateral sclerosis ......59 Alzheimer's disease ...................60 Role of NO in pathophysiology of Alzheimer's disease .............60 Role of ApoE genotype ...............63 Parkinson's disease ...................63 Traumatic brain injury 65 Epilepsy 65 Stroke .66 Pathophysiology of cerebral ischemia................66 Role of NO in cerebral ischemia...67 eNOS gene polymorphisms as predictor of cerebral aneurysm rupture ...........68 Role of NO in assessment of cerebral and retinal blood flow.....68 Role of NO in neuroprotection .....69 Stroke and heart disease............69 Role of NO in peripheral neuropathy .69 iNOS induction in experimental allergic neuritis..69 Role of NO in sciatica.................69 Role of NO in the pathogenesis of muscular dystrophy .................70 Role of NO in psychiatric disorders . 70 NO-dysregulation in schizophrenia....70 Role of NO in pathomechanism of cardiovascular disorders..... 71 Oxidative stress as a cause of cardiovascular disease ..................71 Role of NO in pathomechanism of cardiovascular diseases............71 Role of iNOS in cardiovascular disease ..............72 Role of eNOS in cardiovascular disease .............72 Role nNOS in cardiac arrhythmia and sudden death................73 NO and atherosclerosis ...................73 Role of NO in cardiopulmonary disorders................74 Role of NO in disturbances of vasodilation ..............75 Role of NO in hypercholesterolemia ..75 Pulmonary hypertension..................76 NO and systemic hypertension.........77 Coronary artery disease ..................77 Role of NO in the pathophysiology of angina pectoris...................78 Congestive heart failure ..................78 Myocardial ischemia/reperfusion injury ..................78 Role of NO in sickle cell disease ...... 80 Role of NO in respiratory disorders . 80 Role of NO in the pathophysiology of asthma ..........80 iNOS gene polymorphisms in asthma................81 Role of S-nitrosoglutathione in bronchodilation in asthma.............82 Monitoring of exhaled NO ................82 Nasal NO as a biomarker of response to rhinosinusitis therapy......83 Elevated urinary NO as a biomarker of improved survival in ARDS 83 - 5 - Role of NO in renal disorders .......... 84 Role of NOS in diabetic nephropathy.84 Role of NO in cancer.... 84 Tumor hypoxia and NO ...................85 NO and p53 mutations86 NO and matrix metalloproteinase .....86 Role of NO in angiogenesis in cancer 86 Role of NO in diseases of the eye .... 88 Glaucoma.................88 Role of NO in metabolic disorders ... 88 Obesity 88 Diabetes mellitus .......88 Role of NO in gastrointestinal disorders............... 89 Role of L-arginine in intestinal adaptation...............89 Role of NO in irritable bowel syndrome ..................89 Role of NO in inflammatory bowel diseases.............89 Role of NO in celiac disease .............90 Role of NO in diabetic gastroparesis..90 NO and diseases of the liver............ 90 Cirrhosis of liver.........90 Hepatic encephalopathy ..................91 Role of NO in skin disorders ............ 91 Role of NO and oxidative stress in the aging skin ....91 Role of NO in wound healing............91 Role of NO in pain ....... 92 NO and pain of spinal cord origin......92 NO interaction with other receptors in pain.............92 nNOS and pain...........92 Role of NO in various types of pain...93 Neuropathic pain...93 Role of NO in diabetic neuropathy 93 NO in oral and facial pain ...........93 Role of NO in migraine ...............94 Role of NO in osteoarthritis.........94 NO and Fibromyalgia syndrome ..95 Role of spinal NO in analgesic action.................95 Role of NO in nicotine addiction ...... 96 Role of NO in carbon monoxide poisoning............ 96 Role of NO in radiation damage....... 96 5. Pharmacology of Nitric Oxide .. 99 Introduction............... 99 Cytoxic vs cytoprotective role of NO 99 Antioxidants............... 99 Ebselen.............. 100 Nicaraven........... 100 Nitroxides .......... 101 Antioxidants in relation to NO ........ 101 Limitation of antioxidant therapy in congestive heart failure ....... 102 NO-related drugs ...... 102 Drugs that activate endothelial NO production ...... 103 Dehydroepiandrosterone .......... 103 Drugs that scavenge free radicals/NO .................. 104 Peroxynitrite scavengers .......... 104 Ruthenium (III) polyaminocarboxylates .......... 104 Nitrones............. 104 Drugs that inhibit NO 105 Ginko biloba ....... 105 Epigallocatechin .. 105 NO Therapeutics ....... 105 Nitric oxide as an antioxidant......... 105 Nitric oxide donors ... 106 Nitroglycerine/glycerine trinitrate ................... 107 Isosorbide dinitrate ................. 107 Sodium nitrite..... 107 Organic nitrites ... 108 NO-releasing NSAIDs............... 108 COX-inhibiting NO-donors ........ 109 Grafting of NO-releasing structures on to existing drugs........ 111 Mesoionic Oxatriazoles............. 113 Adding NO-donating structures to extend life cycle of existing drugs............ 113 - 6 - Cysteine-containing NO donors . 113 Ferrous nitrosyl complexes ....... 114 Syndnonimines ... 114 S-Nitrosothiols .... 114 Diazeniumdiolates ................... 115 COX-2 inhibitors.. 115 NO hydrogels...... 116 Novel NO donors . 116 NO mimetics....... 116 Comparison of classical nitrates, grafted NO donors, and NO mimetics......... 117 NO donors and soluble guanylate cyclase activation.............. 117 NO donors for increasing the efficacy of chemotherapy ......... 118 Modulators of cyclic guanosine-3',5'-monophosphate-dependent protein kinases ................... 118 L-Arginine ............... 119 Delivery of nitric oxide .................. 119 Targeted delivery of NO donors. 120 Nitric oxide delivery by encapsulated cells ....... 120 NO-lipid combination ............... 120 NO-releasing coating to prevent infection of implanted devices ................... 121 Factors that enhance availability of NO.............. 121 NOS-modulating drugs.................. 121 Drugs that activate eNOS.............. 122 Statins............... 122 Angiotensin converting enzyme inhibitors........ 123 17 Beta-estradiol 123 C-2431 .............. 123 NOS inhibitors ......... 123 Rationale of NOS inhibitors....... 123 Design of NOS inhibitors .......... 125 Selective iNOS inhibitors .......... 125 Non-amino acid-based inhibitors 126 Aminoguanidine .. 126 Heme ligands...... 127 Pterin antagonists ................... 127 Fused-ring bio-isoteric models of arginine as NOS inhibitors .. 127 nNOS inhibitors... 127 Lubeluzole.......... 129 Neurotrophic factors ................ 129 Concluding remarks about NOS inhibiting drugs ................... 129 NO and stem cell-based therapy ... 130 Nitric oxide and gene therapy ....... 131 NOS gene transfer.... 131 Inhibition of NOS by antisense technology............ 132 Drugs that modulate NO action on platelets....... 132 Action of NO and NO donors on platelets.............. 133 NOS inhibitors and NO scavengers . 133 Phosphodiesterase inhibitors........ 133 Activators of soluble guanylate cyclase.............. 133 YC-1.. 133 A-350619................ 134 Bay 41-2272 ........... 134 Secondary role of NO in the action of drugs ....... 134 Selective serotonin reuptake inhibitors................. 134 P2Y receptors and NO ................... 135 Calcium channel blockers and NO... 135 Nitric oxide-based transdermal drug delivery ........ 135 NO and nutraceuticals................... 135 L-arginine as a nutraceutical.......... 136 Oleuropein .............. 136 Role of NO in beneficial effects of chocolate.......... 136 6. Therapeutic Applications ....... 139 Introduction............. 139 Role of NO in the management of pulmonary disorders ......... 139 Manufacture of NO gas for inhalation ................... 139 NO inhalation for acute respiratory distress syndrome ............... 139 NO inhalation for premature children with pulmonary dysplasia................... 140 NO inhalation for premature children with respiratory failure . 140 Pulmonary hypertension................ 141 NO-based treatment of pulmonary hypertension .................. 141 Inhaled nebulized nitrite for neonatal pulmonary hypertension 142 - 7 - Gene therapy for pulmonary hypertension....... 142 Asthma................... 142 iNOS inhibitors for asthma........ 143 NO for bronchodilation in asthma ................... 143 Role of NO in acute lung injury after smoke inhalation ............... 143 Cardiovascular disorders............... 144 Role of NO in cardioprotection........ 144 Role of NO in the management of angina pectoris . 144 Role of NO in therapy of coronary heart disease.... 145 NO-releasing aspirin in patients undergoing CABG. 145 Management of coronary restenosis 146 Modified NO donors ................. 146 NO-generating stent for coronary restenosis.... 146 eNOS gene therapy for restenosis .................. 147 Congestive heart failure ................ 148 NO-based therapy for congestive heart failure . 148 eNOS gene therapy for congestive heart failure ................... 149 Gene transfer of nNOS in congestive heart failure ................ 149 NO-based therapy for management of cardiogenic shock ........... 149 Prophylaxis of cardiovascular disorders ................ 150 Prevention of atherosclerosis with aging.......... 150 Peripheral vascular disorders ......... 150 Peripheral atherosclerotic arterial disease........ 150 Peripheral ischemic disease ...... 151 An eNOS mutant as therapeutic for peripheral vascular ischemia................. 151 Raynaud's phenomenon ........... 152 Neurological disorders .................. 152 Cerebrovascular ischemic disorders 152 Attenuation of NO for neuroprotection in cerebral ischemia.... 153 Us |
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