US20070191478A1 - Methods of treating cardio pulmonary diseases with NO group compounds - Google Patents
Methods of treating cardio pulmonary diseases with NO group compounds Download PDFInfo
- Publication number
- US20070191478A1 US20070191478A1 US11/231,162 US23116205A US2007191478A1 US 20070191478 A1 US20070191478 A1 US 20070191478A1 US 23116205 A US23116205 A US 23116205A US 2007191478 A1 US2007191478 A1 US 2007191478A1
- Authority
- US
- United States
- Prior art keywords
- patient
- disorder
- compound
- blood
- hemoglobin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 93
- 150000001875 compounds Chemical class 0.000 title claims abstract description 92
- 201000006306 Cor pulmonale Diseases 0.000 title 1
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical group CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 claims abstract description 104
- 108010054147 Hemoglobins Proteins 0.000 claims abstract description 77
- 102000001554 Hemoglobins Human genes 0.000 claims abstract description 77
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 71
- 239000001301 oxygen Substances 0.000 claims abstract description 71
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 70
- 239000007789 gas Substances 0.000 claims abstract description 65
- 210000004369 blood Anatomy 0.000 claims abstract description 60
- 239000008280 blood Substances 0.000 claims abstract description 60
- 238000011282 treatment Methods 0.000 claims abstract description 49
- 210000003743 erythrocyte Anatomy 0.000 claims abstract description 47
- 210000004072 lung Anatomy 0.000 claims abstract description 47
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 34
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 34
- 235000018417 cysteine Nutrition 0.000 claims abstract description 34
- HYHSBSXUHZOYLX-WDSKDSINSA-N S-nitrosoglutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CSN=O)C(=O)NCC(O)=O HYHSBSXUHZOYLX-WDSKDSINSA-N 0.000 claims abstract description 33
- 230000036760 body temperature Effects 0.000 claims abstract description 25
- 239000003642 reactive oxygen metabolite Substances 0.000 claims abstract description 25
- 208000018875 hypoxemia Diseases 0.000 claims abstract description 20
- 239000012530 fluid Substances 0.000 claims abstract description 17
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 14
- 208000020446 Cardiac disease Diseases 0.000 claims abstract description 13
- 208000019693 Lung disease Diseases 0.000 claims abstract description 13
- 208000019622 heart disease Diseases 0.000 claims abstract description 13
- 208000019838 Blood disease Diseases 0.000 claims abstract description 12
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 208000014951 hematologic disease Diseases 0.000 claims abstract description 12
- 208000018706 hematopoietic system disease Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 230000001976 improved effect Effects 0.000 claims abstract description 9
- 206010053567 Coagulopathies Diseases 0.000 claims abstract description 8
- 206010019280 Heart failures Diseases 0.000 claims abstract description 8
- 230000017531 blood circulation Effects 0.000 claims abstract description 8
- 208000007056 sickle cell anemia Diseases 0.000 claims abstract description 8
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 7
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 7
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 238000012216 screening Methods 0.000 claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 208000035475 disorder Diseases 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 24
- 230000006872 improvement Effects 0.000 claims description 17
- 230000009885 systemic effect Effects 0.000 claims description 17
- 150000003573 thiols Chemical class 0.000 claims description 17
- 238000005259 measurement Methods 0.000 claims description 15
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 15
- 241001465754 Metazoa Species 0.000 claims description 11
- 208000006673 asthma Diseases 0.000 claims description 8
- 230000002085 persistent effect Effects 0.000 claims description 8
- 238000005070 sampling Methods 0.000 claims description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 6
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 6
- 201000008312 primary pulmonary hypertension Diseases 0.000 claims description 6
- 230000035602 clotting Effects 0.000 claims description 5
- 230000000302 ischemic effect Effects 0.000 claims description 5
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 230000010339 dilation Effects 0.000 claims description 4
- 230000001668 ameliorated effect Effects 0.000 claims description 3
- 210000004204 blood vessel Anatomy 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 208000028867 ischemia Diseases 0.000 claims description 3
- 230000035488 systolic blood pressure Effects 0.000 claims description 3
- 230000000287 tissue oxygenation Effects 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 abstract description 25
- 238000006213 oxygenation reaction Methods 0.000 abstract description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 51
- 229910002089 NOx Inorganic materials 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 230000002685 pulmonary effect Effects 0.000 description 18
- 230000036772 blood pressure Effects 0.000 description 13
- 230000036593 pulmonary vascular resistance Effects 0.000 description 13
- 210000001147 pulmonary artery Anatomy 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 230000007954 hypoxia Effects 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 108010061951 Methemoglobin Proteins 0.000 description 8
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 238000009423 ventilation Methods 0.000 description 8
- 230000004872 arterial blood pressure Effects 0.000 description 7
- 239000002840 nitric oxide donor Substances 0.000 description 7
- 230000008901 benefit Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 241000282887 Suidae Species 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000000004 hemodynamic effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 230000004873 systolic arterial blood pressure Effects 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- 206010008479 Chest Pain Diseases 0.000 description 4
- 108010024636 Glutathione Proteins 0.000 description 4
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 229960004308 acetylcysteine Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 229960003180 glutathione Drugs 0.000 description 4
- 230000001146 hypoxic effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- PGOMVYSURVZIIW-UHFFFAOYSA-N trifluoro(nitroso)methane Chemical compound FC(F)(F)N=O PGOMVYSURVZIIW-UHFFFAOYSA-N 0.000 description 4
- 208000001953 Hypotension Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- -1 Oxygen free radical Chemical class 0.000 description 3
- 206010062237 Renal impairment Diseases 0.000 description 3
- GMZYOWHASMYQLX-UHFFFAOYSA-N [N].CCON=O Chemical compound [N].CCON=O GMZYOWHASMYQLX-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 3
- 229960002428 fentanyl Drugs 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KEJOCWOXCDWNID-UHFFFAOYSA-N Nitrilooxonium Chemical compound [O+]#N KEJOCWOXCDWNID-UHFFFAOYSA-N 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010039163 Right ventricular failure Diseases 0.000 description 2
- 108010001742 S-Nitrosoglutathione Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 238000013276 bronchoscopy Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 2
- 229960000830 captopril Drugs 0.000 description 2
- 229940072645 coumadin Drugs 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- IDNUEBSJWINEMI-UHFFFAOYSA-N ethyl nitrate Chemical compound CCO[N+]([O-])=O IDNUEBSJWINEMI-UHFFFAOYSA-N 0.000 description 2
- 230000005713 exacerbation Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 2
- ONKVXKHGDFDPFZ-UHFFFAOYSA-N perchloryl nitrite Chemical compound O=NOCl(=O)(=O)=O ONKVXKHGDFDPFZ-UHFFFAOYSA-N 0.000 description 2
- 230000036513 peripheral conductance Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 201000004193 respiratory failure Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 239000012414 tert-butyl nitrite Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 1
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000032862 Clinical Deterioration Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- ZUKPVRWZDMRIEO-VKHMYHEASA-N L-cysteinylglycine Chemical compound SC[C@H]([NH3+])C(=O)NCC([O-])=O ZUKPVRWZDMRIEO-VKHMYHEASA-N 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 229910004064 NOBF4 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 108010064719 Oxyhemoglobins Proteins 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 102000029301 Protein S Human genes 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 206010037132 Pseudomonal infections Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000037656 Respiratory Sounds Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- WRFYTQFEOINWQO-UHFFFAOYSA-L [O+]#N.[O+]#N.OP([O-])([O-])=O Chemical compound [O+]#N.[O+]#N.OP([O-])([O-])=O WRFYTQFEOINWQO-UHFFFAOYSA-L 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
- 229960005054 acepromazine Drugs 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005108 alkenylthio group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229960003116 amyl nitrite Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 229940098165 atrovent Drugs 0.000 description 1
- POJCOGNIDQCPQI-UHFFFAOYSA-M azanylidyneoxidanium hydrogen sulfate Chemical compound [O+]#N.OS([O-])(=O)=O POJCOGNIDQCPQI-UHFFFAOYSA-M 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- KEWHKYJURDBRMN-XSAPEOHZSA-M chembl2134724 Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-XSAPEOHZSA-M 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000011976 chest X-ray Methods 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000003017 ductus arteriosus Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 108010036302 hemoglobin AS Proteins 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 230000008696 hypoxemic pulmonary vasoconstriction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 229940063711 lasix Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Chemical group 0.000 description 1
- 239000002184 metal Chemical group 0.000 description 1
- 208000005135 methemoglobinemia Diseases 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 229960003379 pancuronium bromide Drugs 0.000 description 1
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 238000013310 pig model Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000008695 pulmonary vasoconstriction Effects 0.000 description 1
- 230000008704 pulmonary vasodilation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 208000037812 secondary pulmonary hypertension Diseases 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0641—Erythrocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/02—Gases
- A61M2202/0266—Nitrogen (N)
- A61M2202/0275—Nitric oxide [NO]
Definitions
- This invention relates to the treatment of respiratory, cardiac and blood disorders by delivery into the lungs of compound comprising NO substitute.
- Inhaled NO is used to treat elevated pulmonary pressures and pulmonary disorders associated with hypoxemia.
- This method of treatment provides distribution tightly matched to perfusion and local effect because of rapid trapping of inhaled NO by hemoglobin.
- this method of treatment can be readily carried out by an anesthesiologist or a critical care physician who is used to administering gases.
- Side effects include reaction of NO with oxygen or reactive oxygen species to produce NO 2 or other toxic NO x , the toxicity of which is manifested by inflammation, airway hypereactivity, hemorrhage, delay in clinical improvement, renal impairment or death, and reaction with oxyhemoglobin to interfere with its oxygen delivery function, e.g., by forming methemoglobin.
- NO donor is present as solid particles or as particles of liquid.
- This alternative cannot fully avoid the NO 2 /NO x toxicity problem associated with administration of NO but may produce longer lasting effects than inhaled NO.
- the distribution in the lungs is according to particle size and is not matched to perfusion so some NO donor deposits in places where it does not reach the blood or small airways.
- these NO compounds have systemic smooth muscle relaxing effects greater than pulmonary effects, which limit usage for treating pulmonary disorders.
- this method is not as readily carried out by an anesthesiologist since anesthesiologists do not normally administer aerosols or powders.
- NO donors have additional toxicities, that is, they possess toxicities that are unrelated to NO, but that are instead related to the group to which NO is attached or from which NO is generated.
- the disadvantages of administering nebulized NO donor are indicated to be meaningful by the fact that inhaled gaseous NO is approved for use over inhaled liquid or inhaled solid NO-releasing compound.
- One embodiment herein is directed to a method for treating a pulmonary disorder associated with hypoxemia and/or smooth muscle constriction in the lungs and/or inflammation in the lungs in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving effect and a smooth muscle constriction relieving effect and/or an anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature or exert systemic blood pressure compromising effect.
- Another embodiment herein is directed at a method of treating a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, whereby delivering into the lungs causes a systemic effect but does not compromise blood pressure.
- Still another embodiment herein denoted the third embodiment, is directed at a method of treating a blood disorder which is ameliorated by treatment with NO in a patient having said disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, whereby delivery into the lungs causes a desired systemic effect.
- Still another embodiment herein denoted the fourth embodiment, is directed to a method for treating a patient in need of improvement in tissue oxygenation or dilation of a blood vessel or inhibition of clotting (improved oxygenation, blood flow and/or thinning of blood), said method comprising providing in the patient a therapeutically effective amount of red blood cells loaded with nitrosylated hemoglobin, thereby to cause improved oxygen delivery or blood flow.
- the red blood cells loaded with nitrosylated hemoglobin can be provided in the patient by methods comprising, for example, (1) delivering into the lungs of the patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in the blood; (2) infusing into the patient a solution of a compound which reacts preferentially with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90; and (3) transfusing into the patient blood containing red blood cells loaded with
- Exemplary of compound useful in the first, second and third embodiments and in (1) of the fourth embodiment is ethyl nitrite, which is also known as O-nitrosoethanol, used in gaseous form.
- Advantages of embodiments herein include: (1), elimination of the toxicity caused by NO 2 /NO x formation when NO is administered; (2), the option of administering the compound comprising NO group together with oxygen, without NO 2 /NO x production; (3), no interference with the oxygen carrying function of hemoglobins since compounds administered herein do not react with heme in hemoglobin, so the physiological level in blood of methemoglobin will be less than 5% in blood; (4), NO bioactivity is preserved when the compound administered reacts with cysteine of hemoglobin; (5), is more efficient and selective at loading hemoglobin cysteine with NO group than free NO or nebulized nitric oxide-releasing compound liquid or solid; (6), the advantages associated with administration of a gas including matching ventilation to blood perfusion (ideal distribution), relatively localized lung effect compared to normal systemic administration of solutions and familiarity of anesthesiologists with the procedure whereby the administration is carried out; (6), less expensive administration since administration can be carried out using a ventilator rather than the very expensive
- NO x means NO, N 2 O 3 , N 2 O 4 , OONO ⁇ , OONO ⁇ and any products of their interaction or their reaction with NO or NO 2 .
- reactive oxygen species is singlet oxygen, superoxide, hydrogen peroxide or hydroxyl radical.
- hypoxemia means low blood oxygen content compared to normal, i.e., a hemoglobin saturation less than 95% and a PaO 2 less than 90 in arterial blood in someone breathing room air.
- Pa O2 means the partial pressure of oxygen in gases in arterial blood.
- red blood cells loaded with nitrosylated hemoglobin means red blood cells containing from 100 nanomolar to 10 micromolar nitrosylated hemoglobin, above baseline, preferably from 100 nanomolar to 1 micromolar above baseline. In the red blood cells, the nitrosylated hemoglobin is in equilibrium with nitrosoglutathione.
- the term “rebound” is used to mean lowering in blood oxygen level or increase in pulmonary artery pressure or resistance after increased blood oxygen level or decreased pulmonary vascular pressure/resistance is obtained by treatment, by at least 10%, when used in relation to blood oxygen levels or pulmonary hypertension, and in general means decrease from improvement after treatment.
- One additional embodiment denoted the fifth embodiment, is directed to red blood cells loaded with nitrosylated hemoglobin, outside the body.
- Another additional embodiment denoted the sixth embodiment, is directed to a method of screening for drugs that increase the level of nitrosoglutathione in airway lining fluid, comprising administering a putative drug in gas form into the lung of a model animal, sampling airway lining fluid from the animal, and assaying for nitrosoglutathione in the sample obtained by sampling.
- FIG. 1 depicts graphs of pulmonary artery pressure for three doses of ethyl nitrite gas and shows results of Example I.
- FIG. 2 depicts graphs of pulmonary vascular resistance for three doses of ethyl nitrite gas and shows results of Example I.
- FIG. 3 depicts graphs of pulmonary artery flow for three doses of ethyl nitrite gas and shows results of Example I.
- FIG. 4 depicts graphs of cardiac output for two doses of ethyl nitrite gas and shows results of Example I.
- FIG. 5 depicts graphs of mean blood pressure for three doses of ethyl nitrite gas and shows results of Example I.
- FIG. 6 depicts graphs of heart rate for three doses of ethyl nitrite gas and shows results of Example I.
- FIG. 7 shows gas chromatography/mass spectral analysis results on ethyl nitrite gas delivered through the ventilation system of Example I at 75 ppm.
- FIG. 8 depicts graphs of PaO 2 (i.e., Pa O2 ) level without treatment, with treatment with ethyl nitrite (EtONO), post EtONO treatment, with treatment with NO, and post NO treatment and shows results of Example XII.
- EpONO ethyl nitrite
- FIG. 9 depicts graphs of change in cardiac output without treatment, with treatment with ethyl nitrite (EtONO), post EtONO treatment, with treatment with NO, and post NO treatment and shows results of Example XII.
- EtONO ethyl nitrite
- FIG. 10 is a graph of fold increase in airway SNO (nitrosoglutathione) with ppm of inhaled EtNO (ethyl nitrite) versus inhaled NO and shows results of Example XIV.
- FIGS. 11A, 11B , 11 C and 11 D are graphs of tension versus time and show results of Example XV.
- a pulmonary disorder associated with smooth muscle constriction in lungs and/or hypoxemia and/or inflammation in the lungs in a patient having such disorder comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving effect and a smooth muscle constriction relieving effect and an anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature or exert systemic blood pressure compromising effect.
- the pulmonary disorders treatable by this method include, for example, pulmonary hypertension including persistent pulmonary hypertension in human babies and primary and secondary pulmonary hypertension in human adults, acute respiratory distress syndrome (ARDS), asthma, cystic fibrosis and respiratory failure.
- pulmonary hypertension including persistent pulmonary hypertension in human babies and primary and secondary pulmonary hypertension in human adults
- ARDS acute respiratory distress syndrome
- asthma cystic fibrosis and respiratory failure.
- Pulmonary hypertension is associated with smooth muscle constriction in the lungs and it can be associated with hypoxemia.
- ARDS is a radiographic manifestation associated with low oxygen content in blood and typically is also associated with elevated pulmonary pressures.
- Oxygen free radical injury contributes to the pathophysiology. Free NO can aggravate the injury by reacting with oxygen free radicals to form toxic products of reaction (i.e., they damage tissues), but the compounds administered herein do not have this effect because they do not react with oxygen free radicals. Inhaled NO has been showing to result in increased morbidity and mortality. This disorder is associated with hypoxemia and it can be associated with smooth muscle constriction in the lungs.
- Asthma is associated with smooth muscle constriction in the lungs and can be associated with hypoxemia.
- Cystic fibrosis is associated with smooth muscle construction in the lungs and can be associated with hypoxemia.
- These compounds include, for example, those having the formula RX—NO y where R is either not present or is hydrogen/proton or C 1 -C 7 -alkyl and X is an oxygen, sulfur, nitrogen or metal selected, for example, from the group consisting of iron, copper, ruthenium and cobalt atoms or an alkyl or alkenyl or alkylthio or alkenylthio group containing from 1 to 7, e.g., 1 to 6, carbon atoms which is straight chain or branched, CF 3 — and CF 3 S—, and y is 1 or 2, excluding nitrogen dioxide and NO x .
- Specific treating agents for use herein include, for example, ethyl nitrite (which is used in examples herein), methyl nitrite, tert-butyl nitrite, isoamyl nitrite; trifluoronitrosomethane (CF 3 NO), CF 3 SNO, CH 3 SNO, CH 2 ⁇ CHSNO, CH 2 ⁇ CHCH 2 SNO, ONSCH 2 —CH 2 —CH 2 SNO and CH 3 CH 2 CH 2 SNO.
- Alkyl nitrites can be prepared as described in Landscheidt et al. U.S. Pat. No. 5,412,147.
- Ethyl nitrite is available commercially, e.g., diluted in ethanol.
- CF 3 NO is a commercial product or can be made by treatment of CF 3 I with NO ⁇ as described in J. Phys. Chem. 100, 10641 (1996).
- Aliphatic thionitrites i.e., compounds of the form RSNO where R describes an alkyl or alkenyl or hydrogen moiety, can be prepared by treatment of the corresponding thiol with a source of NO + including, but not limited to, one or more of the following: tert-butyl nitrite, ethyl nitrite, nitrosonium tetrafluoborate (NOBF 4 ), nitrosonium perchlorate (NOClO 4 ), nitrosonium hydrogen sulfate (NOHSO 4 ), nitrosonium hydrogen phosphate (NOH 2 PO 4 ), or HCl-acidified solutions of sodium nitrite.
- Dilution for example, to a concentration of 1 to 100 ppm is typically appropriate.
- the diluted gas is readily delivered into the lungs, using a ventilator which is a conventional device for administering gases into the lungs of a patient.
- a tube attached to the device passes the gas into the lungs at a rate and pressure consistent with maintaining a Pa O2 of 90 mm Hg.
- Time periods of administration typically range from 1 minute to two or more days, and administration is carried out until symptoms abate. Administration can also be carried out using a face mask.
- a therapeutically effective amount is administered. This is a hypoxemia relieving effective and smooth muscle constriction relieving and an anti-inflammatory or inflammation defending (against) effective amount. Administration is carried out for as long as symptoms ameliorate.
- the dosage will vary from patient to patient. Upon administration, results are noted with variation in dosage and then the dosage is preferably used where the best results are achieved. The most effective dosage can be lower than some of the dosages tried; thus, if after increases in dosage are tried, an increased dosage provides less improvement, then return to the more effective lower dose is indicated.
- the ideal dosage matches ventilation to perfusion.
- Ethyl nitrite is readily delivered to the patient in gaseous form by bubbling N 2 or O 2 through a Milligan gas diffuser containing ethyl nitrite diluted in ethanol (e.g., from 0.00125 to 0.5% ethyl nitrate in ethanol (v/v), preferably from 0.0025 to 0.125% ethyl nitrite in ethanol (v/v)), e.g., at a flow rate of 0.5 liters/min to 1.5 liters/min, to produce N 2 or O 2 containing ethyl nitrite and introducing this into the ventilation system by mixing the output from the ventilator at a total of 5 to 15 liters/min with the N 2 or O 2 containing ethyl nitrite, for example, to produce a concentration of 1 to 100 ppm ethyl nitrite in the resulting gas, and delivering this to the patient at a rate and pressure to maintain Pa O2 at 90 mm
- An advantage for treatment using ethyl nitrite compared to administration of NO is that no new equipment is needed for ethyl nitrite administration whereas a machine costing tens of thousands of dollars is required to administer NO. Thus, it is less expensive to administer ethyl nitrite than it is to administer NO.
- ethyl nitrite improves oxygenation without the toxic NO 2 and NO x formation associated with administration of NO and without the rebound to lower oxygen levels or higher pulmonary pressures once administration is stopped that is characteristic of what occurs on administration of NO.
- ethyl nitrite stops cardiac output from going down in disease. This is not the case for administration of NO.
- administration of ethyl nitrite is better than administration of NO in raising the level of NO bound to cysteine in hemoglobin.
- nitrosoglutathione loading (that is increase in nitrosoglutathione in airway lining fluid) is the basis for the improved oxygenation without rebound to lower levels after administration is stopped and the stopping of cardiac output from going down.
- Administration of ethyl nitrite causes glutathione loading whereas administration of NO does not.
- ethyl nitrite compared to NO is that, unlike NO, it can be administered in oxygen.
- NO is not stable in oxygen and has to be given in a nitrogen base which dilutes inspired O 2 concentration. Because of this, a patient that is given inhaled NO gas cannot be given a higher concentration of O 2 than 95%.
- ethyl nitrite can be given with 100% O 2 and does not dilute oxygen concentration at all, so a patient given inhaled ethyl nitrite can be given a higher concentration of oxygen than a patient given inhaled NO. Therefore, in the treatment of persistent pulmonary hypertension, babies that required 100% oxygen can be continued on 100% oxygen when ethyl nitrite is administered whereas the final inspired concentration of oxygen drops when NO is administered.
- a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder
- said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature.
- the cardiac disorders treatable by this method include angina, myocardial infarction, heart failure and hypertension.
- the NO-group containing compound administered is one that reacts with cysteine in hemoglobin as discussed below, e.g., ethyl nitrite, and that a thiol also be administered systemically or by inhaled route to promote systemic release of NO from binding to cysteine of hemoglobin.
- the NO-containing compound administered is one that reacts with cysteine in hemoglobin, e.g., ethyl nitrite
- a thiol also be administered systemically (e.g., intravenously or orally or nebulized) or by inhaled route to cause systemic release of NO from binding to cysteine of hemoglobin.
- Suitable thiols include, for example, N-acetylcysteine (dosage, e.g., ranging from 50 to 200 mg/kg intravenously or 600 mg three times a day orally or nebulized according to the FDA approved PDR dosage, with a preferred route of administration being intravenous or nebulized), glutathione (dosage, e.g., ranging from 50 to 200 mg/kg with preferred route of administration being intravenous), and cysteinylglycine (dosage, e.g., ranging from 50 to 200 mg/kg with preferred route of administration being intravenous).
- concentrations of NO-containing compound and methods of administration applicable to the method of treating a pulmonary disorder described above are applicable to the method herein for treating cardiac disorders.
- a therapeutically effective amount of NO-containing compound in gas form is administered in the method herein for treating cardiac disorders.
- This is a chest pain reducing effective amount for angina, a heart failure resolving effective amount for myocardial infarction, a pulmonary pressure reducing and peripheral vascular resistance reducing effective amount for heart failure and a blood pressure lowering effective amount for hypertension.
- the most effective dosage will vary from patient to patient, so it is preferred in each case to try a plurality of dosages and then to utilize dosage where the best results were achieved.
- ethyl nitrite for treating cardiac disorders, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- a blood disorder in a patient having said disorder comprising delivering into the lungs of said patient. as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature.
- the blood disorders are those ameliorated by treatment with NO or related molecules, i.e., where NO would change the shape of red blood cells to normal or restore their function to normal or would cause dissolution of blood or blood platelet clots.
- NO would change the shape of red blood cells to normal or restore their function to normal or would cause dissolution of blood or blood platelet clots.
- DIC disseminated intravascular coagulation
- heart attack stroke
- stroke Coumadin induced clotting caused by Coumadin blocking protein C and protein S.
- concentrations of NO-containing compound and methods of administration applicable to the method for treating a pulmonary disorder described above are applicable to the method herein for treating blood disorders.
- a therapeutically effective amount of NO-containing compound in gas form is administered in the method herein for treating blood disorders.
- This is a red blood cell shape restoring and/or red blood cell function restoring effective amount for sickle cell disease and a clot dissolving and/or clot formation preventing amount for clotting disorders.
- the most effective dosage will vary from patient to patient, so it is preferred in each case to try a plurality of dosages and then to utilize the dosage where the best results were achieved.
- the NO-group containing compound administered for treating a blood disorder is one that reacts with cysteine in hemoglobin
- Suitable thiols, dosages and routes of administration are those described in conjunction with thiols above.
- ethyl nitrite for treating blood disorders, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- This method finds applicability, for example, in treating patients affected with sickle cell disease and ischemic disorders, e.g., angina, heart attack or stroke.
- ischemic disorders e.g., angina, heart attack or stroke.
- the red blood cells loaded with hemoglobin are provided in the patient by a method comprising delivering into the lungs of the patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in blood.
- a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in blood This case will be referred to hereinafter as the first case of the fourth embodiment.
- concentrations of NO-containing compound and methods of administration applicable to the method of treating a pulmonary disorder described above are applicable to the method herein for treating the first case of the fourth embodiment.
- a therapeutically effective amount for the first case of the fourth embodiment is an oxygen delivery or blood flow increasing or blood thinning effective amount.
- the NO-group containing compound administered for treating the first case of the fourth embodiment is one that reacts with cysteine in hemoglobin
- Suitable thiols, dosages and routes of administration are those described in conjunction with thiols above.
- ethyl nitrite for treating the first case of the fourth embodiment, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- Measurement of nitrosylated hemoglobin in the blood can be carried out as described in Jia, L., et al., Nature, Vol. 380, 221-226 (1996).
- the red blood cells loaded with hemoglobin are provided in the patient by a method comprising infusing into the patient a solution of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 or NO x in the presence of oxygen or reactive oxygen species at body temperature in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90.
- the limitation about blood pressure is included because ethyl nitrite when infused as a liquid, causes a drop in blood pressure. This case will be referred to hereinafter as the second case of the fourth embodiment.
- the compounds for use in the second case of the fourth embodiment can be the same as those used in the first case of the fourth embodiment but unlike in the first case of the fourth embodiment, they are infused in liquid form instead of being administered as gases.
- the liquid form can be obtained by administering the compounds dissolved in a solvent, e.g., a protic solvent such as an alcohol.
- a solvent e.g., a protic solvent such as an alcohol.
- Ethyl nitrite dissolved in ethanol to provide an ethanol solution containing 0.00125 to 0.5 percent (v/v) ethyl nitrite is a preferred agent for the second case of the fourth embodiment and the solution more preferably contains 0.0025 to 0.125 percent ethyl nitrite (v/v).
- a therapeutically effective amount for the second case of the fourth embodiment is an oxygenation improving or blood flow improving effective amount.
- Administration of the solution of compound that reacts with cysteine in hemoglobin and/or dissolves in blood is preferably carried out intravenously.
- the NO-group containing compound administered for treating is one that reacts with cysteine in hemoglobin
- Suitable thiols, dosages and routes of administration including intravenously, orally and nebulized, are those described in conjunction with thiols above.
- the red blood cells loaded with hemoglobin are provided in the patient by a method comprising transfusing into the patient blood containing red blood cells loaded with nitrosylated hemoglobin.
- the blood containing red blood cells loaded with hemoglobin can be obtained by incubating blood for 1 minute to 1 hour, e.g., 1 minute to 10 minutes, at 25 to 37° C. with a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 or NO x in the presence of oxygen of reactive oxygen species at body temperature.
- the compounds can be the same as those described above for compound that reacts with cysteine and/or dissolves in blood and has an NO group which is bound in the compound so that it does not form NO 2 or NO x in the presence of oxygen or reaction oxygen species at body temperature.
- the incubation is preferably carried out by incubating blood with an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite, preferably containing from 0.0025 to 0.125% (v/v) ethyl nitrite, with the amount of ethyl nitrite to hemoglobin present for incubation ranging from 1:1000 to 10:1, preferably from 1:100 to 10:1.
- This case will be referred to hereinafter as the third case of the fourth embodiment.
- thiol is co-administered for the third case of the fourth embodiment.
- Suitable thiols, dosage and routes of administration are those described in conjunction with thiol administration above.
- a therapeutically effective amount of red blood cells loaded with nitrosylated hemoglobin is 0.1 to 3 units of blood having nitrosylated hemoglobin increased 0.1 to 1 micromolar over baseline or equivalent.
- Administration is preferably carried out by transfusion.
- Model animals include, for example, neonatal pigs, guinea pigs, rats and dogs.
- a sample of airway lining fluid is readily obtained by bronchoscopy.
- Assay for nitrosoglutathione in sample is readily carried out, for example, as described in Gaston, B., et al., PNAS, Vol. 90, 10957-10961 (1993).
- a level indicating increase of nitrosoglutathione at least 50% above baseline indicates a candidate for a drug for increasing level of nitrosoglutathione in airway lining fluid of mammals including humans.
- the experiment was carried out using a pig model of pulmonary hypertension as follows:
- a catheter was placed in the carotid artery for measurement of systolic arterial pressure (SAP). After the tracheostomy, halothane was discontinued, assisted ventilation was started, and paralysis was obtained using pancuronium bromide (0.1 mg/kg) every 45 minutes. Further bolus doses of fentanyl (5-10 ⁇ g/kg) were administered as necessary.
- SAP systolic arterial pressure
- a 22-gauge catheter was inserted into the root of the pulmonary artery through a purse string suture for the continuous measurement of pulmonary artery pressure (PAP).
- the systemic and pulmonary catheters were connected to pressure transducers and together with the ECG signal, displayed on a neonatal monitor (Model 78833B, Hewlett Packard, Waltham, Mass.).
- Systemic oxygen saturation (SaO 2 ) was measured using a subcutaneous pulse oximeter (N200, Nellcor Inc., Hayward, Calif.).
- a continuous infusion of bicarbonate (15 mEq/100 mL of i.v. fluid) was given to prevent severe acidosis during periods of hypoxia. Cardiac output was determined from measurements of the calibrated ultrasonic flow probe.
- hypoxia was induced by reduction of the inspired oxygen concentration to 10 to 14% to produce a target SaO 2 of 35 to 45%.
- a stable hypoxic baseline was obtained (2 minutes).
- An arterial blood specimen was obtained for the measurement of blood gases and methemoglobin.
- Ethyl nitrite (EtONO) was then administered according to a computer-generated random sequence in doses of 1.5, 15 or 75 ppm by changing the EtONO concentration (at a fixed flow rate), maintaining the fractional inspired oxygen saturation (FiO 2 ) at the same level.
- the ethyl nitrite was administered with nitrogen by introducing nitrogen ethyl nitrite admixture into the ventilation system by mixing the output from the ventilator with said admixture.
- the ethyl nitrite nitrogen admixture was generated by bubbling nitrogen through a Milligan gas diffuser (Fisher Scientific) containing ethyl nitrite diluted in ethanol (0.075% (v/v) ethyl nitrate) at a flow rate of 0.6 liters/min to produce nitrogen containing ethyl nitrite which is then blended in the ventilator with the incoming gas for a flow rate of 6 liters/min.
- the concentration of ethyl nitrite in the gas to be administered is directly proportional to the flow of nitrogen into the Milligan gas diffuser and/or the concentration of ethyl nitrite in ethanol.
- the physiologic parameters of interest were acquired through a personal computer (Dell 486/33, Dell Computer Corporation, Richmond Hill, Ontario, Canada) using an analog-to-digital converter (DT 2801, Data Translation Inc., Marborough, Mass.).
- Software for acquisition analysis was written using Asyst Scientific Software System (Macmillan Software Co., New York, N.Y.). With this software, continuous acquisition of the measured parameters was performed for a 2-minute period at baseline, and a 1-minute period after stability during each hypoxic EtONO exposure. The computer-generated averages of the measured parameters were then utilized for subsequent analyses.
- the time responses of the changes in PAP were similarly analyzed using the average values for 1 second for the PAP to determine the time response of the change in PAP compared to baseline.
- Results are shown in FIGS. 1-6 .
- FIG. 1 depicts graphs of PAP in mm Hg for the three concentrations of EtONO administration with data points at baseline, hypoxia (stable hypoxic baseline), EtONO (when no further changes in PAP for one minute), post EtONO (4 minutes after EtONO discontinuance) and baseline (when PAP normalized, approximately 4 minutes after post EtONO data).
- hypoxia stable hypoxic baseline
- EtONO when no further changes in PAP for one minute
- post EtONO 4 minutes after EtONO discontinuance
- baseline when PAP normalized, approximately 4 minutes after post EtONO data.
- the data shows hypoxia increased PAP and that EtONO administration reverses hypoxic pulmonary vasoconstriction.
- FIG. 2 depicts graphs of PVR in dynes ⁇ 5 ⁇ cm ⁇ 1 for the three concentrations of EtONO administration with data points at the same stages as for FIG. 1 .
- the data shows hypoxia increased PVR and that EtONO administration restores PVR toward initial baseline.
- any progressive loss of effect of hypoxia on pulmonary vascular hemodynamics is consistent with a positive effect of EtONO.
- FIG. 3 depicts graphs of pulmonary artery flow in minimum for the three concentrations of EtONO administration with data points at the same stages as for FIG. 1 .
- the data shows EtONO administration increases pulmonary artery flow at 75 ppm.
- FIG. 4 depicts graphs of cardiac output in ml/min for two concentrations of EtONO administration with data points at the same stages as for FIG. 1 .
- the data shows that EtONO administration tends to normalize the hypoxia induced increase in cardiac output.
- FIG. 5 depicts graphs of mean blood pressure in mm Hg for three concentrations of EtONO administration with data points at the same stages as for FIG. 1 .
- the data shows that EtONO administration has no effect on blood pressure.
- FIG. 6 depicts graphs of heart rate in beats per minute for three concentrations of EtONO administration with data points at the same stages as for FIG. 1 .
- the data shows that EtONO administration has no effect on heart rate.
- a 30-year-old white female with pulmonary pressures of 70/40 mm Hg is admitted into an intensive care unit and deteriorates due to right heart failure, and is given for inhalation through a face mask an admixture of O 2 , N 2 and ethyl nitrite such that the Pa O2 is maintained at 90 and ethyl nitrite is present at 70 ppm. Pulmonary pressures fall to 30/15 and right heart failure disappears.
- an identical patient receives the same treatment except for 80 ppm inhaled NO in place of the 70 ppm ethyl nitrite. Pulmonary pressures drop but the patient develops airway hyperreactivity (slight wheezing) and a chemiluminescence analyzer shows threefold increase in NO 2 concentration in exhaled air. Moreover, methemoglobin content in the blood is measured at 10%. The patient is switched from NO to inhaled ethyl nitrite (70 ppm), and NO 2 and methemoglobin levels drop and recovery is maintained.
- a 60-year-old male cancer patient develops radiographic changes consistent with ARDS, post-chemotherapy.
- the patient's Pa O2 falls to 50 mm Hg despite being on 100% oxygen and a right heart catheterization reveals a normal left ventricular endiastolic pressure.
- the patient is administered 40 ppm inhaled ethyl nitrite.
- the Pa O2 increases to 70 mm Hg.
- a 26-year-old white female asthmatic gets intubated because of a severe asthmatic exacerbation.
- the patient is administered nebulized epinephrine and Atrovent but is failing to ventilate.
- the physician adds 100 ppm inhaled ethyl nitrite via a rebreathing face mask to the treatment, and the patient's Pa O2 improves from 60 to 80 and ventilation becomes easier as evidenced by lower airway pressures (lung compliance).
- a 12-year-old girl with cystic fibrosis presents with pseudomonal infection leading to pulmonary exacerbation.
- the patient is given nebulized antibiotics but continues to spike fever and do poorly.
- Inhaled ethyl nitrite is given at 80 ppm in oxygen with resolution of the infection over four days.
- a 65-year-old white male is admitted to a hospital with unstable angina.
- the patient is given i.v. nitroglycerin, heparin and a beta blocker.
- nitroglycerin, heparin and a beta blocker is given.
- the patient continues to experience intermittent-chest pain at rest.
- the patient is given 20 ppm inhaled ethyl nitrite in oxygen.
- the chest pain resolves.
- a 70-year-old white male presents with myocardial infarction.
- the patient's hematocrit is 26.
- the patient is given two units of blood but goes into heart failure.
- the patient is started on 60 ppm inhaled ethyl nitrite in nitrogen, with resolution of the heart failure.
- the patient also receives the standard medical regimen of tissue plasminogen activator, a beta blocker and an ACE inhibitor.
- An 80-year-old presents with stage 3 biventricular failure and pulmonary arterial pressures of 50/30.
- the patient is given Captopril, digoxin and lasix but still has a systemic pressure of 140/80 with increased vascular resistance.
- the patient receives 80 ppm inhaled ethyl nitrite gas in oxygen.
- the patient's pulmonary pressures drop to 20/10 and systemic arterial pressure drops to 100/80 with normal peripheral vascular resistance. Ethyl nitrite administration is stopped and the pressures remain low.
- a 40-year-old black male presents with malignant hypertension (blood pressure of 240/160).
- the patient receives Captopril and nitroprusside and blood pressure drops to 200/120.
- the patient receives 80 ppm inhaled ethyl nitrite in nitrogen over the next day with an intravenous bolus of 200 mg/kg N-acetylcysteine administered at 6 hours after ethyl nitrite therapy was started. Blood pressure drops to 170/95.
- a 60-year-old white male with leukemia presents with disseminated intravascular coagulation.
- a digit becomes ischemic.
- the patient is started on 80 ppm inhaled ethyl nitrite in oxygen and is given 100 mg/kg infusion of N-acetylcysteine. Blood flow improves to the digit.
- pulmonary hypertension was induced in intubated neonatal pigs breathing 100% oxygen by repeated saline lavage (to remove surfactant), until the Pa O2 fell below 100 mm Hg and stayed there for 30 minutes.
- Either NO or ethyl nitrite (EtONO) was administered by 2 hours. The NO was administered at 20 ppm for 10 minutes followed by 5 ppm. The EtONO was administered at 20 ppm. Results presented here are for Pa O2 ( FIG. 8 ) and for cardiac output ( FIG. 9 ).
- EtONO administration caused significant increase in Pa O2 at the two hour mark and post treatment there was further improvement.
- NO administration caused significant increase in Pa O2 at the 2 hour mark but post treatment there was rebound and lowering of Pa O2 .
- For EtONO there was no change or better Pa O2 levels for 20 minutes after administration was discontinued.
- For NO there was a change for the worse 3 minutes after administration was discontinued.
- both drugs decreased pulmonary vascular resistance to comparable degrees but rebound occurred when NO was discontinued whereas pulmonary vascular resistance remained unchanged when EtONO was discontinued.
- EtONO administration caused increase in cardiac output from a level of minus 40% from normal (control animal had heart failure) to a significant increase in cardiac output to minus 27% from normal at the time of discontinuance of administration and further increase in cardiac output to about minus 20% from normal after discontinuance of treatment whereas NO administration did not cause significant increase in cardiac output.
- Ethyl nitrite has been used under the direction of one of the inventors herein to treat four human babies with persistent pulmonary hypertension and/or hypoxemia. The results were dramatic improvement in blood oxygen levels, no rebound, no methemoglobinemia and improvement in cardiac output. Pressor support was able to be stopped within a short period of time after EtONO therapy was started. One baby responded to ethyl nitrite that did not respond to NO.
- Ethyl nitrite has been used to treat six adults with primary pulmonary hypertension. The results were improvement in blood oxygen levels, decrease in pulmonary vascular resistance and improvement in cardiac output.
- a baby with persistent pulmonary hypertension administered epinephrine as required to maintain blood pressure was administered 1.5 ppm ethyl nitrite (EtONO) for 15 minutes, then increasing to 75 ppm EtONO for the next 15 minutes, then 75 ppm EtONO for the next 30 minutes, then 15 ppm EtONO for the next 3 hours whereupon administration was stopped for 29 minutes and then NO was administered according to conventional treatment for 4 hours.
- the EtONO was administered via ventilator in the gas being administered via the ventilator.
- the initial Pa O2 was 29 which is not compatible with life (and means the baby was dying).
- the Pa O2 increased to 54 at the conclusion of EtONO therapy, then further increased to 86 during the about 30 minutes between treatments.
- Ethyl nitrite (EtONO) or NO was added to the inhaled gas of neonatal pigs in doses as shown in FIG. 10 .
- the EtONO was added at 0.6 liters/min into room air (20% oxygen).
- the NO was blended with 100% nitrogen.
- airway lining fluid in lung was sampled by bronchoscopy. Aspirates were collected in phosphate buffered saline (PBS) containing 100 ⁇ M diethylenetriaminepentaacetic acid and assayed immediately for SNO content by chemical reduction-chemiluminescence, and for protein content by the Lowry method.
- PBS phosphate buffered saline
- SNO concentrations normalized to protein content are expressed as fold increase over endogenous levels (0.145 ⁇ 0.03 nM/ ⁇ g for NO group, 0.22 ⁇ 0.04 nM/ ⁇ g for EtONO group).
- Results are given in FIG. 10 where EtONO and NO doses expressed in ppm denote the X-axis and the Y-axis is fold increase in SNO.
- EtONO at the lowest dose caused a 5-fold increase in GSNO and at all doses there is at least this increase.
- NO is shown to give a slight increase in SNO suggesting that most of the NO participates in an alternative chemical reaction with O 2 and/or reactive oxygen species which would be a basis for its toxicity.
- EtONO loads natural glutathione to increase the pool of nitrosoglutathione (GSNO).
- FIG. 7 indicates that this occurs without the release of NO.
- EtONO administration selectively repletes lung SNO (i.e., increases SNO without causing the toxic effects that NO causes). Since depletion of GSNO occurs in patient's airway lining fluid with cystic fibrosis, asthma, hypoxemia and respiratory failure, treatment of these with EtONO is suggested.
- the data here suggests that a mechanism for the effect of EtONO is formation of GSNO whereas the mechanism for effect of NO is the relaxation effect of NO.
- Direct administration of GSNO into the lungs has to be carried out by nebulizing.
- GSNO GSNO deposits in larger airways and does not cross cells
- nebulizing it into the lungs does not cause it to distribute evenly.
- patients cannot tolerate GSNO administration since it causes then to cough. Because of this, N-acetylcysteine administration has been tried; it does not work to increase GSNO levels.
- direct administration of GSNO is not a substitute or alternative or equivalent for the invention herein.
- EtONO inhaled ethyl nitrite
- the patient's red blood cells were drawn from an indwelling arterial line and measurements were carried out in rabbit aortic bioassays on intact red blood cells and on hemolysate obtained by lysing red blood cells with hypotonic saline.
- the rabbit aortic bioassays were carried out on rabbit aorta pieces hung on stirrups and attached to force transducers and measurement was carried out for increase and decrease in tension as described in Stamler, J., et al., PNAS, Vol. 89, 444-448 (1992). Assay was carried out at approximately 1% oxygen to simulate what would occur in tissues (which contain low Pa O2 ). The results are shown in FIGS.
- 11A control for intact red blood cells, no treatment
- 11 B intact red blood cells, EtONO treatment
- 11 C control for hemolysate, no treatment
- 11 D hemolysate, EtONO treatment
- FIG. 11A one sees a small transient decrease induced by native red blood cells, but as shown in FIG. 11B , a significantly greater drop in tension induced by red blood cells from the EtONO treated patient.
- the reason for the ensuing increase in tension is that exporter in red blood cells releases all the activity. However, the activity is shown to be more than enough to achieve the biological effect desired.
- FIG. 11C shows hemolysate from native blood cells produces a very small relaxation under low Pa O2 followed by a contraction
- FIG. 11D shows hemolysate from blood cells from an EtONO treated patient produces a stronger dilation and no contraction compared to baseline.
- Red blood cells are incubated with an alcohol solution of ethyl nitrite containing various concentrations of ethyl nitrite with a mole ratio of 1:50 ethyl nitrite to hemoglobin at 37° C. for 15 minutes.
- the result is red blood cells loaded with nitrosylated hemoglobin and nitrosylated glutathione in equilibrium and containing about 10 ⁇ M S-nitrosylated hemoglobin.
- red blood cells are useful, for example, for treating sickle cell disease or ischemic disorder, e.g., angina.
- Neonatal pigs as in Example XIV are administered inhaled gaseous drugs. After 5 minutes, airway lining fluid is sampled and assayed for nitrosoglutathione (GSNO) by the method described in Gaston, B., et al., PNAS, Vol. 90, 10957-10961 (1993). Screening shows that ethyl nitrite and amyl nitrite, but not NO, increase GSNO in airway lining fluid more than 50% compared to baseline.
- GSNO nitrosoglutathione
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Emergency Medicine (AREA)
- Diabetes (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
Treatment of pulmonary disorders associated with hypoxemia and/or smooth muscle constriction and/or inflammation comprises administering into the lungs as a gas a compound with an NO group which does not form NO2/NOx in the presence of oxygen or reactive oxygen species at body temperature. Treatment of cardiac and blood disorders, e.g., angina, myocardial infarction, heart failure, hypertension, sickle cell disease and clotting disorders, comprises administering into the lungs as a gas, a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2/NOx in the presence of oxygen or reactive oxygen species at body temperature. Exemplary of the compound administered in each case is ethyl nitrite. Treatment of patient in need of improved oxygenation, blood flow of and/or thinning of blood comprises providing in the patient a therapeutic amount of red blood cells loaded with nitrosylated hemoglobin. A method is directed to screening drugs that increase level of nitrosoglutathione in airway lining fluid.
Description
- This invention relates to the treatment of respiratory, cardiac and blood disorders by delivery into the lungs of compound comprising NO substitute.
- Inhaled NO is used to treat elevated pulmonary pressures and pulmonary disorders associated with hypoxemia. This method of treatment provides distribution tightly matched to perfusion and local effect because of rapid trapping of inhaled NO by hemoglobin. Moreover, this method of treatment can be readily carried out by an anesthesiologist or a critical care physician who is used to administering gases. Side effects include reaction of NO with oxygen or reactive oxygen species to produce NO2 or other toxic NOx, the toxicity of which is manifested by inflammation, airway hypereactivity, hemorrhage, delay in clinical improvement, renal impairment or death, and reaction with oxyhemoglobin to interfere with its oxygen delivery function, e.g., by forming methemoglobin.
- An alternative to inhaled NO gas is nebulized NO donor where the NO donor is present as solid particles or as particles of liquid. This alternative cannot fully avoid the NO2/NOx toxicity problem associated with administration of NO but may produce longer lasting effects than inhaled NO. The distribution in the lungs is according to particle size and is not matched to perfusion so some NO donor deposits in places where it does not reach the blood or small airways. In the general case, these NO compounds have systemic smooth muscle relaxing effects greater than pulmonary effects, which limit usage for treating pulmonary disorders. Furthermore, this method is not as readily carried out by an anesthesiologist since anesthesiologists do not normally administer aerosols or powders. Moreover, some classes of NO donors have additional toxicities, that is, they possess toxicities that are unrelated to NO, but that are instead related to the group to which NO is attached or from which NO is generated. The disadvantages of administering nebulized NO donor are indicated to be meaningful by the fact that inhaled gaseous NO is approved for use over inhaled liquid or inhaled solid NO-releasing compound.
- Use of inhaled NO and use of nitric oxide-releasing compounds inhaled as solids or liquids in an aerosol to treat pulmonary vasoconstriction and asthma are described in Zapol U.S. Pat. No. 5,823,180.
- It is an object of an embodiment herein to provide selective pulmonary vasodilation and hypoxemia relieving effect by administration to the lungs of a gas without the toxicity associated with NO use.
- It is an object of an embodiment herein to systemically deliver NO/SNO by administering into the lungs of a gas without interfering with the oxygen delivery function of hemoglobin. It also is an object of this embodiment to endow hemoglobin with improved and/or novel NO donor/releasing function.
- It is an additional object to deliver NO/SNO without the toxicity (loss of specificity) associated with certain classes of NO donors.
- One embodiment herein, denoted the first embodiment, is directed to a method for treating a pulmonary disorder associated with hypoxemia and/or smooth muscle constriction in the lungs and/or inflammation in the lungs in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving effect and a smooth muscle constriction relieving effect and/or an anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature or exert systemic blood pressure compromising effect.
- Another embodiment herein, denoted the second embodiment, is directed at a method of treating a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, whereby delivering into the lungs causes a systemic effect but does not compromise blood pressure.
- Still another embodiment herein, denoted the third embodiment, is directed at a method of treating a blood disorder which is ameliorated by treatment with NO in a patient having said disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, whereby delivery into the lungs causes a desired systemic effect.
- Still another embodiment herein, denoted the fourth embodiment, is directed to a method for treating a patient in need of improvement in tissue oxygenation or dilation of a blood vessel or inhibition of clotting (improved oxygenation, blood flow and/or thinning of blood), said method comprising providing in the patient a therapeutically effective amount of red blood cells loaded with nitrosylated hemoglobin, thereby to cause improved oxygen delivery or blood flow. The red blood cells loaded with nitrosylated hemoglobin can be provided in the patient by methods comprising, for example, (1) delivering into the lungs of the patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in the blood; (2) infusing into the patient a solution of a compound which reacts preferentially with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90; and (3) transfusing into the patient blood containing red blood cells loaded with nitrosylated hemoglobin.
- Exemplary of compound useful in the first, second and third embodiments and in (1) of the fourth embodiment is ethyl nitrite, which is also known as O-nitrosoethanol, used in gaseous form.
- Advantages of embodiments herein include: (1), elimination of the toxicity caused by NO2/NOx formation when NO is administered; (2), the option of administering the compound comprising NO group together with oxygen, without NO2/NOx production; (3), no interference with the oxygen carrying function of hemoglobins since compounds administered herein do not react with heme in hemoglobin, so the physiological level in blood of methemoglobin will be less than 5% in blood; (4), NO bioactivity is preserved when the compound administered reacts with cysteine of hemoglobin; (5), is more efficient and selective at loading hemoglobin cysteine with NO group than free NO or nebulized nitric oxide-releasing compound liquid or solid; (6), the advantages associated with administration of a gas including matching ventilation to blood perfusion (ideal distribution), relatively localized lung effect compared to normal systemic administration of solutions and familiarity of anesthesiologists with the procedure whereby the administration is carried out; (6), less expensive administration since administration can be carried out using a ventilator rather than the very expensive machine used for administration of NO; (7), improved oxygenation, without rebound or with less rebound than when NO is administered; (8), some patients respond to administration of ethyl nitrite who do not respond to administration of NO; (9), cardiac output improves whereas this is not the case when NO is administered; (10), improvement in oxygen delivery without risk of hypotension occurring (the pulmonary effect is greater than the systemic effect but the systemic effect occurs in proportion to the oxygen requirement); and (11), loading the endogenous nitrosoglutathione pool. The methods of embodiments employing gaseous treating agent preserve the advantages of both NO gas inhalation and nebulized nitric oxide-releasing compound administration while minimizing the disadvantages associated with these known methods.
- As used herein the term NOx means NO, N2O3, N2O4, OONO−, OONO− and any products of their interaction or their reaction with NO or NO2.
- As used herein the term reactive oxygen species is singlet oxygen, superoxide, hydrogen peroxide or hydroxyl radical.
- As used herein the term hypoxemia means low blood oxygen content compared to normal, i.e., a hemoglobin saturation less than 95% and a PaO2 less than 90 in arterial blood in someone breathing room air.
- As used herein the term PaO2 means the partial pressure of oxygen in gases in arterial blood.
- As used herein the term “red blood cells loaded with nitrosylated hemoglobin” means red blood cells containing from 100 nanomolar to 10 micromolar nitrosylated hemoglobin, above baseline, preferably from 100 nanomolar to 1 micromolar above baseline. In the red blood cells, the nitrosylated hemoglobin is in equilibrium with nitrosoglutathione.
- As used herein the term “rebound” is used to mean lowering in blood oxygen level or increase in pulmonary artery pressure or resistance after increased blood oxygen level or decreased pulmonary vascular pressure/resistance is obtained by treatment, by at least 10%, when used in relation to blood oxygen levels or pulmonary hypertension, and in general means decrease from improvement after treatment.
- Other embodiments are as follows:
- One additional embodiment, denoted the fifth embodiment, is directed to red blood cells loaded with nitrosylated hemoglobin, outside the body.
- Another additional embodiment, denoted the sixth embodiment, is directed to a method of screening for drugs that increase the level of nitrosoglutathione in airway lining fluid, comprising administering a putative drug in gas form into the lung of a model animal, sampling airway lining fluid from the animal, and assaying for nitrosoglutathione in the sample obtained by sampling.
-
FIG. 1 depicts graphs of pulmonary artery pressure for three doses of ethyl nitrite gas and shows results of Example I. -
FIG. 2 depicts graphs of pulmonary vascular resistance for three doses of ethyl nitrite gas and shows results of Example I. -
FIG. 3 depicts graphs of pulmonary artery flow for three doses of ethyl nitrite gas and shows results of Example I. -
FIG. 4 depicts graphs of cardiac output for two doses of ethyl nitrite gas and shows results of Example I. -
FIG. 5 depicts graphs of mean blood pressure for three doses of ethyl nitrite gas and shows results of Example I. -
FIG. 6 depicts graphs of heart rate for three doses of ethyl nitrite gas and shows results of Example I. -
FIG. 7 shows gas chromatography/mass spectral analysis results on ethyl nitrite gas delivered through the ventilation system of Example I at 75 ppm. -
FIG. 8 depicts graphs of PaO2 (i.e., PaO2) level without treatment, with treatment with ethyl nitrite (EtONO), post EtONO treatment, with treatment with NO, and post NO treatment and shows results of Example XII. -
FIG. 9 depicts graphs of change in cardiac output without treatment, with treatment with ethyl nitrite (EtONO), post EtONO treatment, with treatment with NO, and post NO treatment and shows results of Example XII. -
FIG. 10 is a graph of fold increase in airway SNO (nitrosoglutathione) with ppm of inhaled EtNO (ethyl nitrite) versus inhaled NO and shows results of Example XIV. -
FIGS. 11A, 11B , 11C and 11D are graphs of tension versus time and show results of Example XV. - We turn now to the method for treating a pulmonary disorder associated with smooth muscle constriction in lungs and/or hypoxemia and/or inflammation in the lungs in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving effect and a smooth muscle constriction relieving effect and an anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature or exert systemic blood pressure compromising effect.
- The pulmonary disorders treatable by this method include, for example, pulmonary hypertension including persistent pulmonary hypertension in human babies and primary and secondary pulmonary hypertension in human adults, acute respiratory distress syndrome (ARDS), asthma, cystic fibrosis and respiratory failure.
- Pulmonary hypertension is associated with smooth muscle constriction in the lungs and it can be associated with hypoxemia.
- ARDS is a radiographic manifestation associated with low oxygen content in blood and typically is also associated with elevated pulmonary pressures. Oxygen free radical injury contributes to the pathophysiology. Free NO can aggravate the injury by reacting with oxygen free radicals to form toxic products of reaction (i.e., they damage tissues), but the compounds administered herein do not have this effect because they do not react with oxygen free radicals. Inhaled NO has been showing to result in increased morbidity and mortality. This disorder is associated with hypoxemia and it can be associated with smooth muscle constriction in the lungs.
- Asthma is associated with smooth muscle constriction in the lungs and can be associated with hypoxemia.
- Cystic fibrosis is associated with smooth muscle construction in the lungs and can be associated with hypoxemia.
- We turn now to the compounds having an NO group and having a hypoxemia relieving and a smooth muscle constriction relieving effect and an anti-inflammation or inflammation defending effect with said NO group being bound in said compound. These compounds are less reactive with oxygen or with oxygen free radicals at body temperature than NO and are more potent antimicrobials than NO. These compounds include, for example, those having the formula RX—NOy where R is either not present or is hydrogen/proton or C1-C7-alkyl and X is an oxygen, sulfur, nitrogen or metal selected, for example, from the group consisting of iron, copper, ruthenium and cobalt atoms or an alkyl or alkenyl or alkylthio or alkenylthio group containing from 1 to 7, e.g., 1 to 6, carbon atoms which is straight chain or branched, CF3— and CF3S—, and y is 1 or 2, excluding nitrogen dioxide and NOx.
- Specific treating agents for use herein include, for example, ethyl nitrite (which is used in examples herein), methyl nitrite, tert-butyl nitrite, isoamyl nitrite; trifluoronitrosomethane (CF3NO), CF3SNO, CH3SNO, CH2═CHSNO, CH2═CHCH2SNO, ONSCH2—CH2—CH2SNO and CH3CH2CH2SNO. Alkyl nitrites can be prepared as described in Landscheidt et al. U.S. Pat. No. 5,412,147. Ethyl nitrite is available commercially, e.g., diluted in ethanol. CF3NO is a commercial product or can be made by treatment of CF3I with NO− as described in J. Phys. Chem. 100, 10641 (1996). Aliphatic thionitrites, i.e., compounds of the form RSNO where R describes an alkyl or alkenyl or hydrogen moiety, can be prepared by treatment of the corresponding thiol with a source of NO+ including, but not limited to, one or more of the following: tert-butyl nitrite, ethyl nitrite, nitrosonium tetrafluoborate (NOBF4), nitrosonium perchlorate (NOClO4), nitrosonium hydrogen sulfate (NOHSO4), nitrosonium hydrogen phosphate (NOH2PO4), or HCl-acidified solutions of sodium nitrite.
- We turn now to the administration of these compounds. Those that are normally gases are readily administered diluted in nitrogen or other inert gas and can be administered in admixture with oxygen. Those that are not normally gases are converted to gas for administration and are administered diluted as in the case of the NO-containing compounds that are normally gases. The compounds should not have a boiling point such that the temperature required to maintain them as gases in diluted form would harm the lungs and preferably would not condense in the lungs.
- Dilution, for example, to a concentration of 1 to 100 ppm is typically appropriate.
- The diluted gas is readily delivered into the lungs, using a ventilator which is a conventional device for administering gases into the lungs of a patient. A tube attached to the device passes the gas into the lungs at a rate and pressure consistent with maintaining a PaO2 of 90 mm Hg. Time periods of administration typically range from 1 minute to two or more days, and administration is carried out until symptoms abate. Administration can also be carried out using a face mask.
- As indicated above, a therapeutically effective amount is administered. This is a hypoxemia relieving effective and smooth muscle constriction relieving and an anti-inflammatory or inflammation defending (against) effective amount. Administration is carried out for as long as symptoms ameliorate. The dosage will vary from patient to patient. Upon administration, results are noted with variation in dosage and then the dosage is preferably used where the best results are achieved. The most effective dosage can be lower than some of the dosages tried; thus, if after increases in dosage are tried, an increased dosage provides less improvement, then return to the more effective lower dose is indicated. The ideal dosage matches ventilation to perfusion.
- Ethyl nitrite is readily delivered to the patient in gaseous form by bubbling N2 or O2 through a Milligan gas diffuser containing ethyl nitrite diluted in ethanol (e.g., from 0.00125 to 0.5% ethyl nitrate in ethanol (v/v), preferably from 0.0025 to 0.125% ethyl nitrite in ethanol (v/v)), e.g., at a flow rate of 0.5 liters/min to 1.5 liters/min, to produce N2 or O2 containing ethyl nitrite and introducing this into the ventilation system by mixing the output from the ventilator at a total of 5 to 15 liters/min with the N2 or O2 containing ethyl nitrite, for example, to produce a concentration of 1 to 100 ppm ethyl nitrite in the resulting gas, and delivering this to the patient at a rate and pressure to maintain PaO2 at 90 mm Hg or to improve PaO2 or to decrease pulmonary vascular resistance. The concentration of ethyl nitrite gas administered is proportional to the flow rate of N2 or O2 and the concentration of ethyl nitrite liquid in ethanol.
- An advantage for treatment using ethyl nitrite compared to administration of NO is that no new equipment is needed for ethyl nitrite administration whereas a machine costing tens of thousands of dollars is required to administer NO. Thus, it is less expensive to administer ethyl nitrite than it is to administer NO.
- Furthermore, use of ethyl nitrite improves oxygenation without the toxic NO2 and NOx formation associated with administration of NO and without the rebound to lower oxygen levels or higher pulmonary pressures once administration is stopped that is characteristic of what occurs on administration of NO.
- Furthermore, administration of ethyl nitrite stops cardiac output from going down in disease. This is not the case for administration of NO.
- Furthermore, administration of ethyl nitrite is better than administration of NO in raising the level of NO bound to cysteine in hemoglobin.
- While not being bound by the mechanism stated, it is considered that nitrosoglutathione loading (that is increase in nitrosoglutathione in airway lining fluid) is the basis for the improved oxygenation without rebound to lower levels after administration is stopped and the stopping of cardiac output from going down. Administration of ethyl nitrite causes glutathione loading whereas administration of NO does not.
- Another advantage for ethyl nitrite compared to NO is that, unlike NO, it can be administered in oxygen. NO is not stable in oxygen and has to be given in a nitrogen base which dilutes inspired O2 concentration. Because of this, a patient that is given inhaled NO gas cannot be given a higher concentration of O2 than 95%. In contrast, ethyl nitrite can be given with 100% O2 and does not dilute oxygen concentration at all, so a patient given inhaled ethyl nitrite can be given a higher concentration of oxygen than a patient given inhaled NO. Therefore, in the treatment of persistent pulmonary hypertension, babies that required 100% oxygen can be continued on 100% oxygen when ethyl nitrite is administered whereas the final inspired concentration of oxygen drops when NO is administered.
- When NO is used to treat babies with persistent pulmonary hypertension, the treatment is expensive, there is a need to monitor NO2 and NOx formation or pulmonary vascular resistance, methemoglobin is formed, and there is rebound in every case of improved blood oxygen levels. With NO, there is hemodynamic collapse in 25% of patients if something further is not done. There is an advantage for ethyl nitrite administration in all these cases and there is not the hemodynamic collapse problem or rebound. Moreover, some babies respond to ethyl nitrite that do not respond to administration of NO. Furthermore, cardiac output improves with ethyl nitrite administration but not with administration of NO.
- We turn now to the method for treating a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
- The cardiac disorders treatable by this method include angina, myocardial infarction, heart failure and hypertension.
- In the case of treating hypertension, it is required that the NO-group containing compound administered is one that reacts with cysteine in hemoglobin as discussed below, e.g., ethyl nitrite, and that a thiol also be administered systemically or by inhaled route to promote systemic release of NO from binding to cysteine of hemoglobin. In the cases of treating other cardiac disorders, where the NO-containing compound administered is one that reacts with cysteine in hemoglobin, e.g., ethyl nitrite, it is an option that a thiol also be administered systemically (e.g., intravenously or orally or nebulized) or by inhaled route to cause systemic release of NO from binding to cysteine of hemoglobin. Suitable thiols include, for example, N-acetylcysteine (dosage, e.g., ranging from 50 to 200 mg/kg intravenously or 600 mg three times a day orally or nebulized according to the FDA approved PDR dosage, with a preferred route of administration being intravenous or nebulized), glutathione (dosage, e.g., ranging from 50 to 200 mg/kg with preferred route of administration being intravenous), and cysteinylglycine (dosage, e.g., ranging from 50 to 200 mg/kg with preferred route of administration being intravenous).
- We turn now to the compounds which react with cysteine in hemoglobin and/or dissolve in blood and have an NO group which is bound in said compounds so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, for use in the method herein for treating cardiac disorders. These compounds include, for example, those having the formula RX—NOy described above and the species of this class recited above (ethyl nitrite is used in working examples hereinafter); as indicated above, those compounds that are not normally gases, i.e., not gases at room and body temperature, are converted to gas for administration.
- The concentrations of NO-containing compound and methods of administration applicable to the method of treating a pulmonary disorder described above are applicable to the method herein for treating cardiac disorders.
- As indicated above, a therapeutically effective amount of NO-containing compound in gas form is administered in the method herein for treating cardiac disorders. This is a chest pain reducing effective amount for angina, a heart failure resolving effective amount for myocardial infarction, a pulmonary pressure reducing and peripheral vascular resistance reducing effective amount for heart failure and a blood pressure lowering effective amount for hypertension. The most effective dosage will vary from patient to patient, so it is preferred in each case to try a plurality of dosages and then to utilize dosage where the best results were achieved.
- For administration of ethyl nitrite for treating cardiac disorders, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- When ethyl nitrite is administered, there is improvement without rebound.
- We turn now to the method for treating a blood disorder in a patient having said disorder, said method comprising delivering into the lungs of said patient. as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
- The blood disorders are those ameliorated by treatment with NO or related molecules, i.e., where NO would change the shape of red blood cells to normal or restore their function to normal or would cause dissolution of blood or blood platelet clots. These include sickle cell disease and clotting disorders including disseminated intravascular coagulation (DIC), heart attack, stroke, and Coumadin induced clotting caused by Coumadin blocking protein C and protein S.
- We turn now td the compounds which react with cysteine in hemoglobin and/or dissolve in blood and have an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, for use in the method herein for treating blood disorders. These compounds are the same as those recited for treating cardiac disorders and include, for example, those having the formula RX—NOy described above and the species of this class recited above (ethyl nitrite is used in working examples herein); as indicated above, those compounds that are not normally gases, are converted to gas form for administration.
- The concentrations of NO-containing compound and methods of administration applicable to the method for treating a pulmonary disorder described above are applicable to the method herein for treating blood disorders.
- As indicated above, a therapeutically effective amount of NO-containing compound in gas form is administered in the method herein for treating blood disorders. This is a red blood cell shape restoring and/or red blood cell function restoring effective amount for sickle cell disease and a clot dissolving and/or clot formation preventing amount for clotting disorders. The most effective dosage will vary from patient to patient, so it is preferred in each case to try a plurality of dosages and then to utilize the dosage where the best results were achieved.
- Where the NO-group containing compound administered for treating a blood disorder is one that reacts with cysteine in hemoglobin, it is advantageous to administer the NO-group containing compound in conjunction with a thiol to cause systemic release of NO from binding to cysteine of hemoglobin. Suitable thiols, dosages and routes of administration are those described in conjunction with thiols above.
- For administration of ethyl nitrite for treating blood disorders, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- We turn now to the embodiment herein directed to a method for treating a patient in need of improvement of tissue oxygenation, dilation of a blood vessel or inhibition of clotting, said method comprising providing in the patient a therapeutically effective amount of red blood cells loaded with nitrosylated hemoglobin, thereby to cause improved oxygenation or blood flow.
- This method finds applicability, for example, in treating patients affected with sickle cell disease and ischemic disorders, e.g., angina, heart attack or stroke.
- As indicated above, in one case, the red blood cells loaded with hemoglobin are provided in the patient by a method comprising delivering into the lungs of the patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in blood. This case will be referred to hereinafter as the first case of the fourth embodiment.
- We turn now to the compounds which react with cysteine in hemoglobin and/or dissolve in blood and have an NO group which is bound in said compounds so it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, for use in the method herein for the first case of the fourth embodiment. These compounds are the same as those recited for treating cardiac disorders and for treating blood disorders and include, for example, those having the formula RX—NOy described above and the species of this class recited above, including ethyl nitrite; as indicated above, those compounds that are not normally gases, are converted to gas for administration.
- The concentrations of NO-containing compound and methods of administration applicable to the method of treating a pulmonary disorder described above are applicable to the method herein for treating the first case of the fourth embodiment.
- A therapeutically effective amount for the first case of the fourth embodiment is an oxygen delivery or blood flow increasing or blood thinning effective amount.
- Where the NO-group containing compound administered for treating the first case of the fourth embodiment is one that reacts with cysteine in hemoglobin, it is advantageous to administer the NO-group containing compound in conjunction with a thiol to cause systemic release of NO from binding to cysteine of hemoglobin. Suitable thiols, dosages and routes of administration are those described in conjunction with thiols above.
- For administration of ethyl nitrite for treating the first case of the fourth embodiment, the same concentrations and methods of administration are applicable as are described above for treating pulmonary disorders.
- Measurement of nitrosylated hemoglobin in the blood can be carried out as described in Jia, L., et al., Nature, Vol. 380, 221-226 (1996).
- As further indicated above, in another case, the red blood cells loaded with hemoglobin are provided in the patient by a method comprising infusing into the patient a solution of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90. The limitation about blood pressure is included because ethyl nitrite when infused as a liquid, causes a drop in blood pressure. This case will be referred to hereinafter as the second case of the fourth embodiment.
- The compounds for use in the second case of the fourth embodiment can be the same as those used in the first case of the fourth embodiment but unlike in the first case of the fourth embodiment, they are infused in liquid form instead of being administered as gases. The liquid form can be obtained by administering the compounds dissolved in a solvent, e.g., a protic solvent such as an alcohol. Ethyl nitrite dissolved in ethanol to provide an ethanol solution containing 0.00125 to 0.5 percent (v/v) ethyl nitrite is a preferred agent for the second case of the fourth embodiment and the solution more preferably contains 0.0025 to 0.125 percent ethyl nitrite (v/v).
- A therapeutically effective amount for the second case of the fourth embodiment is an oxygenation improving or blood flow improving effective amount.
- Administration of the solution of compound that reacts with cysteine in hemoglobin and/or dissolves in blood is preferably carried out intravenously.
- Where the NO-group containing compound administered for treating is one that reacts with cysteine in hemoglobin, it is advantageous to administer the NO-group containing compound in conjunction with a thiol to cause systemic release of NO from binding to cysteine of hemoglobin. Suitable thiols, dosages and routes of administration including intravenously, orally and nebulized, are those described in conjunction with thiols above.
- As still further indicated above, in another case, the red blood cells loaded with hemoglobin are provided in the patient by a method comprising transfusing into the patient blood containing red blood cells loaded with nitrosylated hemoglobin. The blood containing red blood cells loaded with hemoglobin can be obtained by incubating blood for 1 minute to 1 hour, e.g., 1 minute to 10 minutes, at 25 to 37° C. with a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen of reactive oxygen species at body temperature. The compounds can be the same as those described above for compound that reacts with cysteine and/or dissolves in blood and has an NO group which is bound in the compound so that it does not form NO2 or NOx in the presence of oxygen or reaction oxygen species at body temperature. The incubation is preferably carried out by incubating blood with an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite, preferably containing from 0.0025 to 0.125% (v/v) ethyl nitrite, with the amount of ethyl nitrite to hemoglobin present for incubation ranging from 1:1000 to 10:1, preferably from 1:100 to 10:1. This case will be referred to hereinafter as the third case of the fourth embodiment.
- Preferably, thiol is co-administered for the third case of the fourth embodiment. Suitable thiols, dosage and routes of administration are those described in conjunction with thiol administration above.
- A therapeutically effective amount of red blood cells loaded with nitrosylated hemoglobin is 0.1 to 3 units of blood having nitrosylated hemoglobin increased 0.1 to 1 micromolar over baseline or equivalent.
- Administration is preferably carried out by transfusion.
- We turn now to the embodiment herein which is red blood cells loaded with nitrosylated hemoglobin outside the body. These are readily made as described in the third case of the fourth embodiment.
- We turn now to the method herein for screening for drugs that increase the level of nitrosoglutathione in airway lining fluid, comprising administering the drug in gas form into the lung of a model animal, sampling airway lining fluid and assaying for nitrosoglutathione in the sample obtained by sampling. Model animals include, for example, neonatal pigs, guinea pigs, rats and dogs. A sample of airway lining fluid is readily obtained by bronchoscopy. Assay for nitrosoglutathione in sample is readily carried out, for example, as described in Gaston, B., et al., PNAS, Vol. 90, 10957-10961 (1993). A level indicating increase of nitrosoglutathione at least 50% above baseline indicates a candidate for a drug for increasing level of nitrosoglutathione in airway lining fluid of mammals including humans.
- The invention herein is illustrated by, but not limited by, the following working examples.
- The experiment was carried out using a pig model of pulmonary hypertension as follows:
- Mixed strain two-three weeks old piglets were utilized. Initial anesthetic induction was by inhaled halomethane 5%, reduced to 2% when the animal was stable. A bolus of 20 μg/kg of fentanyl and 0.2 mg/kg of acepromazine was given after tracheostomy surgery and insertion of a jugular venous line, followed by a continuous fentanyl infusion of 10 μg/kg/hr. An incision in the right side of the neck allowed the insertion of a catheter through the external jugular vein into the right atrium, through which maintenance i.v. fluid of 30 mL/kg/hr of 5% glucose was infused. A catheter was placed in the carotid artery for measurement of systolic arterial pressure (SAP). After the tracheostomy, halothane was discontinued, assisted ventilation was started, and paralysis was obtained using pancuronium bromide (0.1 mg/kg) every 45 minutes. Further bolus doses of fentanyl (5-10 μg/kg) were administered as necessary. Through a left thoracotomy, a 6- or 8-mm ultrasound flow probe (Transonic Inc., Rochester, N.Y.) was placed around the pulmonary artery for measurement of cardiac output and a 4- to 6-mm probe was placed around the ductus arteriosus. A 22-gauge catheter was inserted into the root of the pulmonary artery through a purse string suture for the continuous measurement of pulmonary artery pressure (PAP). The systemic and pulmonary catheters were connected to pressure transducers and together with the ECG signal, displayed on a neonatal monitor (Model 78833B, Hewlett Packard, Waltham, Mass.). Systemic oxygen saturation (SaO2) was measured using a subcutaneous pulse oximeter (N200, Nellcor Inc., Hayward, Calif.). A continuous infusion of bicarbonate (15 mEq/100 mL of i.v. fluid) was given to prevent severe acidosis during periods of hypoxia. Cardiac output was determined from measurements of the calibrated ultrasonic flow probe.
- After this instrumentation, the animal was allowed to rest for 20 minutes to ensure stability, which was defined as less than 5% variation in heart rate, SAP, and PAP over a 5-minute period, and thereafter hypoxia was induced by reduction of the inspired oxygen concentration to 10 to 14% to produce a target SaO2 of 35 to 45%. After induction of hypoxia, a stable hypoxic baseline was obtained (2 minutes). An arterial blood specimen was obtained for the measurement of blood gases and methemoglobin.
- Ethyl nitrite (EtONO) was then administered according to a computer-generated random sequence in doses of 1.5, 15 or 75 ppm by changing the EtONO concentration (at a fixed flow rate), maintaining the fractional inspired oxygen saturation (FiO2) at the same level. The ethyl nitrite was administered with nitrogen by introducing nitrogen ethyl nitrite admixture into the ventilation system by mixing the output from the ventilator with said admixture. The ethyl nitrite nitrogen admixture was generated by bubbling nitrogen through a Milligan gas diffuser (Fisher Scientific) containing ethyl nitrite diluted in ethanol (0.075% (v/v) ethyl nitrate) at a flow rate of 0.6 liters/min to produce nitrogen containing ethyl nitrite which is then blended in the ventilator with the incoming gas for a flow rate of 6 liters/min. The concentration of ethyl nitrite in the gas to be administered is directly proportional to the flow of nitrogen into the Milligan gas diffuser and/or the concentration of ethyl nitrite in ethanol. Measurements were obtained at each dose when there were no further changes in PAP, SaO2, SAP, or cardiac output, and the signals were recorded for 1 minute. At this point, EtONO administration was discontinued. Post EtONO data was from
samples 4 minutes after EtONO discontinuance and final baseline samples were taken when the parameter being measured stabilized (about 4 minutes after the post EtONO sample). This procedure was repeated until all doses of EtONO had been administered. If an animal experienced significant hypotension (systolic arterial pressure decreasing to less than 60% of hypoxic baseline) the hypoxia was terminated, and the animal was allowed to recover before reintroducing hypoxia. - The physiologic parameters of interest were acquired through a personal computer (Dell 486/33, Dell Computer Corporation, Richmond Hill, Ontario, Canada) using an analog-to-digital converter (DT 2801, Data Translation Inc., Marborough, Mass.). Software for acquisition analysis was written using Asyst Scientific Software System (Macmillan Software Co., New York, N.Y.). With this software, continuous acquisition of the measured parameters was performed for a 2-minute period at baseline, and a 1-minute period after stability during each hypoxic EtONO exposure. The computer-generated averages of the measured parameters were then utilized for subsequent analyses. The time responses of the changes in PAP were similarly analyzed using the average values for 1 second for the PAP to determine the time response of the change in PAP compared to baseline. All signals were acquired at 24 Hz. In order to compensate for sampling delay time for the analyzer which was approximately 5 seconds, initiation of the response was considered to be 5 seconds before the initial indication that the results of the appropriate dose had been measured by the analyzer (measured by GC mass spectral analysis using a model system). Cardiac Index was calculated as cardiac output divided by the animal's weight in kilograms. Pulmonary Vascular Resistance (PVR) was calculated as mean PAP divided by cardiac index. Pulmonary Artery Flow (
FIG. 3 ) was measured using a Doppler flow probe. - Results are shown in
FIGS. 1-6 . -
FIG. 1 depicts graphs of PAP in mm Hg for the three concentrations of EtONO administration with data points at baseline, hypoxia (stable hypoxic baseline), EtONO (when no further changes in PAP for one minute), post EtONO (4 minutes after EtONO discontinuance) and baseline (when PAP normalized, approximately 4 minutes after post EtONO data). The data shows hypoxia increased PAP and that EtONO administration reverses hypoxic pulmonary vasoconstriction. -
FIG. 2 depicts graphs of PVR in dynes×5×cm−1 for the three concentrations of EtONO administration with data points at the same stages as forFIG. 1 . The data shows hypoxia increased PVR and that EtONO administration restores PVR toward initial baseline. - For
FIGS. 1 and 2 , any progressive loss of effect of hypoxia on pulmonary vascular hemodynamics is consistent with a positive effect of EtONO. -
FIG. 3 depicts graphs of pulmonary artery flow in minimum for the three concentrations of EtONO administration with data points at the same stages as forFIG. 1 . The data shows EtONO administration increases pulmonary artery flow at 75 ppm. -
FIG. 4 depicts graphs of cardiac output in ml/min for two concentrations of EtONO administration with data points at the same stages as forFIG. 1 . The data shows that EtONO administration tends to normalize the hypoxia induced increase in cardiac output. -
FIG. 5 depicts graphs of mean blood pressure in mm Hg for three concentrations of EtONO administration with data points at the same stages as forFIG. 1 . The data shows that EtONO administration has no effect on blood pressure. -
FIG. 6 depicts graphs of heart rate in beats per minute for three concentrations of EtONO administration with data points at the same stages as forFIG. 1 . The data shows that EtONO administration has no effect on heart rate. - Blood samples taken during inhalation of the highest dose of EtONO administered (75 ppm) show methemoglobin content ranging from 0.5 to 4.5% (n=5), i.e., well within the acceptable physiological range.
- Gas chromatography/mass spectrometer analysis on gas delivered on admixture of nitrogen ethyl nitrite admixture with ventilator output, at 75 ppm ethyl nitrite, was carried out. In particular, a 100 μl gas sample was taken from the expiratory arm of the respiration system (using a glove as a model lung) with ethyl nitrite being delivered from the system to the patient at 75 ppm. The gas sample was injected into an HP GC/MS system using a 30 m 0.53 μm GS-Q column. Ethyl nitrite is decomposed within the mass spectrometer producing ethanol (mass 46) and some NO (mass 30) but virtually no free NO was generated. The results are shown in
FIG. 7 . Unbound nitric oxide elutes from the GS-Q column at approximately 1.5 minutes and ethyl nitrite elutes from the column at 4.1 minutes. The data shows virtually no free NO or NO2 is detected. - The experiment of this example was carried out to show reversal of pathologic symptoms an administration and was not to assess rebound. Rebound was not appropriately assessed because the subjects were still sufficiently hypoxemic at the conclusion of treatment, that the normal response of pulmonary artery pressure increase occurred as a result. Rebound is assessed in Example XII below.
- In another case with piglets, increased PaO2 and decreased pulmonary vascular resistence was obtained with 100 ppm trifluoronitrosomethane in place of ethyl nitrite.
- A 30-year-old white female with pulmonary pressures of 70/40 mm Hg is admitted into an intensive care unit and deteriorates due to right heart failure, and is given for inhalation through a face mask an admixture of O2, N2 and ethyl nitrite such that the PaO2 is maintained at 90 and ethyl nitrite is present at 70 ppm. Pulmonary pressures fall to 30/15 and right heart failure disappears.
- In another case, an identical patient receives the same treatment except for 80 ppm inhaled NO in place of the 70 ppm ethyl nitrite. Pulmonary pressures drop but the patient develops airway hyperreactivity (slight wheezing) and a chemiluminescence analyzer shows threefold increase in NO2 concentration in exhaled air. Moreover, methemoglobin content in the blood is measured at 10%. The patient is switched from NO to inhaled ethyl nitrite (70 ppm), and NO2 and methemoglobin levels drop and recovery is maintained.
- A 60-year-old male cancer patient develops radiographic changes consistent with ARDS, post-chemotherapy. The patient's PaO2 falls to 50 mm Hg despite being on 100% oxygen and a right heart catheterization reveals a normal left ventricular endiastolic pressure. The patient is administered 40 ppm inhaled ethyl nitrite. The PaO2 increases to 70 mm Hg.
- An identical patient is given 30 ppm inhaled NO and acute PaO2 improvement occurs but then clinical deterioration occurs characterized by worsening chest X-rays (due to inflammation) and renal impairment and PaO2 drops from 70 to 60 mm Hg. The patent is switched to 50 ppm inhaled ethyl nitrite and the radiographic changes and renal impairment stabilize and PaO2 increases to 90 mm Hg.
- A 26-year-old white female asthmatic gets intubated because of a severe asthmatic exacerbation. The patient is administered nebulized epinephrine and Atrovent but is failing to ventilate. The physician adds 100 ppm inhaled ethyl nitrite via a rebreathing face mask to the treatment, and the patient's PaO2 improves from 60 to 80 and ventilation becomes easier as evidenced by lower airway pressures (lung compliance).
- A 12-year-old girl with cystic fibrosis presents with pseudomonal infection leading to pulmonary exacerbation. The patient is given nebulized antibiotics but continues to spike fever and do poorly. Inhaled ethyl nitrite is given at 80 ppm in oxygen with resolution of the infection over four days.
- A 65-year-old white male is admitted to a hospital with unstable angina. The patient is given i.v. nitroglycerin, heparin and a beta blocker. However, the patient continues to experience intermittent-chest pain at rest. The patient is given 20 ppm inhaled ethyl nitrite in oxygen. The chest pain resolves.
- A 70-year-old white male presents with myocardial infarction. The patient's hematocrit is 26. The patient is given two units of blood but goes into heart failure. The patient is started on 60 ppm inhaled ethyl nitrite in nitrogen, with resolution of the heart failure. The patient also receives the standard medical regimen of tissue plasminogen activator, a beta blocker and an ACE inhibitor.
- An 80-year-old presents with stage 3 biventricular failure and pulmonary arterial pressures of 50/30. The patient is given Captopril, digoxin and lasix but still has a systemic pressure of 140/80 with increased vascular resistance. The patient receives 80 ppm inhaled ethyl nitrite gas in oxygen. The patient's pulmonary pressures drop to 20/10 and systemic arterial pressure drops to 100/80 with normal peripheral vascular resistance. Ethyl nitrite administration is stopped and the pressures remain low.
- A 40-year-old black male presents with malignant hypertension (blood pressure of 240/160). The patient receives Captopril and nitroprusside and blood pressure drops to 200/120. The patient receives 80 ppm inhaled ethyl nitrite in nitrogen over the next day with an intravenous bolus of 200 mg/kg N-acetylcysteine administered at 6 hours after ethyl nitrite therapy was started. Blood pressure drops to 170/95.
- An 18-year-old black female with homozygous sickle cell disease presents in painful crisis with chest radiographic changes and hypoxemia. The patient complains of severe abdominal and chest pain and is somewhat disoriented. She receives two units of blood while being administered 80 ppm inhaled ethyl nitrite in oxygen. All symptoms and radiographic changes resolve.
- A 60-year-old white male with leukemia presents with disseminated intravascular coagulation. A digit becomes ischemic. The patient is started on 80 ppm inhaled ethyl nitrite in oxygen and is given 100 mg/kg infusion of N-acetylcysteine. Blood flow improves to the digit.
- For a model of lung injury for acute respiratory distress syndrome (ARDS), pulmonary hypertension was induced in intubated neonatal pigs breathing 100% oxygen by repeated saline lavage (to remove surfactant), until the PaO2 fell below 100 mm Hg and stayed there for 30 minutes. Either NO or ethyl nitrite (EtONO) was administered by 2 hours. The NO was administered at 20 ppm for 10 minutes followed by 5 ppm. The EtONO was administered at 20 ppm. Results presented here are for PaO2 (
FIG. 8 ) and for cardiac output (FIG. 9 ). Initial measurements were made (Control), then measurements were made repeatedly in the course of EtONO and NO administration, denoted (EtONO) and (NO), and then hemodynamics were retested every 5 minutes for 20 minutes after abrupt dissemination of inhaled gases (Post EtONO) and (Post NO). EtONO and NO were administered in oxygen gas. - As shown in
FIG. 8 , EtONO administration caused significant increase in PaO2 at the two hour mark and post treatment there was further improvement. As shown inFIG. 8 , NO administration caused significant increase in PaO2 at the 2 hour mark but post treatment there was rebound and lowering of PaO2. For EtONO, there was no change or better PaO2 levels for 20 minutes after administration was discontinued. For NO, there was a change for the worse 3 minutes after administration was discontinued. In addition, both drugs decreased pulmonary vascular resistance to comparable degrees but rebound occurred when NO was discontinued whereas pulmonary vascular resistance remained unchanged when EtONO was discontinued. - The results show that for EtONO administration, there is a dramatic improvement in blood oxygen levels at least as good as for NO during administration and no rebound and further improvement after discontinuance of treatment whereas with NO administration, there is rebound on discontinuance of treatment.
- As shown in
FIG. 9 , EtONO administration caused increase in cardiac output from a level of minus 40% from normal (control animal had heart failure) to a significant increase in cardiac output to minus 27% from normal at the time of discontinuance of administration and further increase in cardiac output to about minus 20% from normal after discontinuance of treatment whereas NO administration did not cause significant increase in cardiac output. - The results depicted in
FIGS. 8 and 9 were based on 15 pigs and inFIGS. 8 and 9 , an asterisk represents significantly different from control (P<0.05). - The same scenario of increased PaO2 with no rebound and decreased pulmonary vascular resistance with no rebound and increased cardiac output with EtONO administration in contrast with increased PaO2 but with rebound and decreased pulmonary vascular resistance but with rebound with NO administration is observed in treatment of human adults for primary pulmonary hypertension or in the treatment of human babies with persistent pulmonary hypertension of multiple etiologies as exemplified in Example XIII below.
- Ethyl nitrite has been used under the direction of one of the inventors herein to treat four human babies with persistent pulmonary hypertension and/or hypoxemia. The results were dramatic improvement in blood oxygen levels, no rebound, no methemoglobinemia and improvement in cardiac output. Pressor support was able to be stopped within a short period of time after EtONO therapy was started. One baby responded to ethyl nitrite that did not respond to NO.
- Ethyl nitrite has been used to treat six adults with primary pulmonary hypertension. The results were improvement in blood oxygen levels, decrease in pulmonary vascular resistance and improvement in cardiac output.
- There was no increase in methemoglobin.
- Details on treatment of one baby with persistent pulmonary hypertension and one adult with primary pulmonary hypertension are set forth below.
- A baby with persistent pulmonary hypertension administered epinephrine as required to maintain blood pressure, was administered 1.5 ppm ethyl nitrite (EtONO) for 15 minutes, then increasing to 75 ppm EtONO for the next 15 minutes, then 75 ppm EtONO for the next 30 minutes, then 15 ppm EtONO for the next 3 hours whereupon administration was stopped for 29 minutes and then NO was administered according to conventional treatment for 4 hours. The EtONO was administered via ventilator in the gas being administered via the ventilator. The initial PaO2 was 29 which is not compatible with life (and means the baby was dying). The PaO2 increased to 54 at the conclusion of EtONO therapy, then further increased to 86 during the about 30 minutes between treatments. Thus, there was improvement in the PaO2 with treatment with EtONO and no rebound after EtONO therapy was stopped. In contrast, the NO therapy caused a decrease in the PaO2 and at the end of 4 hours had to be stopped. The initial PaCO2 (measure of how well lungs are ventilating) was 62 and reduced to 29 at the time of stopping EtONO therapy and as a result ventilation could be stopped. In addition, pressor support was able to be discontinued at the time of stopping of EtONO therapy.
- We turn now to the case of treatment of an adult with primary pulmonary hypertension. The adult was given ethyl nitrite (EtONO) at 1.5 ppm for 10 minutes, 15 ppm for 10 minutes and 75 ppm for 10 minutes, and then EtONO therapy was stopped. As a result of the treatment, the mean pulmonary artery pressure dropped from 56 to 40, the cardiac output rose from 5.3 to 5.9 (which is good) and after treatment dropped to 5.6, the pulmonary vascular resistence reduced from 7.4 to 5.2 and the PaO2 increased from 79 to 94. The results show that the therapy worked to normalize hemodynamics. The goal was to improve oxygenation and lower pulmonary vascular resistance, and this was achieved.
- This experiment was carried out to show that EtONO administration increases GSNO (nitrosoglutathione) in the lung, i.e., airway lining fluid, and that NO administration does not efficiently increase nitrosoglutathione concentration in the lung, thus predisposing to adverse reactions.
- Ethyl nitrite (EtONO) or NO was added to the inhaled gas of neonatal pigs in doses as shown in
FIG. 10 . The EtONO was added at 0.6 liters/min into room air (20% oxygen). The NO was blended with 100% nitrogen. After 5 minutes, airway lining fluid in lung was sampled by bronchoscopy. Aspirates were collected in phosphate buffered saline (PBS) containing 100 μM diethylenetriaminepentaacetic acid and assayed immediately for SNO content by chemical reduction-chemiluminescence, and for protein content by the Lowry method. SNO concentrations normalized to protein content are expressed as fold increase over endogenous levels (0.145±0.03 nM/μg for NO group, 0.22±0.04 nM/μg for EtONO group). Results are given inFIG. 10 where EtONO and NO doses expressed in ppm denote the X-axis and the Y-axis is fold increase in SNO. As shown inFIG. 10 , EtONO at the lowest dose caused a 5-fold increase in GSNO and at all doses there is at least this increase. On the other hand, NO is shown to give a slight increase in SNO suggesting that most of the NO participates in an alternative chemical reaction with O2 and/or reactive oxygen species which would be a basis for its toxicity. A conclusion is that EtONO loads natural glutathione to increase the pool of nitrosoglutathione (GSNO).FIG. 7 indicates that this occurs without the release of NO. Thus, EtONO administration selectively repletes lung SNO (i.e., increases SNO without causing the toxic effects that NO causes). Since depletion of GSNO occurs in patient's airway lining fluid with cystic fibrosis, asthma, hypoxemia and respiratory failure, treatment of these with EtONO is suggested. The data here suggests that a mechanism for the effect of EtONO is formation of GSNO whereas the mechanism for effect of NO is the relaxation effect of NO. Direct administration of GSNO into the lungs has to be carried out by nebulizing. As GSNO deposits in larger airways and does not cross cells, nebulizing it into the lungs does not cause it to distribute evenly. Moreover, patients cannot tolerate GSNO administration since it causes then to cough. Because of this, N-acetylcysteine administration has been tried; it does not work to increase GSNO levels. Thus direct administration of GSNO is not a substitute or alternative or equivalent for the invention herein. - A volunteer patient with primary pulmonary hypotension and hypoxemia who has undergone right heart catheterization to assess responses to therapy, was treated with inhaled ethyl nitrite (EtONO) for 30 minutes with increasing dose titration from 1.5 to 75 ppm (1.5 ppm for 10 minutes, followed by 15 ppm for 10 minutes, followed by 75 ppm). The patient's red blood cells were drawn from an indwelling arterial line and measurements were carried out in rabbit aortic bioassays on intact red blood cells and on hemolysate obtained by lysing red blood cells with hypotonic saline. The rabbit aortic bioassays were carried out on rabbit aorta pieces hung on stirrups and attached to force transducers and measurement was carried out for increase and decrease in tension as described in Stamler, J., et al., PNAS, Vol. 89, 444-448 (1992). Assay was carried out at approximately 1% oxygen to simulate what would occur in tissues (which contain low PaO2). The results are shown in
FIGS. 11A (control for intact red blood cells, no treatment), 11B (intact red blood cells, EtONO treatment, 11C (control for hemolysate, no treatment), and 11D (hemolysate, EtONO treatment) which are tracings of tension (Y-axis) versus time (X-axis) with downward direction indicating relaxation and upward direction indicating contraction. As shown inFIG. 11A , one sees a small transient decrease induced by native red blood cells, but as shown inFIG. 11B , a significantly greater drop in tension induced by red blood cells from the EtONO treated patient. The reason for the ensuing increase in tension is that exporter in red blood cells releases all the activity. However, the activity is shown to be more than enough to achieve the biological effect desired. Turning now to the results on hemolysate,FIG. 11C shows hemolysate from native blood cells produces a very small relaxation under low PaO2 followed by a contraction whereasFIG. 11D shows hemolysate from blood cells from an EtONO treated patient produces a stronger dilation and no contraction compared to baseline. InFIGS. 11A, 11B , 11C and 11D, an asterisk represents significantly different from control (p<0.05) and # means p=0.06. The reason for the difference between the results for intact red blood cells and hemolysate is the hemolysate does not contain the functional exporter. - Measurements and data have indicated that in intact red blood cells and in hemolysate from EtONO treated patients, a mixture of nitrosylated hemoglobin and S-nitrosoglutathione is formed and that EtONO treatment increases the level of both (the nitrosylated hemoglobin and S-nitrosoglutathione being in equilibrium) in red blood cells in the patient.
- Red blood cells are incubated with an alcohol solution of ethyl nitrite containing various concentrations of ethyl nitrite with a mole ratio of 1:50 ethyl nitrite to hemoglobin at 37° C. for 15 minutes. The result is red blood cells loaded with nitrosylated hemoglobin and nitrosylated glutathione in equilibrium and containing about 10 μM S-nitrosylated hemoglobin.
- The resulting red blood cells are useful, for example, for treating sickle cell disease or ischemic disorder, e.g., angina.
- Neonatal pigs as in Example XIV are administered inhaled gaseous drugs. After 5 minutes, airway lining fluid is sampled and assayed for nitrosoglutathione (GSNO) by the method described in Gaston, B., et al., PNAS, Vol. 90, 10957-10961 (1993). Screening shows that ethyl nitrite and amyl nitrite, but not NO, increase GSNO in airway lining fluid more than 50% compared to baseline.
- Variations
- Variations of the above will be obvious to those skilled in the art. Thus, the scope of the invention is defined by the claims.
Claims (35)
1. A method for treating a pulmonary disorder associated with hypoxemia and/or smooth muscle constriction and/or inflammation in the lungs in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving and smooth muscle constriction relieving and/or anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
2. The method of claim 1 wherein the compound is ethyl nitrite.
3. The method of claim 2 where the disorder is pulmonary hypertension.
4. The method of claim 2 where the disorder is acute respiratory distress syndrome.
5. The method of claim 2 where the disorder is asthma.
6. The method of claim 2 where the disorder is cystic fibrosis.
7. The method of claim 1 where the disorder is pulmonary hypertension.
8. The method of claim 1 where the disorder is acute respiratory distress syndrome.
9. The method of claim 1 where the disorder is asthma.
10. The method of claim 1 where the disorder is cystic fibrosis.
11. A method for treating a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
12. The method of claim 11 where the disorder is angina.
13. The method of claim 11 where the disorder is myocardial infarction.
14. The method of claim 11 where the disorder is heart failure.
15. The method of claim 11 where the disorder is hypertension and where thiol is administered systemically or by inhaled route to cause systemic release of NO from binding to cysteine of hemoglobin.
16. The method of claim 11 wherein said compound is ethyl nitrite.
17. A method for treating a blood disorder which is ameliorated by treatment with NO in a patient having said disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
18. The method of claim 17 where the disorder is sickle cell disease.
19. The method of claim 17 where the disorder is a clotting disorder.
20. The method of claim 17 where the compound is ethyl nitrite.
21. The method of claim 7 where the disorder is persistent pulmonary hypertension in a human baby.
22. The method of claim 7 where the disorder is primary pulmonary hypertension in an adult.
23. A method for treating a patient in need of improvement in tissue oxygenation or dilation of a blood vessel or inhibition of clotting, said method comprising providing in the patient a therapeutic amount of red blood cells loaded with nitrosylated hemoglobin, thereby to cause improved oxygen delivery or blood flow.
24. The method of claim 23 where the patient is afflicted with sickle cell disease.
25. The method of claim 23 where the patient is afflicted with an ischemic disorder.
26. The method of claim 25 where the ischemic disorder is angina.
27. The method of claim 23 where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by a method comprising delivering into the lungs of said patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in the blood.
28. The method of claim 27 wherein said compound is ethyl nitrite.
29. The method of claim 23 where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by a method comprising infusing into the patient a solution of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90.
30. The method of claim 29 where the solution of compound is an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite.
31. The method of claim 23 where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by transfusing into the patient blood containing red blood cells loaded with nitrosylated hemoglobin.
32. The method of claim 31 where the blood containing red blood cells loaded with nitrosylated hemoglobin is provided by incubating blood for 1 minute to 1 hour at 25 to 37° C. with a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature.
33. The method of claim 32 wherein blood containing red blood cells loaded with hemoglobin is provided by incubating blood with an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite with the amount of ethyl nitrite to hemoglobin present during the incubating ranging from 1:1000 to 10:1.
34. Blood containing red blood cells loaded with nitrosylated hemoglobin, outside the body.
35. A method for screening for drug that increase level of nitrosoglutathione in airway lining fluid, comprising administering putative drug in gas form into the lung of a model animal, sampling airway lining fluid and assaying for nitrosoglutathione in the sample obtained by sampling.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/231,162 US20070191478A1 (en) | 1999-09-08 | 2005-09-20 | Methods of treating cardio pulmonary diseases with NO group compounds |
US13/848,202 US8871506B2 (en) | 1999-09-08 | 2013-03-21 | Methods for treating cardio pulmonary diseases with NO group compounds |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/390,215 US6314956B1 (en) | 1999-09-08 | 1999-09-08 | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
US10/069,114 US6945247B1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
PCT/US2000/020784 WO2001017596A1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
US11/231,162 US20070191478A1 (en) | 1999-09-08 | 2005-09-20 | Methods of treating cardio pulmonary diseases with NO group compounds |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10069114 Division | 2000-08-18 | ||
US10/069,114 Division US6945247B1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
PCT/US2000/020784 Division WO2001017596A1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/848,202 Division US8871506B2 (en) | 1999-09-08 | 2013-03-21 | Methods for treating cardio pulmonary diseases with NO group compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070191478A1 true US20070191478A1 (en) | 2007-08-16 |
Family
ID=23541588
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/390,215 Expired - Lifetime US6314956B1 (en) | 1999-09-08 | 1999-09-08 | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
US10/069,114 Expired - Fee Related US6945247B1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
US11/231,162 Abandoned US20070191478A1 (en) | 1999-09-08 | 2005-09-20 | Methods of treating cardio pulmonary diseases with NO group compounds |
US13/848,202 Expired - Fee Related US8871506B2 (en) | 1999-09-08 | 2013-03-21 | Methods for treating cardio pulmonary diseases with NO group compounds |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/390,215 Expired - Lifetime US6314956B1 (en) | 1999-09-08 | 1999-09-08 | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
US10/069,114 Expired - Fee Related US6945247B1 (en) | 1999-09-08 | 2000-08-18 | Method of treating cardio pulmonary diseases with no group compounds |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/848,202 Expired - Fee Related US8871506B2 (en) | 1999-09-08 | 2013-03-21 | Methods for treating cardio pulmonary diseases with NO group compounds |
Country Status (6)
Country | Link |
---|---|
US (4) | US6314956B1 (en) |
EP (1) | EP1229954B1 (en) |
JP (1) | JP5004391B2 (en) |
AU (1) | AU772858B2 (en) |
CA (1) | CA2383174C (en) |
WO (1) | WO2001017596A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010011928A1 (en) * | 2008-07-24 | 2010-01-28 | Geno Llc | Methods for diagnosing and treating a heart condition in a patient |
US20130210136A1 (en) * | 1999-09-08 | 2013-08-15 | Duke University | Methods For Treating Cardio Pulmonary Diseases With NO Group Compounds |
WO2021252347A1 (en) * | 2020-06-09 | 2021-12-16 | The Texas A&M University System | Therapeutics for treatment of covid-19 symptoms |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7045152B2 (en) * | 1999-09-08 | 2006-05-16 | Duke University | Treating pulmonary disorders with gaseous agent causing repletion of GSNO |
US7100603B1 (en) | 2000-08-31 | 2006-09-05 | Alan Krasberg | System for providing protection from reactive oxygen species |
JP4194364B2 (en) * | 2000-10-16 | 2008-12-10 | デューク・ユニバーシティ | Therapeutic use of aerosolized S-nitrosoglutathione in cystic fibrosis |
US20040225275A1 (en) * | 2001-08-02 | 2004-11-11 | Reynolds James Dixon | Fetal physiology during maternal surgery or diagnosis |
US6676855B2 (en) * | 2001-08-02 | 2004-01-13 | Duke University | Use of a blood-flow decrease preventing agent in conjunction with insufflating gas |
WO2003015605A2 (en) * | 2001-08-20 | 2003-02-27 | University Of Virginia Patent Foundation | Use of s-nitrosothiol signaling to treat disordered control of breathing |
US20030070674A1 (en) * | 2001-10-12 | 2003-04-17 | Bryan Perry | Use of aerosolized compounds in the treatment of exercise induced pulmonary hemorrhage in an equine |
GB0125222D0 (en) * | 2001-10-19 | 2001-12-12 | Barts & London Nhs Trust | Composition for the treatment of microbial infections |
US6472390B1 (en) * | 2001-11-13 | 2002-10-29 | Duke University | Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure |
US20040110691A1 (en) * | 2001-11-13 | 2004-06-10 | Stamler Jonathan S. | Thiol reactive agents as a therapeutic modality |
US6627602B2 (en) * | 2001-11-13 | 2003-09-30 | Duke University | Preventing desensitization of receptors |
US6705316B2 (en) | 2002-03-11 | 2004-03-16 | Battelle Pulmonary Therapeutics, Inc. | Pulmonary dosing system and method |
JP2005527834A (en) * | 2002-05-29 | 2005-09-15 | デューク・ユニバーシティー | Measurement of nitric oxide in blood gas and treatment based on it |
JP5564158B2 (en) | 2003-07-09 | 2014-07-30 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンテッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Methods of treating certain cardiovascular conditions with nitrite |
US7362274B1 (en) * | 2004-07-09 | 2008-04-22 | Huan-Cheng Lien | Coupled feed-in butterfly shaped left/right hand circularly polarized microstrip antenna |
US7238027B2 (en) * | 2004-07-20 | 2007-07-03 | Cardiac Pacemakers, Inc. | Device functionality representation tool |
US7338670B2 (en) | 2005-04-14 | 2008-03-04 | Duke University | Use of an agent that restores tissue perfusion and oxygenation |
US8557300B2 (en) * | 2005-05-19 | 2013-10-15 | University Of Cincinnati | Methods for treating bacterial respiratory tract infections in an individual using acidified nitrite |
US20070135784A1 (en) * | 2005-12-13 | 2007-06-14 | Kimberly-Clark Worldwide, Inc. | Surgical drape with superabsorbent fluid management members |
US20070243262A1 (en) * | 2005-12-21 | 2007-10-18 | Hurley Kevin P | Stable S-nitrosothiol formulations |
US7968533B2 (en) | 2006-03-07 | 2011-06-28 | Duke University | Ethyl nitrite as a gastrointestinal smooth muscle relaxant and diagnostic and therapeutic uses thereof |
WO2008079993A2 (en) * | 2006-12-22 | 2008-07-03 | Ikaria, Inc. | Combinations of nitric oxide and sulfide and methods of use and manufacture thereof |
WO2009035550A1 (en) * | 2007-09-10 | 2009-03-19 | Duke University | Treating patients with subarachnoid hemorrhage |
US9649334B2 (en) | 2007-11-15 | 2017-05-16 | The Uab Research Foundation | Use of nitrite salts in chronic ischemia |
AU2008345034A1 (en) * | 2007-12-27 | 2009-07-09 | Aires Pharmaceuticals, Inc. | Aerosolized nitrite and nitric oxide - donating compounds and uses thereof |
EP2297183A4 (en) * | 2008-05-09 | 2012-07-04 | Univ Duke | Treatment for diseases relying on discovery that thioredoxin mediates nitric oxide release in cells |
DE102009013396B3 (en) * | 2009-03-16 | 2010-08-05 | Dräger Medical AG & Co. KG | Apparatus and method for controlling the oxygen dosage of a ventilator |
US20120201906A1 (en) * | 2009-09-08 | 2012-08-09 | Reynolds James D | Novel medical uses for no and no donor compounds |
JP5758904B2 (en) | 2009-10-14 | 2015-08-05 | セラバスク インコーポレーテッド | Nitrite pharmaceutical formulations and their use |
US20120107423A1 (en) | 2010-11-01 | 2012-05-03 | Ino Therapeutics Llc | Methods of Using Inhaled Nitric Oxide Gas for Treatment of Acute Respiratory Distress Syndrome |
US9629358B2 (en) * | 2013-03-15 | 2017-04-25 | Mallinckrodt Hospital Products IP Limited | Administration and monitoring of nitric oxide in ex vivo fluids |
GB201500512D0 (en) * | 2015-01-13 | 2015-02-25 | Soe Health Ltd | Therapeutic treatment methods, and apparatus for use therein |
EP3634523A1 (en) | 2017-06-08 | 2020-04-15 | Case Western Reserve University | Devices and methods for nitrosylation of blood |
Citations (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4353843A (en) * | 1981-01-23 | 1982-10-12 | Union Carbide Corporation | Preparation of nitrite esters |
US4721060A (en) * | 1986-07-17 | 1988-01-26 | Battelle Memorial Institute | Nose-only exposure system |
US4752780A (en) * | 1984-02-03 | 1988-06-21 | Pipkin Neil L | Opto-electronic satellite antenna position sensor |
US4908466A (en) * | 1987-09-29 | 1990-03-13 | Union Carbide Chemicals And Plastics Company Inc. | Process and reaction vessel for production of alkyl nitrite |
US5278192A (en) * | 1992-07-02 | 1994-01-11 | The Research Foundation Of State University Of New York | Method of vasodilator therapy for treating a patient with a condition |
US5412147A (en) * | 1992-12-01 | 1995-05-02 | Bayer Aktiengesellschaft | Process for the continuous preparation of alkyl nitrites |
US5485827A (en) * | 1990-12-05 | 1996-01-23 | The General Hospital Corporation | Methods and devices for treating plumonary vasoconstriction and asthma |
US5571524A (en) * | 1994-06-30 | 1996-11-05 | Unitika Ltd. | Agent for curing ischemic myocardial disease |
US5570683A (en) * | 1990-12-05 | 1996-11-05 | The General Hospital Corporation | Methods and devices for treating pulmonary vasoconstriction and asthma |
US5583101A (en) * | 1994-07-15 | 1996-12-10 | Harvard College | Use of nitrogen oxide species and adducts to inhibit skeletal muscle contraction |
US5649322A (en) * | 1993-03-08 | 1997-07-15 | Bayer Aktiengesellschaft | Process for the preparation of C1 -C4 -alkyl nitrites |
US5713349A (en) * | 1993-06-02 | 1998-02-03 | Keaney; Niall | Inhalation therapy |
US5770645A (en) * | 1996-08-02 | 1998-06-23 | Duke University Medical Center | Polymers for delivering nitric oxide in vivo |
US5823180A (en) * | 1995-04-03 | 1998-10-20 | The General Hospital Corporation | Methods for treating pulmonary vasoconstriction and asthma |
US5824669A (en) * | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US5958427A (en) * | 1996-11-08 | 1999-09-28 | Salzman; Andrew L. | Nitric oxide donor compounds and pharmaceutical compositions for pulmonary hypertension and other indications |
US5962421A (en) * | 1996-05-16 | 1999-10-05 | Zambon, S.A. | Pharmacological association between N-acetylcysteine and levulose for preventing cellular death and related diseases |
US6153186A (en) * | 1995-09-15 | 2000-11-28 | Duke University Medical Center | Red blood cells loaded with S-nitrosothiol and uses therefor |
US6314956B1 (en) * | 1999-09-08 | 2001-11-13 | Duke University | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
US6916471B2 (en) * | 1995-09-15 | 2005-07-12 | Duke University | Red blood cells loaded with S-nitrosothiol and uses therefor |
US7045152B2 (en) * | 1999-09-08 | 2006-05-16 | Duke University | Treating pulmonary disorders with gaseous agent causing repletion of GSNO |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4256908A (en) | 1978-07-03 | 1981-03-17 | Ube Industries, Ltd. | Process for preparing diesters of malonic acid |
EP1023900B1 (en) | 1991-11-14 | 2005-03-16 | The Brigham And Women's Hospital, Inc. | Pharmaceutical composition containing S-nitroso-lipoproteins and use thereof |
JP2937292B2 (en) | 1993-11-26 | 1999-08-23 | 宇部興産株式会社 | Continuous production method of dimethyl carbonate |
DE69823211T2 (en) * | 1997-02-06 | 2004-08-26 | Duke University | No-modified hemoglobins and use therefor |
AU4841700A (en) * | 1999-05-12 | 2000-11-21 | Nitromed, Inc. | Nitrosated and nitrosylated potassium channel activators, compositions and methods of use |
JP4194364B2 (en) | 2000-10-16 | 2008-12-10 | デューク・ユニバーシティ | Therapeutic use of aerosolized S-nitrosoglutathione in cystic fibrosis |
-
1999
- 1999-09-08 US US09/390,215 patent/US6314956B1/en not_active Expired - Lifetime
-
2000
- 2000-08-18 CA CA2383174A patent/CA2383174C/en not_active Expired - Fee Related
- 2000-08-18 EP EP00955290A patent/EP1229954B1/en not_active Expired - Lifetime
- 2000-08-18 WO PCT/US2000/020784 patent/WO2001017596A1/en active IP Right Grant
- 2000-08-18 US US10/069,114 patent/US6945247B1/en not_active Expired - Fee Related
- 2000-08-18 AU AU67515/00A patent/AU772858B2/en not_active Ceased
- 2000-08-18 JP JP2001521381A patent/JP5004391B2/en not_active Expired - Fee Related
-
2005
- 2005-09-20 US US11/231,162 patent/US20070191478A1/en not_active Abandoned
-
2013
- 2013-03-21 US US13/848,202 patent/US8871506B2/en not_active Expired - Fee Related
Patent Citations (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4353843A (en) * | 1981-01-23 | 1982-10-12 | Union Carbide Corporation | Preparation of nitrite esters |
US4752780A (en) * | 1984-02-03 | 1988-06-21 | Pipkin Neil L | Opto-electronic satellite antenna position sensor |
US4721060A (en) * | 1986-07-17 | 1988-01-26 | Battelle Memorial Institute | Nose-only exposure system |
US4908466A (en) * | 1987-09-29 | 1990-03-13 | Union Carbide Chemicals And Plastics Company Inc. | Process and reaction vessel for production of alkyl nitrite |
US5485827A (en) * | 1990-12-05 | 1996-01-23 | The General Hospital Corporation | Methods and devices for treating plumonary vasoconstriction and asthma |
US5873359A (en) * | 1990-12-05 | 1999-02-23 | The General Hospital Corporation | Methods and devices for treating pulmonary vasoconstriction and asthma |
US5570683A (en) * | 1990-12-05 | 1996-11-05 | The General Hospital Corporation | Methods and devices for treating pulmonary vasoconstriction and asthma |
US5278192A (en) * | 1992-07-02 | 1994-01-11 | The Research Foundation Of State University Of New York | Method of vasodilator therapy for treating a patient with a condition |
US5489610A (en) * | 1992-07-02 | 1996-02-06 | Research Foundation Of The State University Of New York | Sustained release organic nitrite therapy |
US5412147A (en) * | 1992-12-01 | 1995-05-02 | Bayer Aktiengesellschaft | Process for the continuous preparation of alkyl nitrites |
US5649322A (en) * | 1993-03-08 | 1997-07-15 | Bayer Aktiengesellschaft | Process for the preparation of C1 -C4 -alkyl nitrites |
US5713349A (en) * | 1993-06-02 | 1998-02-03 | Keaney; Niall | Inhalation therapy |
US5571524A (en) * | 1994-06-30 | 1996-11-05 | Unitika Ltd. | Agent for curing ischemic myocardial disease |
US5583101A (en) * | 1994-07-15 | 1996-12-10 | Harvard College | Use of nitrogen oxide species and adducts to inhibit skeletal muscle contraction |
US5823180A (en) * | 1995-04-03 | 1998-10-20 | The General Hospital Corporation | Methods for treating pulmonary vasoconstriction and asthma |
US6203789B1 (en) * | 1995-09-15 | 2001-03-20 | Duke University | Red blood cells loaded with S-nitrosothiol and uses therefor |
US7329543B2 (en) * | 1995-09-15 | 2008-02-12 | Duke University | Red blood cells loaded with S-nitrosothiol and uses therefor |
US6916471B2 (en) * | 1995-09-15 | 2005-07-12 | Duke University | Red blood cells loaded with S-nitrosothiol and uses therefor |
US6153186A (en) * | 1995-09-15 | 2000-11-28 | Duke University Medical Center | Red blood cells loaded with S-nitrosothiol and uses therefor |
US5824669A (en) * | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US5962421A (en) * | 1996-05-16 | 1999-10-05 | Zambon, S.A. | Pharmacological association between N-acetylcysteine and levulose for preventing cellular death and related diseases |
US5770645A (en) * | 1996-08-02 | 1998-06-23 | Duke University Medical Center | Polymers for delivering nitric oxide in vivo |
US5958427A (en) * | 1996-11-08 | 1999-09-28 | Salzman; Andrew L. | Nitric oxide donor compounds and pharmaceutical compositions for pulmonary hypertension and other indications |
US6314956B1 (en) * | 1999-09-08 | 2001-11-13 | Duke University | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
US6945247B1 (en) * | 1999-09-08 | 2005-09-20 | Duke University | Method of treating cardio pulmonary diseases with no group compounds |
US7045152B2 (en) * | 1999-09-08 | 2006-05-16 | Duke University | Treating pulmonary disorders with gaseous agent causing repletion of GSNO |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130210136A1 (en) * | 1999-09-08 | 2013-08-15 | Duke University | Methods For Treating Cardio Pulmonary Diseases With NO Group Compounds |
US8871506B2 (en) * | 1999-09-08 | 2014-10-28 | Duke University | Methods for treating cardio pulmonary diseases with NO group compounds |
WO2010011928A1 (en) * | 2008-07-24 | 2010-01-28 | Geno Llc | Methods for diagnosing and treating a heart condition in a patient |
US20100030091A1 (en) * | 2008-07-24 | 2010-02-04 | Fine David H | Methods for diagnosing and treating a heart condition in a patient |
AU2009273911B2 (en) * | 2008-07-24 | 2016-09-08 | VERO Biotech LLC. | Methods for diagnosing and treating a heart condition in a patient |
US11000484B2 (en) | 2008-07-24 | 2021-05-11 | Vero Biotech LLC | Methods for diagnosing and treating a heart condition in a patient |
WO2021252347A1 (en) * | 2020-06-09 | 2021-12-16 | The Texas A&M University System | Therapeutics for treatment of covid-19 symptoms |
Also Published As
Publication number | Publication date |
---|---|
WO2001017596A1 (en) | 2001-03-15 |
US20130210136A1 (en) | 2013-08-15 |
EP1229954B1 (en) | 2012-11-28 |
AU772858B2 (en) | 2004-05-06 |
US6314956B1 (en) | 2001-11-13 |
CA2383174C (en) | 2012-01-24 |
EP1229954A1 (en) | 2002-08-14 |
AU6751500A (en) | 2001-04-10 |
US6945247B1 (en) | 2005-09-20 |
CA2383174A1 (en) | 2001-03-15 |
JP2003524630A (en) | 2003-08-19 |
JP5004391B2 (en) | 2012-08-22 |
EP1229954A4 (en) | 2005-05-25 |
US8871506B2 (en) | 2014-10-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8871506B2 (en) | Methods for treating cardio pulmonary diseases with NO group compounds | |
US5885621A (en) | Treatment of a hemoglobinopathy | |
US6063407A (en) | Treatment of vascular thrombosis and restenosis with inhaled nitric oxide | |
JP3779726B2 (en) | Use of gaseous nitric oxide to produce a pharmaceutical composition | |
DK1516639T4 (en) | Use of NO to treat persistent pulmonary hypertension in newborns | |
STEINHORN et al. | Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension | |
Troncy et al. | Extra-pulmonary effects of inhaled nitric oxide in swine with and without phenylephrine | |
JP2003524630A5 (en) | ||
Jacobs et al. | Aerosolized soluble nitric oxide donor improves oxygenation and pulmonary hypertension in acute lung injury | |
Etches et al. | Nitric oxide reverses acute hypoxic pulmonary hypertension in the newborn piglet | |
US20050255178A1 (en) | Enhancing the effectiveness of an inhaled therapeutic gas | |
Fischer et al. | Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis | |
Combes et al. | Effect of 48 hours of nitric oxide inhalation on pulmonary vasoreactivity in rats | |
Holzmann et al. | Inhibition of nitric oxide synthase prevents hyporesponsiveness to inhaled nitric oxide in lungs from endotoxin-challenged rats | |
Lindberg et al. | Inhaled nitric oxide reveals and attenuates endothelial dysfunction after lung transplantation | |
Ichinose et al. | Inhaled nitric oxide—current practice and future potential uses and development | |
Ko et al. | Clinical response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn | |
Angdin et al. | No effect of L‐arginine supplementation on pulmonary endothelial dysfunction after cardiopulmonary bypass | |
EP3797784A1 (en) | Anti-coagulant agent, blood coagulation improving device, blood coagulation improving method, vascular endothelial cell function improving method, and metabolism improving method | |
EP1712226A2 (en) | Treatment of a Hemoglobinopathy | |
Payen et al. | Almitrine and inhaled nitric oxide in acute respiratory failure | |
Bjertnaes et al. | Nebulized nitric oxide/nucleophile adduct reduces pulmonary vascular resistance in mechanically ventilated septicemic sheep | |
Lorenzo Berra et al. | Autologous Transfusion of Stored Red Blood Cells Increases Pulmonary Artery Pressure | |
Breuer et al. | Inhaled nitric oxide treatment of children with pulmonary hypertension after cardiac surgery | |
MXPA98008195A (en) | Treatment of a hemoglobinopa |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |