US20230108186A1 - Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto - Google Patents
Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto Download PDFInfo
- Publication number
- US20230108186A1 US20230108186A1 US17/797,776 US202117797776A US2023108186A1 US 20230108186 A1 US20230108186 A1 US 20230108186A1 US 202117797776 A US202117797776 A US 202117797776A US 2023108186 A1 US2023108186 A1 US 2023108186A1
- Authority
- US
- United States
- Prior art keywords
- cancer
- alkyl
- compound
- disorder
- group
- 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.)
- Pending
Links
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims abstract description 559
- 150000001875 compounds Chemical class 0.000 title claims abstract description 272
- 238000000034 method Methods 0.000 title claims abstract description 72
- 230000003578 releasing effect Effects 0.000 title claims abstract description 34
- 239000000203 mixture Substances 0.000 title description 140
- 238000009472 formulation Methods 0.000 title description 22
- 230000000844 anti-bacterial effect Effects 0.000 title description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 94
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 38
- 201000010099 disease Diseases 0.000 claims abstract description 35
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 206010061218 Inflammation Diseases 0.000 claims abstract description 19
- 230000004054 inflammatory process Effects 0.000 claims abstract description 18
- 208000037803 restenosis Diseases 0.000 claims abstract description 18
- 230000002159 abnormal effect Effects 0.000 claims abstract description 16
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 15
- 208000002193 Pain Diseases 0.000 claims abstract description 12
- 206010037660 Pyrexia Diseases 0.000 claims abstract description 12
- 230000004663 cell proliferation Effects 0.000 claims abstract description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 10
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 10
- 201000004384 Alopecia Diseases 0.000 claims abstract description 9
- 230000003676 hair loss Effects 0.000 claims abstract description 9
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 9
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 7
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 7
- 230000001575 pathological effect Effects 0.000 claims abstract description 7
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 7
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 6
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 6
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 6
- 208000019553 vascular disease Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 145
- 208000035475 disorder Diseases 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 125000001072 heteroaryl group Chemical group 0.000 claims description 52
- 239000003814 drug Substances 0.000 claims description 35
- 238000011282 treatment Methods 0.000 claims description 33
- 150000001768 cations Chemical class 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 229940079593 drug Drugs 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 208000027866 inflammatory disease Diseases 0.000 claims description 17
- 208000007536 Thrombosis Diseases 0.000 claims description 16
- 208000027418 Wounds and injury Diseases 0.000 claims description 14
- 230000006378 damage Effects 0.000 claims description 13
- 208000028867 ischemia Diseases 0.000 claims description 11
- 210000003169 central nervous system Anatomy 0.000 claims description 10
- 208000014674 injury Diseases 0.000 claims description 8
- 208000007056 sickle cell anemia Diseases 0.000 claims description 8
- 206010063837 Reperfusion injury Diseases 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 230000018537 nitric oxide storage Effects 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 206010043778 thyroiditis Diseases 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 208000008158 Chorioamnionitis Diseases 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 208000009525 Myocarditis Diseases 0.000 claims description 4
- 206010039705 Scleritis Diseases 0.000 claims description 4
- 206010043255 Tendonitis Diseases 0.000 claims description 4
- 206010047115 Vasculitis Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 230000001434 glomerular Effects 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 210000004872 soft tissue Anatomy 0.000 claims description 4
- 208000003265 stomatitis Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 201000009906 Meningitis Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 208000020832 chronic kidney disease Diseases 0.000 claims description 3
- 201000001981 dermatomyositis Diseases 0.000 claims description 3
- 206010014599 encephalitis Diseases 0.000 claims description 3
- 210000000750 endocrine system Anatomy 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- 206010062269 Adrenalitis Diseases 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 206010060937 Amniotic cavity infection Diseases 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 206010003011 Appendicitis Diseases 0.000 claims description 2
- 206010004078 Balanoposthitis Diseases 0.000 claims description 2
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010006448 Bronchiolitis Diseases 0.000 claims description 2
- 206010006811 Bursitis Diseases 0.000 claims description 2
- 208000034598 Caecitis Diseases 0.000 claims description 2
- 206010068406 Capillaritis Diseases 0.000 claims description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
- 206010062746 Carditis Diseases 0.000 claims description 2
- 206010007882 Cellulitis Diseases 0.000 claims description 2
- 206010008685 Chondritis Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- 206010011841 Dacryoadenitis acquired Diseases 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
- 208000004145 Endometritis Diseases 0.000 claims description 2
- 208000004232 Enteritis Diseases 0.000 claims description 2
- 201000011275 Epicondylitis Diseases 0.000 claims description 2
- 206010015084 Episcleritis Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010016228 Fasciitis Diseases 0.000 claims description 2
- 206010016936 Folliculitis Diseases 0.000 claims description 2
- 208000007882 Gastritis Diseases 0.000 claims description 2
- 208000005577 Gastroenteritis Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 208000005232 Glossitis Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 206010062767 Hypophysitis Diseases 0.000 claims description 2
- 206010061252 Intraocular melanoma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010023567 Labyrinthitis Diseases 0.000 claims description 2
- 201000008197 Laryngitis Diseases 0.000 claims description 2
- 208000010315 Mastoiditis Diseases 0.000 claims description 2
- 208000003926 Myelitis Diseases 0.000 claims description 2
- 201000002481 Myositis Diseases 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 206010029240 Neuritis Diseases 0.000 claims description 2
- 206010030216 Oesophagitis Diseases 0.000 claims description 2
- 206010031149 Osteitis Diseases 0.000 claims description 2
- 208000002804 Osteochondritis Diseases 0.000 claims description 2
- 201000009859 Osteochondrosis Diseases 0.000 claims description 2
- 206010031252 Osteomyelitis Diseases 0.000 claims description 2
- 206010033078 Otitis media Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010033847 Parametritis Diseases 0.000 claims description 2
- 206010034038 Parotitis Diseases 0.000 claims description 2
- 208000002471 Penile Neoplasms Diseases 0.000 claims description 2
- 206010034464 Periarthritis Diseases 0.000 claims description 2
- 208000006735 Periostitis Diseases 0.000 claims description 2
- 201000007100 Pharyngitis Diseases 0.000 claims description 2
- 206010035742 Pneumonitis Diseases 0.000 claims description 2
- 206010036379 Posthitis Diseases 0.000 claims description 2
- 206010036774 Proctitis Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000004328 Pulpitis Diseases 0.000 claims description 2
- 206010037464 Pulpitis dental Diseases 0.000 claims description 2
- 206010037596 Pyelonephritis Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010038910 Retinitis Diseases 0.000 claims description 2
- 208000007893 Salpingitis Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 206010039954 Seminal vesiculitis Diseases 0.000 claims description 2
- 206010040628 Sialoadenitis Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 201000002661 Spondylitis Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000000491 Tendinopathy Diseases 0.000 claims description 2
- 208000004760 Tenosynovitis Diseases 0.000 claims description 2
- 206010044302 Tracheitis Diseases 0.000 claims description 2
- 208000023915 Ureteral Neoplasms Diseases 0.000 claims description 2
- 206010046458 Urethral neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006374 Uterine Cervicitis Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 201000005969 Uveal melanoma Diseases 0.000 claims description 2
- 206010046851 Uveitis Diseases 0.000 claims description 2
- 206010046914 Vaginal infection Diseases 0.000 claims description 2
- 201000008100 Vaginitis Diseases 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 239000003146 anticoagulant agent Substances 0.000 claims description 2
- 229940127219 anticoagulant drug Drugs 0.000 claims description 2
- 206010003074 arachnoiditis Diseases 0.000 claims description 2
- 206010003230 arteritis Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 201000010313 ascending cholangitis Diseases 0.000 claims description 2
- 208000002479 balanitis Diseases 0.000 claims description 2
- 208000010217 blepharitis Diseases 0.000 claims description 2
- 208000018339 bone inflammation disease Diseases 0.000 claims description 2
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 206010008323 cervicitis Diseases 0.000 claims description 2
- 208000007287 cheilitis Diseases 0.000 claims description 2
- 208000003167 cholangitis Diseases 0.000 claims description 2
- 201000001352 cholecystitis Diseases 0.000 claims description 2
- 201000004709 chorioretinitis Diseases 0.000 claims description 2
- 208000024207 chronic leukemia Diseases 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 208000030381 cutaneous melanoma Diseases 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 201000004400 dacryoadenitis Diseases 0.000 claims description 2
- 206010013864 duodenitis Diseases 0.000 claims description 2
- 206010014665 endocarditis Diseases 0.000 claims description 2
- 208000010227 enterocolitis Diseases 0.000 claims description 2
- 208000020947 enthesitis Diseases 0.000 claims description 2
- 201000010063 epididymitis Diseases 0.000 claims description 2
- 208000006881 esophagitis Diseases 0.000 claims description 2
- 208000028149 female reproductive system neoplasm Diseases 0.000 claims description 2
- 206010064502 funisitis Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000007565 gingivitis Diseases 0.000 claims description 2
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 208000002557 hidradenitis Diseases 0.000 claims description 2
- 208000009326 ileitis Diseases 0.000 claims description 2
- 208000021646 inflammation of heart layer Diseases 0.000 claims description 2
- 206010023332 keratitis Diseases 0.000 claims description 2
- 201000003265 lymphadenitis Diseases 0.000 claims description 2
- 206010025226 lymphangitis Diseases 0.000 claims description 2
- 230000000527 lymphocytic effect Effects 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 208000004396 mastitis Diseases 0.000 claims description 2
- 201000001231 mediastinitis Diseases 0.000 claims description 2
- 208000005135 methemoglobinemia Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 230000000414 obstructive effect Effects 0.000 claims description 2
- 201000002575 ocular melanoma Diseases 0.000 claims description 2
- 206010030306 omphalitis Diseases 0.000 claims description 2
- 208000005963 oophoritis Diseases 0.000 claims description 2
- 201000005737 orchitis Diseases 0.000 claims description 2
- 206010033072 otitis externa Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 206010033675 panniculitis Diseases 0.000 claims description 2
- 208000008494 pericarditis Diseases 0.000 claims description 2
- 206010034674 peritonitis Diseases 0.000 claims description 2
- 208000001297 phlebitis Diseases 0.000 claims description 2
- 201000007094 prostatitis Diseases 0.000 claims description 2
- 201000001474 proteinuria Diseases 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 206010039083 rhinitis Diseases 0.000 claims description 2
- 210000004761 scalp Anatomy 0.000 claims description 2
- 208000001050 sialadenitis Diseases 0.000 claims description 2
- 201000009890 sinusitis Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 201000003708 skin melanoma Diseases 0.000 claims description 2
- 210000000813 small intestine Anatomy 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000004595 synovitis Diseases 0.000 claims description 2
- 201000004415 tendinitis Diseases 0.000 claims description 2
- 206010044008 tonsillitis Diseases 0.000 claims description 2
- 210000000626 ureter Anatomy 0.000 claims description 2
- 206010051250 ureteritis Diseases 0.000 claims description 2
- 208000000143 urethritis Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 201000010653 vesiculitis Diseases 0.000 claims description 2
- 208000002003 vulvitis Diseases 0.000 claims description 2
- 208000010643 digestive system disease Diseases 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 208000018685 gastrointestinal system disease Diseases 0.000 claims 1
- 238000002054 transplantation Methods 0.000 abstract 1
- -1 small molecule nitric oxide donors Chemical class 0.000 description 52
- 125000000623 heterocyclic group Chemical group 0.000 description 50
- 125000000753 cycloalkyl group Chemical group 0.000 description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 42
- 239000002840 nitric oxide donor Substances 0.000 description 33
- 239000002245 particle Substances 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 32
- 210000001519 tissue Anatomy 0.000 description 31
- 229920000642 polymer Polymers 0.000 description 30
- 125000004429 atom Chemical group 0.000 description 29
- 238000012384 transportation and delivery Methods 0.000 description 28
- 125000005842 heteroatom Chemical group 0.000 description 26
- 125000002947 alkylene group Chemical group 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 125000003342 alkenyl group Chemical group 0.000 description 21
- 125000000304 alkynyl group Chemical group 0.000 description 21
- 125000000392 cycloalkenyl group Chemical group 0.000 description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 21
- 210000004072 lung Anatomy 0.000 description 20
- 230000003232 mucoadhesive effect Effects 0.000 description 20
- 239000000499 gel Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 17
- 230000000845 anti-microbial effect Effects 0.000 description 16
- 210000004556 brain Anatomy 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 125000003277 amino group Chemical group 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 14
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 14
- 230000008499 blood brain barrier function Effects 0.000 description 14
- 210000001218 blood-brain barrier Anatomy 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 229960004502 levodopa Drugs 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 230000008901 benefit Effects 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 241000894007 species Species 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 229910001868 water Inorganic materials 0.000 description 12
- 208000012661 Dyskinesia Diseases 0.000 description 11
- 230000009471 action Effects 0.000 description 11
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000002502 liposome Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 10
- 208000015181 infectious disease Diseases 0.000 description 10
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000443 aerosol Substances 0.000 description 9
- 210000001772 blood platelet Anatomy 0.000 description 9
- 229960003711 glyceryl trinitrate Drugs 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 230000036542 oxidative stress Effects 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- 230000008439 repair process Effects 0.000 description 9
- 208000016285 Movement disease Diseases 0.000 description 8
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000004599 antimicrobial Substances 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 230000000813 microbial effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000009885 systemic effect Effects 0.000 description 8
- MUMXDRRTIYLYMY-YJKCNMNRSA-N (Z)-[dodecyl-[6-(dodecylazaniumyl)hexyl]amino]-oxido-oxidoiminoazanium Chemical compound CCCCCCCCCCCC[NH2+]CCCCCCN(CCCCCCCCCCCC)[N+](\[O-])=N\[O-] MUMXDRRTIYLYMY-YJKCNMNRSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 206010052428 Wound Diseases 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 238000002663 nebulization Methods 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 125000003003 spiro group Chemical group 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 6
- 108060006698 EGF receptor Proteins 0.000 description 6
- 239000004721 Polyphenylene oxide Substances 0.000 description 6
- 241000589516 Pseudomonas Species 0.000 description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 6
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000012491 analyte Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 6
- 208000010877 cognitive disease Diseases 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 6
- 230000033001 locomotion Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 210000003097 mucus Anatomy 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 208000033808 peripheral neuropathy Diseases 0.000 description 6
- 230000004962 physiological condition Effects 0.000 description 6
- 229920000570 polyether Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 230000002685 pulmonary effect Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000000717 retained effect Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 6
- 230000008685 targeting Effects 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 5
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 5
- 208000035143 Bacterial infection Diseases 0.000 description 5
- 206010012289 Dementia Diseases 0.000 description 5
- 208000020401 Depressive disease Diseases 0.000 description 5
- 201000011240 Frontotemporal dementia Diseases 0.000 description 5
- 208000027626 Neurocognitive disease Diseases 0.000 description 5
- 229920002807 Thiomer Polymers 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 208000022362 bacterial infectious disease Diseases 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 210000000748 cardiovascular system Anatomy 0.000 description 5
- 239000002738 chelating agent Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000004087 circulation Effects 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 210000000987 immune system Anatomy 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000015654 memory Effects 0.000 description 5
- 208000030159 metabolic disease Diseases 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000035479 physiological effects, processes and functions Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000029865 regulation of blood pressure Effects 0.000 description 5
- 210000002345 respiratory system Anatomy 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 208000020925 Bipolar disease Diseases 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 206010008748 Chorea Diseases 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 208000014094 Dystonic disease Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 208000024248 Vascular System injury Diseases 0.000 description 4
- 208000012339 Vascular injury Diseases 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000036760 body temperature Effects 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 208000024732 dysthymic disease Diseases 0.000 description 4
- 208000010118 dystonia Diseases 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000003483 hypokinetic effect Effects 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 4
- 201000001119 neuropathy Diseases 0.000 description 4
- 230000007823 neuropathy Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 4
- 210000005166 vasculature Anatomy 0.000 description 4
- 239000002525 vasculotropin inhibitor Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 3
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 3
- 208000027448 Attention Deficit and Disruptive Behavior disease Diseases 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 108090001090 Lectins Proteins 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 3
- 208000009829 Lewy Body Disease Diseases 0.000 description 3
- 201000002832 Lewy body dementia Diseases 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 3
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 3
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- 208000019022 Mood disease Diseases 0.000 description 3
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 3
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010034010 Parkinsonism Diseases 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000005631 S-sulfonamido group Chemical group 0.000 description 3
- 206010039710 Scleroderma Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 description 3
- 201000004810 Vascular dementia Diseases 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000003466 anti-cipated effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 208000016097 disease of metabolism Diseases 0.000 description 3
- 229940052760 dopamine agonists Drugs 0.000 description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- KHKNSUCGCADPLR-UHFFFAOYSA-N imino(dioxido)azanium methane Chemical compound C.[O-][N+]([O-])=N.[O-][N+]([O-])=N.[O-][N+]([O-])=N KHKNSUCGCADPLR-UHFFFAOYSA-N 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 239000002523 lectin Substances 0.000 description 3
- 238000002483 medication Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 150000002826 nitrites Chemical class 0.000 description 3
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 230000010118 platelet activation Effects 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 229940083618 sodium nitroprusside Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 230000024883 vasodilation Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- YZBAXVICWUUHGG-UHFFFAOYSA-N 2-[[4-[2-[dimethyl(oxido)azaniumyl]ethylamino]-5,8-dihydroxy-9,10-dioxoanthracen-1-yl]amino]-n,n-dimethylethanamine oxide Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCC[N+](C)(C)[O-])=CC=C2NCC[N+](C)([O-])C YZBAXVICWUUHGG-UHFFFAOYSA-N 0.000 description 2
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- REQFUGYVPAQCTH-UHFFFAOYSA-N 5-[[5-[(4-hydroxyphenyl)methyl]-4-[(4-methoxyphenyl)methyl]-1-methylimidazol-2-yl]amino]-3-methylimidazole-2,4-dione Chemical compound C1=CC(OC)=CC=C1CC1=C(CC=2C=CC(O)=CC=2)N(C)C(NC=2C(N(C)C(=O)N=2)=O)=N1 REQFUGYVPAQCTH-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 206010058504 Ballismus Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 208000025721 COVID-19 Diseases 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 108090000994 Catalytic RNA Proteins 0.000 description 2
- 102000053642 Catalytic RNA Human genes 0.000 description 2
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 2
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 241001227713 Chiron Species 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 208000027691 Conduct disease Diseases 0.000 description 2
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 2
- 102100021906 Cyclin-O Human genes 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000058063 Glucose Transporter Type 1 Human genes 0.000 description 2
- 108700006771 Glut1 Deficiency Syndrome Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000000269 Hyperkinesis Diseases 0.000 description 2
- 208000006083 Hypokinesia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 208000015592 Involuntary movements Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 229940124761 MMP inhibitor Drugs 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 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 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 2
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 2
- 239000000006 Nitroglycerin Substances 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- 208000007641 Pinealoma Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 208000027030 Premenstrual dysphoric disease Diseases 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 208000005793 Restless legs syndrome Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 108091006296 SLC2A1 Proteins 0.000 description 2
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 2
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000027522 Sydenham chorea Diseases 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- HJSSPYJVWLTYHG-UHFFFAOYSA-N XL765 Chemical compound COC1=CC(OC)=CC(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=CC(NC(=O)C=3C=C(OC)C(C)=CC=3)=CC=2)=C1 HJSSPYJVWLTYHG-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229950008995 aducanumab Drugs 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 125000005264 aryl amine group Chemical group 0.000 description 2
- 208000025748 atypical depressive disease Diseases 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- 229950002826 canertinib Drugs 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 230000006652 catabolic pathway Effects 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940107161 cholesterol Drugs 0.000 description 2
- 208000012601 choreatic disease Diseases 0.000 description 2
- 229950009003 cilengitide Drugs 0.000 description 2
- AMLYAMJWYAIXIA-VWNVYAMZSA-N cilengitide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1CC1=CC=CC=C1 AMLYAMJWYAIXIA-VWNVYAMZSA-N 0.000 description 2
- 230000005794 circulatory dysfunction Effects 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- XRKMNJXYOFSTBE-UHFFFAOYSA-N disodium;iron(4+);nitroxyl anion;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+4].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] XRKMNJXYOFSTBE-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 230000003779 hair growth Effects 0.000 description 2
- 208000024963 hair loss Diseases 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 210000003041 ligament Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000000569 multi-angle light scattering Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 208000008795 neuromyelitis optica Diseases 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000009635 nitrosylation Effects 0.000 description 2
- 208000024196 oppositional defiant disease Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001987 poloxamine Polymers 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000004648 relaxation of smooth muscle Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 108091092562 ribozyme Proteins 0.000 description 2
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 208000012672 seasonal affective disease Diseases 0.000 description 2
- 229950003647 semaxanib Drugs 0.000 description 2
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000012385 systemic delivery Methods 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- 229940061353 temodar Drugs 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 229940094720 viagra Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 1
- 229930014124 (-)-epigallocatechin gallate Natural products 0.000 description 1
- FUXUMEVLBNCHHR-NGJCQDCLSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[(4R)-4-carbamoyl-1,3-thiazolidin-3-yl]-4-methylpentan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-(3-phenylpropanoylamino)pentanediamide Chemical compound CC(C)C[C@@H](CN1CSC[C@H]1C(N)=O)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)CCc1ccccc1)C(C)C FUXUMEVLBNCHHR-NGJCQDCLSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- JVAZJLFFSJARQM-RMPHRYRLSA-N (2r,3r,4s,5s,6r)-2-hexoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-RMPHRYRLSA-N 0.000 description 1
- HEGSGKPQLMEBJL-RQICVUQASA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-6-octoxyoxane-3,4,5-triol Chemical compound CCCCCCCCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RQICVUQASA-N 0.000 description 1
- IDXCXSCCZNCXCL-XMADEQCMSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-[[2-[[(2s,4r)-1-[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]pyrrolidine Chemical compound C1=CC(OC)=CC=C1C[C@@H](CN[C@@H](CCCN=C(N)N)C(O)=O)NC(=O)[C@H]1N(C(=O)[C@H](CO)NC(=O)[C@H](CC=2SC=CC=2)NC(=O)CNC(=O)[C@H]2N(C[C@H](O)C2)C(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCN=C(N)N)CCC1 IDXCXSCCZNCXCL-XMADEQCMSA-N 0.000 description 1
- JDRSMPFHFNXQRB-IWQYDBTJSA-N (3r,4s,5s,6r)-2-decoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCCCCCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JDRSMPFHFNXQRB-IWQYDBTJSA-N 0.000 description 1
- HVGGGVAREUUJQV-CHHVJCJISA-N (4z)-4-[3-(2,5-dichloro-4,6-dimethyl-1-oxidopyridin-1-ium-3-yl)-2h-1,2,4-oxadiazol-5-ylidene]-2-hydroxy-6-nitrocyclohexa-2,5-dien-1-one Chemical compound CC1=C(Cl)C(C)=[N+]([O-])C(Cl)=C1C(NO1)=N\C1=C\1C=C([N+]([O-])=O)C(=O)C(O)=C/1 HVGGGVAREUUJQV-CHHVJCJISA-N 0.000 description 1
- KMPLYESDOZJASB-PAHRJMAXSA-N (6s,8r,9s,10r,13s,14s,17r)-17-acetyl-17-hydroxy-6-methoxy-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-3-one;(z)-n-carbamoyl-2-ethylbut-2-enamide;6-ethoxy-1,3-benzothiazole-2-sulfonamide Chemical compound CC\C(=C\C)C(=O)NC(N)=O.CCOC1=CC=C2N=C(S(N)(=O)=O)SC2=C1.C([C@@]12C)CC(=O)C=C1[C@@H](OC)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 KMPLYESDOZJASB-PAHRJMAXSA-N 0.000 description 1
- GPMIHHFZKBVWAZ-LMMKTYIZSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-6-methyl-5-phenylmethoxyoxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)CC1=CC=CC=C1 GPMIHHFZKBVWAZ-LMMKTYIZSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- YNRCBOXEDICOIX-CLFYSBASSA-N (Z)-[bis(2-aminoethyl)amino]-hydroxyimino-oxidoazanium Chemical compound NCCN(CC[NH3+])[N+](\[O-])=N\[O-] YNRCBOXEDICOIX-CLFYSBASSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- LKLLNYWECKEQIB-UHFFFAOYSA-N 1,3,5-triazinane Chemical compound C1NCNCN1 LKLLNYWECKEQIB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- QVFHFKPGBODJJB-UHFFFAOYSA-N 1,3-oxathiane Chemical compound C1COCSC1 QVFHFKPGBODJJB-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JBYHSSAVUBIJMK-UHFFFAOYSA-N 1,4-oxathiane Chemical compound C1CSCCO1 JBYHSSAVUBIJMK-UHFFFAOYSA-N 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical group CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- CUCJJMLDIUSNPU-UHFFFAOYSA-N 1-oxidopiperidin-1-ium Chemical compound [O-][NH+]1CCCCC1 CUCJJMLDIUSNPU-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- UDSAJFSYJMHNFI-UHFFFAOYSA-N 2,6-diazaspiro[3.3]heptane Chemical compound C1NCC11CNC1 UDSAJFSYJMHNFI-UHFFFAOYSA-N 0.000 description 1
- YVCXQRVVNQMZEI-UHFFFAOYSA-N 2,6-dibromo-4-[(6,7-dimethoxy-4-quinazolinyl)amino]phenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(Br)=C(O)C(Br)=C1 YVCXQRVVNQMZEI-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 1
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical group C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 description 1
- PSNDWZOXFDKLLH-UHFFFAOYSA-N 2-azaspiro[3.4]octane Chemical compound C1NCC11CCCC1 PSNDWZOXFDKLLH-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- KIHAGWUUUHJRMS-JOCHJYFZSA-N 2-octadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@H](CO)COP(O)(=O)OCCN KIHAGWUUUHJRMS-JOCHJYFZSA-N 0.000 description 1
- HPJALMWOZYIZGE-UHFFFAOYSA-N 2-oxa-6-azaspiro[3.3]heptane Chemical compound C1NCC11COC1 HPJALMWOZYIZGE-UHFFFAOYSA-N 0.000 description 1
- SUSDYISRJSLTST-UHFFFAOYSA-N 2-oxaspiro[3.3]heptane Chemical compound C1CCC21COC2 SUSDYISRJSLTST-UHFFFAOYSA-N 0.000 description 1
- NTMUDPWGPGZGQW-UHFFFAOYSA-N 2-oxaspiro[3.4]octane Chemical compound C1OCC11CCCC1 NTMUDPWGPGZGQW-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- UFKLYTOEMRFKAD-UHFFFAOYSA-N 3-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-5-(4-methoxycyclohexyl)-7,8-dihydropyrazino[2,3-b]pyrazin-6-one Chemical compound C1CC(OC)CCC1N1C2=NC(C=3C=NC(=CC=3)C(C)(C)O)=CN=C2NCC1=O UFKLYTOEMRFKAD-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- PMYJGTWUVVVOFO-UHFFFAOYSA-N 4-phenyl-3-furoxancarbonitrile Chemical compound N#CC1=[N+]([O-])ON=C1C1=CC=CC=C1 PMYJGTWUVVVOFO-UHFFFAOYSA-N 0.000 description 1
- MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- OONFNUWBHFSNBT-HXUWFJFHSA-N AEE788 Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)C=C1 OONFNUWBHFSNBT-HXUWFJFHSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 206010001541 Akinesia Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 206010001881 Alveolar proteinosis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 108090000644 Angiozyme Proteins 0.000 description 1
- 206010002515 Animal bite Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000009017 Athetosis Diseases 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UFKLYTOEMRFKAD-SHTZXODSSA-N C1C[C@@H](OC)CC[C@@H]1N1C2=NC(C=3C=NC(=CC=3)C(C)(C)O)=CN=C2NCC1=O Chemical compound C1C[C@@H](OC)CC[C@@H]1N1C2=NC(C=3C=NC(=CC=3)C(C)(C)O)=CN=C2NCC1=O UFKLYTOEMRFKAD-SHTZXODSSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 208000014882 Carotid artery disease Diseases 0.000 description 1
- 208000034628 Celiac artery compression syndrome Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010068768 Cerebellar cognitive affective syndrome Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- PBEVPBFDKPJIOM-HQKLUXGTSA-N Cl.Cl.C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@](OC)(COC(=O)CCNC(=O)[C@@H](N)CCCCN)[C@]4(C)O1 Chemical compound Cl.Cl.C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@](OC)(COC(=O)CCNC(=O)[C@@H](N)CCCCN)[C@]4(C)O1 PBEVPBFDKPJIOM-HQKLUXGTSA-N 0.000 description 1
- 208000036166 Classic glucose transporter type 1 deficiency syndrome Diseases 0.000 description 1
- 102100027995 Collagenase 3 Human genes 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000016270 Corticobasal syndrome Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 208000008960 Diabetic foot Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000001308 Fasciculation Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000007686 GLUT1 deficiency syndrome Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018338 Glioma Diseases 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
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 108700017667 Hca(6)-Leu(13)-psi(CH2N)-Tac(14)- bombesin(6-14) Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 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
- 206010019909 Hernia Diseases 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000005230 Leg Ulcer Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000025380 Logopenic progressive aphasia Diseases 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 102100030417 Matrilysin Human genes 0.000 description 1
- 108090000855 Matrilysin Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000009645 Mitochondrial Aldehyde Dehydrogenase Human genes 0.000 description 1
- 108010009513 Mitochondrial Aldehyde Dehydrogenase Proteins 0.000 description 1
- 208000019430 Motor disease Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010028293 Muscle contractions involuntary Diseases 0.000 description 1
- 206010028403 Mutism Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- BTYYWOYVBXILOJ-UHFFFAOYSA-N N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}but-2-ynamide Chemical compound C12=CC(NC(=O)C#CC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 BTYYWOYVBXILOJ-UHFFFAOYSA-N 0.000 description 1
- FTFRZXFNZVCRSK-UHFFFAOYSA-N N4-(3-chloro-4-fluorophenyl)-N6-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidine-4,6-diamine Chemical compound C1CN(C)CCC1NC1=NC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=N1 FTFRZXFNZVCRSK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 206010050487 Pinealoblastoma Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000026301 Postoperative Cognitive Complications Diseases 0.000 description 1
- 201000009916 Postpartum depression Diseases 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 208000010291 Primary Progressive Nonfluent Aphasia Diseases 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000025535 REM sleep behavior disease Diseases 0.000 description 1
- 108700031422 RMP 7 Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- 208000008039 Secondary Parkinson Disease Diseases 0.000 description 1
- 206010039917 Selective mutism Diseases 0.000 description 1
- 208000018642 Semantic dementia Diseases 0.000 description 1
- 208000000810 Separation Anxiety Diseases 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- 102100028847 Stromelysin-3 Human genes 0.000 description 1
- 108050005271 Stromelysin-3 Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 229940122777 Tau aggregation inhibitor Drugs 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000023655 Tic Diseases 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 206010044074 Torticollis Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010046814 Uterine prolapse Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- 206010046940 Vaginal prolapse Diseases 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 206010063661 Vascular encephalopathy Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- FOLJTMYCYXSPFQ-CJKAUBRRSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-(octadecanoyloxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl octadecanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCCCCCCCCCC)O[C@@H]1O[C@@]1(COC(=O)CCCCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@H](CO)O1 FOLJTMYCYXSPFQ-CJKAUBRRSA-N 0.000 description 1
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 1
- SPCMQFLNOVTUBM-UHFFFAOYSA-N [7-(dimethylazaniumyl)-10h-phenothiazin-3-yl]-dimethylazanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CS([O-])(=O)=O.C1=C([NH+](C)C)C=C2SC3=CC([NH+](C)C)=CC=C3NC2=C1 SPCMQFLNOVTUBM-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 210000001361 achilles tendon Anatomy 0.000 description 1
- 208000011152 acquired idiopathic torsion dystonia Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229920006318 anionic polymer Polymers 0.000 description 1
- 208000004793 anterograde amnesia Diseases 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229940062310 avandia Drugs 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 229950010936 banoxantrone Drugs 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 238000007681 bariatric surgery Methods 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 1
- 229960000911 benserazide Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 206010005159 blepharospasm Diseases 0.000 description 1
- 230000000744 blepharospasm Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 229960004596 cabergoline Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 230000004706 cardiovascular dysfunction Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 208000010353 central nervous system vasculitis Diseases 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 238000002655 chelation therapy Methods 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N chembl421 Chemical compound C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- ZGHQGWOETPXKLY-XVNBXDOJSA-N chembl77030 Chemical compound NC(=S)C(\C#N)=C\C1=CC=C(O)C(O)=C1 ZGHQGWOETPXKLY-XVNBXDOJSA-N 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 238000011437 continuous method Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 108010044165 crotoxin drug combination cardiotoxin Proteins 0.000 description 1
- 208000029039 cyanide poisoning Diseases 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- DWLTUUXCVGVRAV-XWRHUKJGSA-N davunetide Chemical compound N([C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O DWLTUUXCVGVRAV-XWRHUKJGSA-N 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 208000035548 disruptive behavior disease Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000026663 encephalopathy due to GLUT1 deficiency Diseases 0.000 description 1
- 201000003104 endogenous depression Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 239000000066 endothelium dependent relaxing factor Substances 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
- 229960003337 entacapone Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- CZKPOZZJODAYPZ-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CNC2=CC=CC=C12 CZKPOZZJODAYPZ-LROMGURASA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 208000011149 familial idiopathic torsion dystonia Diseases 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003352 fibrogenic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000017561 flaccidity Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 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
- 229960003883 furosemide Drugs 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108010054561 gastric mucus glycoproteins Proteins 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000000285 glutaminergic effect Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 238000012388 gravitational sedimentation Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000004886 head movement Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 229940056984 integrilin Drugs 0.000 description 1
- 210000001613 integumentary system Anatomy 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000013152 interventional procedure Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000005061 intracellular organelle Anatomy 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 229960003827 isosorbide mononitrate Drugs 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 229940045773 jakafi Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000020796 long term synaptic depression Effects 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000019735 mitochondria-nucleus signaling pathway Effects 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 210000005099 mouse brain capillary cell Anatomy 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- YHYKUSGACIYRML-KRWDZBQOSA-N n-[3-[(5r)-3-amino-2,5-dimethyl-1,1-dioxo-6h-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C1S(=O)(=O)N(C)C(N)=N[C@]1(C)C1=CC(NC(=O)C=2N=CC(F)=CC=2)=CC=C1F YHYKUSGACIYRML-KRWDZBQOSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- UMWKZHPREXJQGR-XOSAIJSUSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]decanamide Chemical compound CCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO UMWKZHPREXJQGR-XOSAIJSUSA-N 0.000 description 1
- VHYYJWLKCODCNM-OIMNJJJWSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]heptanamide Chemical compound CCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO VHYYJWLKCODCNM-OIMNJJJWSA-N 0.000 description 1
- GCRLIVCNZWDCDE-SJXGUFTOSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]nonanamide Chemical compound CCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO GCRLIVCNZWDCDE-SJXGUFTOSA-N 0.000 description 1
- SBWGZAXBCCNRTM-CTHBEMJXSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]octanamide Chemical compound CCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SBWGZAXBCCNRTM-CTHBEMJXSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 230000008599 nitrosative stress Effects 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000005593 norbornanyl group Chemical group 0.000 description 1
- 201000003077 normal pressure hydrocephalus Diseases 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 208000028780 ocular motility disease Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229950008516 olaratumab Drugs 0.000 description 1
- 229950001673 opicapone Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 101710135378 pH 6 antigen Proteins 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 210000003903 pelvic floor Anatomy 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 description 1
- 229960003300 pimavanserin Drugs 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000003113 pineoblastoma Diseases 0.000 description 1
- 206010035059 pineocytoma Diseases 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 229960004310 piribedil Drugs 0.000 description 1
- 229940031999 pneumococcal conjugate vaccine Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 208000001282 primary progressive aphasia Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 201000003489 pulmonary alveolar proteinosis Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 229940099538 rapamune Drugs 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 239000007845 reactive nitrogen species Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 201000009570 retrograde amnesia Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- 229960003271 rosiglitazone maleate Drugs 0.000 description 1
- 210000000513 rotator cuff Anatomy 0.000 description 1
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 1
- ZWOQHSZKILPKKA-MIXAKNBRSA-N s-[2-[3-[[(2r)-4-[[[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethyl] (2s)-2-[4-(2-methylpropyl)phenyl]propanethioate Chemical compound C1=CC(CC(C)C)=CC=C1[C@H](C)C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](OP(O)(O)=O)[C@@H](O)[C@H](N2C3=NC=NC(N)=C3N=C2)O1 ZWOQHSZKILPKKA-MIXAKNBRSA-N 0.000 description 1
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 description 1
- 229950002652 safinamide Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 208000025874 separation anxiety disease Diseases 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- RTVVXRKGQRRXFJ-UHFFFAOYSA-N sodium;2-sulfobutanedioic acid Chemical compound [Na].OC(=O)CC(C(O)=O)S(O)(=O)=O RTVVXRKGQRRXFJ-UHFFFAOYSA-N 0.000 description 1
- BVAWGUAZSIKKKR-UHFFFAOYSA-N sodium;nitroxyl anion Chemical compound [Na+].O=[N-] BVAWGUAZSIKKKR-UHFFFAOYSA-N 0.000 description 1
- 229950007874 solanezumab Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 229940068117 sprycel Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 208000013623 stereotypic movement disease Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 108010084171 vanutide cridificar Proteins 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229950003000 verubecestat Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- 108010025625 vocimagene amiretrorepvec Proteins 0.000 description 1
- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000010388 wound contraction Effects 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/02—Amines; Quaternary ammonium compounds
- A01N33/12—Quaternary ammonium compounds
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N51/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds having the sequences of atoms O—N—S, X—O—S, N—N—S, O—N—N or O-halogen, regardless of the number of bonds each atom has and with no atom of these sequences forming part of a heterocyclic ring
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
- A01N59/06—Aluminium; Calcium; Magnesium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- 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
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- 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
- A61K33/02—Ammonia; Compounds thereof
-
- 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
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P11/12—Mucolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the present disclosure relates generally to nitric oxide-releasing compounds, their synthesis, and their use in treating disorders mediated by nitric oxide.
- Pharmaceutical compositions comprising these compounds and their methods of use are also disclosed.
- Nitric oxide is known to play important functional roles in a variety of physiological systems. Within the vasculature, NO induces vasodilation, inhibits platelet aggregation, prevents neutrophil/platelet adhesion to endothelial cells, inhibits smooth muscle cell proliferation and migration, regulates programmed cell death (apoptosis) and maintains endothelial cell barrier function. NO generated by neurons acts as a neurotransmitter, whereas NO generated by macrophages in response to invading microbes acts as an antimicrobial agent.
- NO is an important regulator of the biology and physiology of the reproductive system (Rosselli et al., Role of nitric oxide in the biology, physiology and pathophysiology of reproduction, Hum Reprod Update. 1998 January-February; 4(1):3-24).
- NO-releasing compounds i.e., NO donors
- NO-releasing compounds have been proposed as therapeutics, often in the form of polymers with side-chains that include nitric oxide-releasing moieties, such as nitrosothiols and diazeniumdiolates.
- Nitric oxide-releasing polymers have hetetofore been underused as therapeutics, based at least in part on limited NO payloads, NO release rates that are more rapid than desired, and the lack of targeted NO delivery.
- NO-donor compounds It would be advantageous to have new NO-donor compounds, pharmaceutical compositions comprising the NO donor compounds, and methods of treating patients suffering from disorders mediated by nitric oxide using these compounds and compositions.
- the present invention provides such compounds, compositions, and methods.
- Nitric oxide an endogenously produced diatomic free radical
- Exogenous NO delivery can be an effective strategy for treating or preventing a variety of disease states, including baldness, ischemia/reperfusion injury, thrombosis/restenosis, a fibrotic disease, a cancer, a cardiovascular disease, a disease of platelet aggregation and platelet adhesion, sickle cell disease, a disease caused by or characterized by low nitric oxide levels, a metabolic disease, or a response to a medical device, pathological conditions resulting from abnormal cell proliferation, autoimmune diseases, inflammation, vascular diseases, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, and sexual dysfunctions. Methods for treating these disorders are also disclosed herein.
- Nitric oxide-releasing compounds also referred to as nitric oxide donors or NO donors
- compositions containing such compounds and methods of treating microbial infections using the compounds and compositions, are disclosed.
- the compounds disclosed herein have the following formula:
- X is selected from the group consisting of H, D, R, and RC(O)—,
- R is C 1-12 alkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, optionally substituted with one or more substituents as defined herein,
- M + is a pharmaceutically-acceptable cation.
- M + is a cation with a valence other than one, for example, +2 or +3 , in which case the ratio of the compound of Formula I to the cation is such that the total positive charge equals the total negative charge. So, for a compound with a total charge of negative three, and a cation with a total charge of positive two, there would be two compounds and three cations.
- Representative positively charged cations include sodium, potassium, lithium, calcium, magnesium, and quaternary ammonium salts.
- compounds with an R(CO)— moiety that does not include acidic ⁇ C—H i.e., alpha to the carbonyl
- acidic ⁇ C—H i.e., alpha to the carbonyl
- aryl, heteraryl, and branched alkyl groups, like t-butyl groups can be prepared by reacting all acidic ⁇ C—H on the methyl group of a compound with the formula R(CO)CH 3 with nitric oxide in basic methanol to give trisdiazeniumdiolates.
- reaction product of acetophenone with nitric oxide in KOH/methanol is:
- compounds where X is H or D can be prepared by reacting acetone with nitric oxide in basic methanol or deuterated methanol to give tris-diazeniumdiolates.
- the NO-releasing compound has the structure of Formula II:
- M + is as defined above with respect to Formula I.
- the cation is sodium, lithium, potassium, or a quaternary ammonium salt.
- the compounds of Formula II can be prepared, for example, by reacting acetone, acetonitrile, or ethanol with NO, optionally at high pressures (i.e., pressures above atmospheric pressure, ideally above about 2 ATM of pressure, and preferably above about 10 ATM of pressure) in the presence of a base, such as a methoxide/methanol solution, to form one or more diazeniumdiolate-containing species.
- high purity compounds greater than about 80%, greater than about 90%, greater than about 95%, or greater than about 98%) can be produced according to the methods disclosed herein.
- the NO-releasing compound has the structure of Formula III:
- the compounds of any of Formulas I, II or III have a purity in excess of 96%, in excess of 97%, in excess of 98%, in excess of 99%, or in excess of 99.5%.
- the present disclosure also relates to compounds having this purity level.
- the nitric oxide-releasing compound has a NO-release half-life, at normal physiological temperature and pH, of between 0.1 and 24 hours. In another embodiment, the NO-release half-life is at least 15 minutes. In some embodiments, the compound has a total releasable NO storage in a range of 2-10 ⁇ mol of NO per mg of NO donor compound. In several embodiments, the compound has a total duration of NO release in the range of 1-60 hours. In several embodiments, the total NO release after 4 hours is in the range between 0.1-1.0 ⁇ mol of NO per mg of compound.
- the compounds can be formulated in a variety of pharmaceutical compositions, for delivery intravenously, via inhalation, via nebulization, via intranasal administration, via oral administration, via injection, via rectal or vaginal administration, and via topical administration.
- the pharmaceutical compositions comprise one or more nitric oxide-releasing compounds described herein and an aqueous solution.
- the nitric oxide releasing compound has an aqueous solubility of at least about 25 mg/ml in the aqueous solution, at a physiologically compatible pH.
- the pharmaceutical compositions can further include one or more additional active agents, depending on the type of disorder to be treated.
- the disorder is cancer
- one or more additional anticancer agents can be co-administered.
- the disorder is an inflammatory disorder
- one or more additional anti-inflammatory compounds can also be present.
- the disorder is an autoimmune disorder
- antibody products and JAK 1/2 inhibitor compounds such as Jakafi or Baricitinib
- dopamine agonists or partial agonists can be co-administered.
- compositions can further include one or more of a chelating agent, a mucoadhesive agent, or a low molecular weight polyethylene glycol.
- the small molecule nitric oxide donors are provided in dilute solutions (e.g., for nebulization, vaporization or inhalation), and in other embodiments, are provided in the form of gels or viscous liquids, for example, for topical administration.
- the methods involve delivering nitric oxide to a subject in need of treatment, by delivering the compounds of any of Formulas I, II or III, and having the compound degrade upon exposure to physiological pH and temperature to release nitric oxide.
- compositions and related methods set forth in further detail below describe certain actions taken by a practitioner; however, it should be understood that they can also include the instructions of those actions by another party.
- actions such as “administering a NO-donating compound” include “instructing the administration of a NO-donating compound.”
- FIG. 1 shows the FTIR spectrum of the compound of Formula III.
- the UV absorbance spectrum of the analyte retained for approximately 6 minutes, the UV absorbance spectrum of the analyte retained for approximately 10 minutes, and the UV absorbance spectrum of the analyte retained for approximately 11 minutes are shown in the insets.
- FIG. 3 shows the 1 H NMR spectrum of the compound of Formula III in D20.
- FIG. 4 shows the 13 C NMR spectrum of the compound of Formula III
- FIG. 5 shows the 2D NMR of the compound of Formula III.
- FIG. 6 shows A) HPLC chromatograms (IEX-UV) with the top chromatogram showing the separation of components prior to acid degradation of the compound of Formula III (referenced as MD3), the middle chromatogram showing the separation of components after 5 h of acid degradation, and the bottom chromatogram showing the separation of components after 24 h of acid degradation, B) the 1 H NMR spectrum of the acid degraded components, C) a table of NOA Totals for compound of Formula III before and after acid degradation.
- IEX-UV HPLC chromatograms
- FIG. 7 is a 1 H NMR spectrum of a the reaction products when compound of Formula III was neutralized (pH 7) at room temperature.
- FIG. 8 is a 13 C NMR spectrum of the reaction products when compound of Formula III was neutralized (pH 7) at room temperature.
- FIG. 9 shows a graphical representation of the nitric oxide analysis (NOA) release profile for compound of Formula III at pH 7.4, as measured by chemiluminescence, showing 6.7 ⁇ mol NO/mg of material being released with a T 1/2 of approximately 3.75 h, suggesting release of only a single diazeniumdiolate group, which has a theoretical load of 7.6 ⁇ mol NO/mg.
- NOA nitric oxide analysis
- Nitric oxide is implicated in a wide variety of disorders, including baldness, ischemia/reperfusion injury, thrombosis/restenosis, a fibrotic disease, a cancer, a cardiovascular disease, a disease of platelet aggregation and platelet adhesion, sickle cell disease, a disease caused by or characterized by low nitric oxide levels, a metabolic disease, or a response to a medical device, pathological conditions resulting from abnormal cell proliferation, autoimmune diseases, inflammation, vascular diseases, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, and sexual dysfunctions, including impotence and hypogonadism, cardiac disorders, and pulmonary disorders.
- NO as a therapeutic has heretofore been underused, based at least in part on limited NO payloads of therapeutic compositions, NO release rates that are more rapid than desired, and a lack of targeted NO delivery.
- NO-releasing compounds compositions comprising such compounds, methods of producing such compounds and compositions, and methods of treating or preventing disorders associated with nitric oxide, are disclosed.
- the compounds are present in pharmaceutical compositions with desired physical properties, such as viscosity and gelation.
- the compounds are small molecules, i.e., have a molecular weight below around 500 g/mol, and, in some embodiments, around 200 g/mol, not including the associated cation.
- One of the advantages of using small molecules over polymers is that the compounds can be prepared with relatively lower impurity levels than polymeric compounds. Further, relative to polymeric compounds, the NO load can be higher, because the percent composition ratio between NO to the scaffold can be maximized, as described herein.
- Small molecule precursor compounds which can be converted to the NO-releasing compounds described herein, can be selected with a relatively low number of reactive groups, for example, a hydrogens adjacent a carbonyl group, reducing the possibility that many different species will result from a nitrosation reaction. As a result, nitrosylation of the NO-precursor can proceed with little or no partial reaction products, which provides the potential for relatively pure products.
- Knowing the structure of the small molecule allows for more predictable release kinetics than that obtainable with polymers.
- an effective amount refers broadly to that amount of a recited compound effective to treat, prevent, reduce the severity or progression of a disorder associated with nitric oxide. microbial load in a subject afflicted with a microbial infection. This includes improving the subject's condition (e.g., in one or more symptoms), delaying or reducting the progression of the disorder, preventing or delaying the onset of the disorder, and/or changing clinical parameters, disease or illness, etc., as would be well known in the art.
- an effective amount can refer to the amount of a composition, compound, or agent that improves a condition in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
- an improvement in a condition can be a reduction in . . . in a subject.
- Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired response for a particular subject.
- the selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the composition, formulation, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated.
- a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein.
- Treat” or “treating” or “treatment” refers broadly to any type of action that imparts a desired physiological effect, including treating or preventing a microbial infection, reducing the microbial load, improving the condition of the subject (e.g., in one or more symptoms), delaying or reducing the progression of the infection, and/or changing one or more clinical parameters.
- nitric oxide donor or “NO donor” refer broadly to species and/or molecules that donate, release and/or directly or indirectly transfer a nitric oxide species, and/or stimulate the endogenous production of nitric oxide in vivo and/or elevate endogenous levels of nitric oxide in vivo, such that the biological activity of the nitric oxide species is expressed at the intended site of action.
- nitric oxide releasing or “nitric oxide donating” refer to species that donate, release and/or directly or indirectly transfer any one (or two or more) of the three redox forms of nitrogen monoxide (NO+, NO ⁇ , NO (e.g., •NO)) and/or methods of donating, releasing and/or directly or indirectly transferring any one (or two or more) of the three redox forms of nitrogen monoxide (NO+, NO ⁇ , NO).
- the nitric oxide releasing is accomplished such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
- the “patient” or “subject” treated as disclosed herein is, in some embodiments, a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications.
- the term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), monkeys, etc.
- Human subjects include neonates, infants, juveniles, adults and geriatric subjects.
- the subject “in need of” the methods disclosed herein can be a subject that is experiencing a disease state and/or is anticipated to experience a disease state, and the methods and compositions of the invention are used for therapeutic and/or prophylactic treatment.
- Such physical properties include solubility, charge, stability, cross-linking, secondary and tertiary structure, and the like. Moreover, if no stereochemistry is indicated for compounds having one or more chiral centers, all enantiomers and diasteromers are included. Similarly, for a recitation of aliphatic or alkyl groups, all structural isomers thereof also are included.
- groups shown as A 1 through A n and referred to herein as an alkyl group are independently selected from alkyl or aliphatic groups, particularly alkyl having 20 or fewer carbon atoms, and even more typically lower alkyl having 10 or fewer atoms, such as methyl, ethyl, propyl, isopropyl, and butyl.
- the alkyl may be optionally substituted (e.g., substituted or not substituted, as disclosed elsewhere herein).
- the alkyl may be a substituted alkyl group, such as alkyl halide (e.g.
- X is a halide, and combinations thereof, either in the chain or bonded thereto), alcohols (e.g. aliphatic or alkyl hydroxyl, particularly lower alkyl hydroxyl) or other similarly substituted moieties such as amino-, amino acid-, aryl-, alkyl aryl-, alkyl ester-, ether-, keto-, nitro-, sulfhydryl-, sulfonyl-, sulfoxide modified-alkyl groups.
- alcohols e.g. aliphatic or alkyl hydroxyl, particularly lower alkyl hydroxyl
- moieties such as amino-, amino acid-, aryl-, alkyl aryl-, alkyl ester-, ether-, keto-, nitro-, sulfhydryl-, sulfonyl-, sulfoxide modified-alkyl groups.
- amino and amine refer to nitrogen-containing groups such as NR 3 , NH 3 , NHR 2 , and NH 2 R, wherein R can be as described elsewhere herein.
- amino as used herein can refer to a primary amine, a secondary amine, or a tertiary amine.
- one R of an amino group can be a diazeniumdiolate (e.g., NONO).
- the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl,
- C a to C b in which “a” and “b” are integers refer to the number of carbon atoms in a group.
- the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
- a “C 1 to C 4 alkyl” or “C 1 -C 4 alkyl” group refers broadly to all alkyl groups having from 1 to 4 carbons, that is, CH 3 —, CH 3 CH 2 —, CH 3 CH 2 CH 2 —, (CH 3 ) 2 CH—, CH 3 CH 2 CH 2 CH 2 —, CH 3 CH 2 CH(CH 3 )— and (CH 3 ) 3 C—. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
- alkyl refers broadly to a fully saturated aliphatic hydrocarbon group.
- the alkyl moiety may be branched or straight chain.
- branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
- straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
- the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers broadly to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
- the “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms.
- the “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms.
- alkyl group may be substituted or unsubstituted.
- C 1 -C 5 alkyl indicates that there are one to five carbon atoms in the alkyl chain, e.g., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), etc.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
- alkylene refers broadly to a bivalent fully saturated straight chain aliphatic hydrocarbon group.
- alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.
- An alkylene group may be represented by followed by the number of carbon atoms, followed by a “*”. For example,
- the alkylene group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers broadly to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated).
- the alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms.
- the alkylene group could also be a lower alkyl having 1 to 6 carbon atoms.
- An alkylene group may be substituted or unsubstituted. For example, a lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C 3-6 monocyclic cycloalkyl group
- alkenyl used herein refers broadly to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
- An alkenyl group may be unsubstituted or substituted.
- alkynyl used herein refers broadly to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.
- cycloalkyl refers broadly to a completely saturated (no double or triple bonds) mono- or multi-cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers broadly to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers broadly to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
- spiro refers broadly to two rings which have one atom in common and the two rings are not linked by a bridge.
- Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- a cycloalkyl group may be unsubstituted or substituted.
- Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl;
- examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro [3.3]heptane and spiro [4.5]decane.
- cycloalkenyl refers broadly to a mono- or multi-cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein).
- Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged, or spiro fashion.
- a cycloalkenyl group may be unsubstituted or substituted.
- aryl refers broadly to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group or a C 6 aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- heteroatoms for example, 1, 2 or 3 heteroatoms
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms.
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,
- heterocyclyl or “heteroalicyclyl” refers broadly to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
- the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
- oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
- the rings When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
- the term “fused” refers to two rings which have two atoms and one bond in common.
- bridged heterocyclyl or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms.
- spiro refers to two rings which have one atom in common and the two rings are not linked by a bridge.
- Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- any nitrogens in a heteroalicyclic may be quaternized.
- Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
- heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazol
- spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro [3.4]octane and 2-azaspiro[3.4]octane.
- aralkyl and “aryl(alkyl)” refer broadly to an aryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
- cycloalkyl(alkyl) refer broadly to an cycloalkyl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted.
- heteroarylkyl and “heteroaryl(alkyl)” refer broadly to a heteroaryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
- heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer broadly to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).
- hydroxy refers broadly to a —OH group.
- alkoxy refers broadly to the Formula —OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- a non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy
- acyl refers broadly to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
- cyano refers broadly to a “—CN” group.
- halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
- a “thiocarbonyl” group refers broadly to a “—C( ⁇ S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
- An “O-carbamyl” group refers to a “—OC( ⁇ O)N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An O-carbamyl may be substituted or unsubstituted.
- N-carbamyl refers broadly to an “ROC( ⁇ O)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-carbamyl may be substituted or unsubstituted.
- An “O-thiocarbamyl” group refers broadly to a “—OC( ⁇ S)—N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An O-thiocarbamyl may be substituted or unsubstituted.
- N-thiocarbamyl refers broadly to an “ROC( ⁇ S)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-thiocarbamyl may be substituted or unsubstituted.
- a “C-amido” group refers broadly to a “—C( ⁇ O)N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- a C-amido may be substituted or unsubstituted.
- N-amido refers broadly to a “RC( ⁇ O)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-amido may be substituted or unsubstituted.
- S-sulfonamido refers broadly to a “—SO 2 N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An S-sulfonamido may be substituted or unsubstituted.
- N-sulfonamido refers broadly to a “RSO 2 N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-sulfonamido may be substituted or unsubstituted.
- An “O-carboxy” group refers broadly to a “RC( ⁇ O)O—” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- An O-carboxy may be substituted or unsubstituted.
- esters and C-carboxy refer broadly to a “—C( ⁇ O)OR” group in which R can be the same as defined with respect to O-carboxy.
- An ester and C-carboxy may be substituted or unsubstituted.
- a “nitro” group refers broadly to an “—NO 2 ” group.
- a “sulfenyl” group refers broadly to an “—SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- a sulfenyl may be substituted or unsubstituted.
- a “sulfinyl” group refers broadly to an “—S( ⁇ O)—R” group in which R can be the same as defined with respect to sulfenyl.
- a sulfinyl may be substituted or unsubstituted.
- a “sulfonyl” group refers broadly to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl.
- a sulfonyl may be substituted or unsubstituted.
- haloalkyl refers broadly to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl).
- a halogen e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl.
- groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl.
- a haloalkyl may be substituted or unsubstituted.
- haloalkoxy refers broadly to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy).
- halogen e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy.
- groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
- a haloalkoxy may be substituted or unsubstituted.
- amino and “unsubstituted amino” as used herein refer broadly to a —NH 2 group.
- a “mono-substituted amine” group refers broadly to a “—NHR A ” group in which R A can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- the R A may be substituted or unsubstituted.
- a mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-C 1 -C 6 alkylamine group, a mono-arylamine group, a mono-C 6 -C 10 arylamine group and the like.
- Examples of mono-substituted amine groups include, but are not limited to, —NH(methyl), —NH(phenyl) and the like.
- a “di-substituted amine” group refers broadly to a “—NR A R B ” group in which R A and R B can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- R A and R B can independently be substituted or unsubstituted.
- a di-substituted amine group can include, for example, a di-alkylamine group, a di-C 1 -C 6 alkylamine group, a di-arylamine group, a di-C 6 -C 10 arylamine group and the like.
- di-substituted amine groups include, but are not limited to, —N(methyl) 2 , —N(phenyl)(methyl), —N(ethyl)(methyl) and the likes used herein, “mono-substituted amine(alkyl)” group refers broadly to a mono-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
- a mono-substituted amine(alkyl) may be substituted or unsubstituted.
- a mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl) group, a mono-C 1 -C 6 alkylamine(C 1 -C 6 alkyl) group, a mono-arylamine(alkyl group), a mono-C 6 -C 10 arylamine(C 1 -C 6 alkyl) group and the like.
- Examples of mono-substituted amine(alkyl) groups include, but are not limited to, —CH 2 NH(methyl), —CH 2 NH(phenyl), —CH 2 CH 2 NH(methyl), —CH 2 CH 2 NH(phenyl) and the like.
- di-substituted amine(alkyl) refers broadly to a di-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
- a di-substituted amine(alkyl) may be substituted or unsubstituted.
- a di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-C 1 -C 6 alkylamine(C 1 -C 6 alkyl) group, a di-arylamine(alkyl) group, a di-C 6 -C 10 arylamine(C 1 -C 6 alkyl) group and the like.
- di-substituted amine(alkyl)groups include, but are not limited to, —CH 2 N(methyl) 2 , —CH 2 N(phenyl)(methyl), —CH 2 N(ethyl)(methyl), —CH 2 CH 2 N(methyl) 2 , —CH 2 CH 2 N(phenyl)(methyl), —NCH 2 CH 2 (ethyl)(methyl) and the like.
- diamino- denotes a “—N(R A )R B —N(R C )(R D )” group in which R A , R C , and R D can be independently a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein R B connects the two “N” groups and can be (independently of R A , R C , and R D ) a substituted or unsubstituted alkylene group.
- R A , R B , R C , and R D can independently further be substituted or unsubstituted.
- polyamino denotes a “—(N(R A )R B —) n —N(R C )(R D )”.
- polyamino can comprise —N(R A )alkyl-N(R A )alkyl-N(R A )alkyl-N(R A )alkyl-H.
- the alkyl of the polyamino is as disclosed elsewhere herein. While this example has only 4 repeat units, the term “polyamino” may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeat units.
- R A , R C , and R D can be independently a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein R B connects the two “N” groups and can be (independently of R A , R C , and R D ) a substituted or unsubstituted alkylene group.
- R A , R C , and R D can independently further be substituted or unsubstituted.
- the polyamino comprises amine groups with intervening alkyl groups (where alkyl is as defined elsewhere herein).
- diether- denotes an “—OR B O—R A ” group in which R A can be a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein R B connects the two “O” groups and can be a substituted or unsubstituted alkylene group.
- R A can independently further be substituted or unsubstituted.
- polyether denotes a repeating —(OR B —) n OR A group.
- polyether can comprise —Oalkyl-Oalkyl-Oalkyl-Oalkyl-OR A .
- the alkyl of the polyether is as disclosed elsewhere herein. While this example has only 4 repeat units, the term “polyether” may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeat units.
- R A can be a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- R B can be a substituted or unsubstituted alkylene group.
- R A can independently further be substituted or unsubstituted.
- the polyether comprises ether groups with intervening alkyl groups (where alkyl is as defined elsewhere herein and can be optionally substituted).
- haloalkyl may include one or more of the same or different halogens.
- C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
- a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
- a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
- radical can be used interchangeably with the term “group.”
- the range includes any number falling within the range and the numbers defining ends of the range.
- integers included in the range are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., up to and including 20.
- the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified amount.
- the term “consists essentially of” (and grammatical variants), shall be given its ordinary meaning and shall also mean that the composition or method referred to can contain additional components as long as the additional components do not materially alter the composition or method.
- the term “consists of” (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to is closed to additional components.
- the term “comprising” (and grammatical variants), shall be given its ordinary meaning and shall also mean that the composition or method referred to is open to contain additional components.
- some embodiments disclosed herein pertain to small molecules capable of delivering NO to achieve microbicidal activity.
- the cations present in the small molecules have antimicrobial or other desired physiological properties.
- the compounds are water-soluble.
- a NO releasing compound which exhibits potent antimicrobial characteristics, comprising the structure of Formula I:
- X is selected from the group consisting of H, D, R, and RC(O)—,
- R is C 1-12 alkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, optionally substituted with one or more substituents,
- substituents are independently selected from the group consisting of —OH, —NH 2 , —OCH 3 , —C(O)OH, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 2 OH, —OCH 2 C(O)OH, —C H 2 OCH 2 C(O)OH, —CH 2 C(O)OH, —NHC(O)—CH 3 , —C(O)O((CH 2 ) a O) b —H, —C(O)O((CH 2 ) a O) b —(CH 2 ) c H, —C(O)O(C 1-5 alkyl), —C(O)—NH—((CH 2 ) d NH) e —H, —C(O)—NH 4 CH 2 ) d NH) e —(CH 2 ) f H, —O—((CH 2 ) aO)
- each instance of a, b, c, d, e, f, g, h, i, j, k, and 1 is independently selected from an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,
- M + is a pharmaceutically-acceptable cation.
- M + is a cation with a valence other than one, for example, +2 or +3 , in which case the ratio of the compound of Formula I to the cation is such that the total positive charge equals the total negative charge. So, for a compound with a total charge of negative three, and a cation with a total charge of positive two, there would be two compounds and three cations.
- Representative positively charged cations include sodium, potassium, lithium, calcium, magnesium, and quaternary ammonium salts.
- the compound has the following structure:
- M + refers to a pharmaceutically-acceptable cation.
- the cation can be any pharmaceutically acceptable, non-toxic cation known to those skilled in the art, including but not limited to sodium, potassium, lithium, calcium, magnesium, ammonium, or substituted ammonium. It will be appreciated by those skilled in the art that when the cation (M) has a valency greater than one, the ratio of negative charge in the methyl trisdiazenium diolate moiety to the positive charge in the cation will balance out.
- the cation (M) has a charge of +2, then there is a ratio of 2 methyl trisdiazenium diolate moieties to three M +2 ions, and if the cation (M) has a charge of +3, then there is a 1/1 ratio of cation to methyl trisdiazenium diolate.
- Formula II is also described as a methane trisdiazeniumdiolate (MTDD), and Formula III as methane trisdiazeniumdiolate sodium salt.
- MTDD methane trisdiazeniumdiolate
- NO donors e.g., diazeniumdiolates, S-nitrosothiols, metal nitrosyls, organic nitrates
- diazeniumdiolate moieties in the compounds disclosed herein are attractive because of their good stability and facile storage, and because they spontaneously undergo proton-triggered dissociation under physiological conditions to regenerate nitric oxide, including NO radicals.
- the C-diazeniumdiolates described herein are pH-triggered NO-release donors. Reacting with protons under physiological conditions (e.g., 37° C., pH 7.4), 1 mole of Formula III generates two moles of NO radicals and 2 to 3 moles of nitroxyl compounds.
- the NO-releasing compounds are stable at a variety of temperatures 20° C. (e.g., 40° C., 45° C., 55° C., 60° C., 80° C., etc.) and are stable for prolonged storage periods (e.g., 10 hours, 20 hours, 22 hours, 25 hours, 30 hours, etc., days such as 1 day, 3 days, 5 days, 6 days, 7 days, 15 days, 30 days, 45 days, etc., weeks such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, etc., months such as 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc., or even years (1 year or greater)).
- temperatures 20° C. e.g., 40° C., 45° C., 55° C., 60° C., 80° C., etc.
- prolonged storage periods e.g., 10 hours, 20 hours, 22 hours, 25 hours, 30 hours, etc., days such as 1 day, 3 days, 5 days, 6 days, 7
- the compounds have NO storage capacities (in ⁇ mol NO/mg of the compounds) of greater than or equal to about: 0.25, 0.4, 0.5, 1.0, 1.5, 2.0, 3.0, or ranges including and/or spanning the aforementioned values. In some embodiments, within 2 h of being added to a PBS buffer solution, the compounds release greater than or equal to about: 25%, 50%, 75%, 85%, 90%, 95%, 100%, or ranges including and/or spanning the aforementioned values, their total wt % of bound NO.
- NO release in use for reducing or eliminating a biofilm occurs in similar amounts, e.g., about 20-25%, about 30-50%, about 60-75%, at least 80%, at least 85%, at least 90%, at least 95%, ranges including and/or spanning the aforementioned values, of the total wt % of bound NO.
- the NO release may occur over a period of about 0.01 hours, 0.1 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours, 36 hours, 48 hours, 60 hours, or ranges including and/or spanning the aforementioned values.
- the NO release half-life is equal to or at least about: 0.01 hours, 0.1 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or ranges including and/or spanning the aforementioned values.
- the NO release occurs in less than or equal to about: 0.01 hours, 0.1 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours or ranges including and/or spanning the aforementioned values.
- the compounds have a degradation rate per hour in an amylase enzyme exposure assay of less than or equal to about: 0.2%, 0.5%, 1.0%, 1.5%, 2.5%, 5.0%, 10%, or ranges including and/or spanning the aforementioned values.
- Several embodiments disclosed herein provide the synthesis and characterization of the diazeniumdiolate NO donor-modified compounds described herein.
- the synthesis of compounds capable of controlled NO storage and release is important for taking advantage of NO's role in physiology and for developing NO-based therapeutics.
- compounds with an R(CO)— moiety that does not include acidic ⁇ C—H i.e., alpha to the carbonyl
- acidic ⁇ C—H i.e., alpha to the carbonyl
- aryl, heteraryl, and branched alkyl groups, like t-butyl groups can be prepared by reacting all acidic ⁇ C—H on the methyl group of a compound with the formula R(CO)CH 3 with nitric oxide in basic methanol to give trisdiazeniumdiolates.
- reaction product of acetophenone with nitric oxide in KOH/methanol is:
- compounds where X is H or D can be prepared by reacting acetone with nitric oxide in basic methanol or deuterated methanol to give tris-diazeniumdiolates.
- Formula II can be prepared via a number of different approaches, including the reaction of ethanol, acetonitrile, or acetone with nitric oxide gas, in the presence of a basic methanol solution.
- the nitric oxide gas is present at a pressure greater than atmospheric pressure, more ideally, greater than two atmospheres of pressure, and, preferably, greater than ten atmospheres of pressure. Higher pressures help ensure complete reaction.
- one of the by-products of the reaction is methane bis-diazeniumdiolate:
- Methane bis-diazeniumdiolate does not release NO or NHO under physiological conditions.
- the degradation pathway is of particular interest, because it provides clarity in how NO is being produced from a carbon bound diazeniumdiolate.
- carbon bound diazeniumdiolates do not generate NO. Instead, they produce HNO, which dimerizes to form nitrous oxide, N 2 O.
- the initial decay of Formula III follows the expected HNO pathway, which in turn leads to the formation of an intermediate alcohol.
- 2 moles of NO gas can be released. This matches the experimental results, which show that one mole of Formula III releases approximately 2 moles of NO.
- the NMR of the degraded Formula III by-product (shown in FIGS. 9 and 10 ) also matches the proposed structure for the fully degraded molecule.
- compositions comprising one or more compounds of Formulas I, II or III, along with a suitable pharmaceutically acceptable carrier or excipient, are also disclosed.
- the compounds described herein can be present in aqueous solutions comprising concentrations equal to or at least about 100 ⁇ g/mL, and can be higher, e.g. about 1 mg/ml, about 5 mg/ml, about 10 mg/ml, about 20/ml, or about 40 mg/ml or higher.
- the amount of the second compound in the aqueous composition can be at least about 10% by weight, based on the weight of the first compound, and may be higher, e.g., at least about 20% by weight, at least about 30% by weight, or at least about 50% by weight, same basis.
- the compounds in an aqueous composition are selected such that compounds are mutually miscible.
- the compositions disclosed herein provide NO-releasing compounds discussed herein having NO storage capacities (in ⁇ mol NO/mg powder) of greater than or equal to about: 2.0, 4.0, 6.0, 8.0, or 10.0 or ranges including and/or spanning the aforementioned values. In some embodiments, within 2 h of being added to a PBS buffer solution as described in the Examples, the NO-releasing compounds, release greater than or equal to about: 25%, 50%, 75%, 85%, 90%, 95%, 100%, or ranges including and/or spanning the aforementioned values, their total wt % of bound NO.
- the compositions are in the form of a liquid, a dry powder, a gel, or an aerosol.
- the compositions may be provided in the form of a formulation loaded into a delivery device, such as an inhaler.
- the composition includes a concentration of less than or equal to about: 1 mg/ml, 10 mg/ml, 20 mg/ml, 50 mg/ml, 100 mg/ml, 250 mg/ml of the compounds described herein, or ranges including and/or spanning the aforementioned values.
- the compounds are administered to the pulmonary tract (i.e., via pulmonary administration).
- pulmonary administration comprises inhalation of the compounds, typically in the form of particles or droplets, such as by nasal, oral inhalation, or both.
- the formulations can be developed to be aerosolized via a metered dose inhaler, a dry powder inhaler, a liquid spray or a nebulizer devises. Nebulization can be accomplished by compressed air, ultrasonic energy, or vibrating mesh to form a plurality of liquid droplets or solid particles comprising the NO-releasing compounds.
- particles may be formulated as an aerosol (i.e.: liquid droplets of a stable dispersion or suspension of particles which include one or more of the compounds described herein in a gaseous medium).
- Particles delivered by aerosol may be deposited in the airways by gravitational sedimentation, inertial impaction, and/or diffusion.
- the particles or droplets can be administered in two or more separate administrations (doses).
- compositions are administered via inhalation to treat bacterial infections related to cystic fibrosis.
- Cystic fibrosis-related bacterial infections include, but are not limited to stenotrophomonis, mybacterium avium intracellulaire and M. abcessus, Burkhoderia cepacia and Pseudomonas aeruginosa ( P. aeruginosa ) infections.
- Biodegradable particles can be used for the controlled-release and delivery of the compounds described herein. Aerosols for the delivery of therapeutic agents to the respiratory tract have been developed. Adjei, A. and Garren, J. Pharm Res. 7, 565-569 (1990); and Zanen, P. and Lamm, J.-W. J. Int. J. Pharm. 114, 111-115 (1995).
- the respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli.
- the upper and lower airways are called the conducting airways.
- the terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung. Gonda, I. “Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract,” in Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313, 1990.
- the deep lung, or alveoli are the primary target of inhaled therapeutic aerosols for systemic drug delivery.
- Relatively large particles tend to get trapped in the oropharyngeal cavity, which can lead to excessive loss of the inhaled drug.
- Relatively smaller particles can be delivered to the deep lung, but can be phagocytosed.
- One way to deliver relatively large particles (sized to avoid phagocytosis), which are light enough to avoid excessive entrapment in the oropharyngeal cavity, is to use porous particles.
- the particles for delivering the compounds described herein to the alveolar regions of the lung are porous, “aerodynamically-light” particles, as described in U.S. Pat. No. 6,977,087.
- Aerodynamically light particles can be made of a biodegradable material, and typically have a tap density less than 0.4 g/cm 3 and a mass mean diameter between 5 ⁇ m and 30 ⁇ m.
- the particles may be formed of biodegradable materials such as biodegradable polymers.
- the particles may be formed of a functionalized polyester graft copolymer consisting of a linear alpha-hydroxy-acid polyester backbone having at least one amino acid group incorporated herein and at least one poly(amino acid) side chain extending from an amino acid group in the polyester backbone.
- aerodynamically light particles having a large mean diameter, for example greater than 5 can be used for enhanced delivery of one or more of the compounds described herein to the alveolar region of the lung.
- the compounds disclosed herein are administered as aqueous solutions, for delivery, for example, topically, intranasally, intraveneously, by injection, and by nebulization.
- the solutions comprise one or more salts and are isotonic.
- compositions can take the form of, for example, tablets, pills, or capsules, prepared using conventional techniques, with pharmaceutically acceptable excipients.
- excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate), wetting agents (e.g., sodium lauryl sulphate), suspending agents, solubilizers, and mixtures thereof.
- binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
- lubricants e.g., magnesium ste
- a therapeutic agent can be formulated in combination with hydrochlorothiazide, and as a pH-stabilized core having an enteric or delayed release coating which protects the therapeutic agent until it reaches the target organ.
- Liquid preparations for oral or topical administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or another suitable vehicle before use.
- Such liquid preparations can be prepared by conventional techniques with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
- suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
- emulsifying agents e.g., lecithin or acacia
- non-aqueous vehicles e.g., almond oil, oily esters,
- compositions also can contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
- Preparations for oral administration can be suitably formulated to provide controlled release of the active compound.
- buccal administration the compositions can take the form of tablets or lozenges formulated in a conventional manner.
- the controlled release nanoparticulate formulations comprise a nanoparticulate active agent to be administered and a rate-controlling polymer which functions to prolong the release of the agent following administration.
- the compositions can release the active agent, following administration, for a time period ranging from about 2 to about 24 hours or up to 30 days or longer.
- Representative controlled release formulations including a nanoparticulate form of the active agent are described, for example, in U.S. Pat. No. 8,293,277.
- Nanoparticulate compositions comprise particles of the active agents described herein, having a non-crosslinked surface stabilizer adsorbed onto, or associated with, their surface.
- the average particle size of the nanoparticulates is typically less than about 800 nm, more typically less than about 600 nm, still more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm.
- at least 50% of the particles of active agent have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques.
- a variety of surface stabilizers are typically used with nanoparticulate compositions to prevent the particles from clumping or aggregating.
- Representative surface stabilizers are selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulo se, hydroxyethylcellulo se, hydroxypropylcellulo se, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,
- Representative rate controlling polymers into which the nanoparticles can be formulated include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl
- the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems.
- a controlled release formulation including but not limited to implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
- enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
- Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (incorporated by reference).
- liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
- appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline
- Mucoadhesion is presently defined as the adhesion between two materials, at least one of which is a mucosal surface.
- Compounds, such as NO donors, are often delivered locally because their half-life is often below the time required for systemic distribution.
- the mucoadhesive agents described herein enable formulations suitable for mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal).
- Mucoadhesive-containing topical and local systems have been shown to exhibit enhanced bioavailability. For example, it typically provides enhanced absorption (compared to a non-mucoadhesive formulation) and taking advantage of mucous tissues having high surface area and high blood flow.
- the mucoadhesive agent is a mucoadhesive polymer.
- the mucoadhesive agent has numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate. These groups enable attachment to mucus or the cell membrane through physical and chemical interactions such as hydrogen bonding, hydrophobic, electrostatic, or conformational interactions. Hydrophilicity augments through drawing water for greater hydration and physically swell if in a gelatinous state. Aspects considered in selecting an appropriate mucoadhesive agent include the following:
- the mucoadhesive agent adheres to the mucosal surface through nonspecific, noncovalent interactions which are primarily electrostatic in nature.
- the mucoadhesive agent adheres to the mucosal surface through hydrophilic functional groups that hydrogen bond with similar groups on biological substrates.
- the mucoadhesive agent adheres to the mucosal surface through specific receptor sites on the cell or mucus surface.
- lectins and thiolated polymers adhere to mucosal surfaces through specific receptor sites on the cell or mucus surfaces.
- lectins are proteins or glycoprotein complexes of nonimmune origin that are able to bind sugars selectively in a noncovalent manner.
- lectins attach to carbohydrates on the mucus or epithelial cell surface.
- Thiolated polymers, or thiomers have pendant thiols providing hydrophilicity, for example to polyacrylates or cellulosic polymeric backbones.
- the thiol group may form stable covalent bonds with mucus glycoproteins resulting in increased residency and improved bioavailability.
- mucoadhesive polymers include but are not limited to carbopols, N-isopropylacrylamide, polyvinyl alcohol/polyvinyl pyrrolidone, dextran, hydroxyethylmethacrylate/methacrylic acid, polyvinyl alcohol, polyacrylamide, polyethylene glycol/poly lactic acid, carboxymethyl chitosan and collagen.
- the mucoadhesive agent may include a polycarbophil and other acrylate/methacrylate polymers, anionic polymers based on methacrylic acid esters, which form pH selectably dissolvable hydrogels that dissolve (enabling physiological conditions to interact with and further initiate the release of NO) within physiochemically specified pH ranges, generally between about pH 5.5 to about pH 7.5.
- pH selectably dissolvable hydrogels that dissolve (enabling physiological conditions to interact with and further initiate the release of NO) within physiochemically specified pH ranges, generally between about pH 5.5 to about pH 7.5.
- Such formulations dissolving in the pH range from about 5.5 to about 6.0 is useful for targeting the duodenum.
- Dissolution at higher pH generally targets lower sections of the intestine.
- a pH of dissolution of between about 6.5 to about 7.0 may be useful for targeting the colon.
- the mucoadhesive agent comprises a water-soluble polymer.
- a water-soluble polymer may or may not form a hydrogel to some extent when hydrated, it is capable of forming a flowable aqueous solution.
- Mucoadhesive agents of this type include but are not limited to polyols and polycarbohydrates, hydroxylated celluloses (hydroxypropylmethyl cellulose and hydroxymethyl cellulose).
- the mucoadhesive agent enhances resonance time of the nitric oxide donor at the targeted site, for example, the respiratory tract.
- the mucoadhesive agent may also possess adhesion specificity to a biofilm comprising a pathogenic species.
- some alginate oligomers are known to interact with pseudomonas Aeruginosa biofilms.
- compositions disclosed herein may include one or more chelating agents.
- a chelating agent is included to scavenge trace metals, so as to quench their potentially deleterious effects on the NO donor compound.
- exemplary chelating agents are known in the art and examples include Ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA), yet other compounds described by Baldari et al., “Current Biomedical Use of Copper Chelation Therapy,” Int J Mol Sci. 2020; 21(3):1069.
- the disclosed compositions also can be formulated as a preparation for implantation.
- the compositions can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
- suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
- ion exchange resins e.g., as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
- the compositions also can be formulated in rectal compositions (e.g., suppositories or retention enemas containing conventional suppository bases, such as cocoa butter or other glycerides), creams or lotions, or transdermal patches.
- the combination of all the various components of the pharmaceutical composition contribute to the tunability of the properties of the compositions disclosed herein.
- one or more properties of the compositions can be tuned according to the preferred properties described herein.
- the NO release rate, antimicrobial effect, water solubility, degradation rate, viscosity, gel firmness (where the formulation forms a gel), viscoelasticity, modulus, etc. are tunable.
- the properties of compositions can be tuned by adjusting the molecular weight of certain polymers used in the formulation.
- the weight-average molecular weight (M w ) in kDa of polymers disclosed herein are greater than or equal to about: 2.5, 5.0, 7.0, 10, 15, 30, 50, 100, 200, 500, 750, 1,000, 2,000, 10,000, or ranges including and/or spanning the aforementioned values.
- the number-average molecular weight (M n ) in kDa of polymers disclosed herein are greater than or equal to about: 2.5, 5.0, 7.0, 10, 15, 30, 50, 90, 100, 200, 500, 700, 1,000, 2,000, 10,000, or ranges including and/or spanning the aforementioned values.
- the polymers disclosed herein may have n repeat units. In several embodiments, n equal to or at least about: 10, 25, 50, 100, 250, 500, 1000, 2500, 5000, 10000, or ranges including and/or spanning the aforementioned values.
- size exclusion chromatography (SEC) can be used to measure the molecular weight of the scaffold structures disclosed herein.
- the scaffold structures can be characterized using their polydispersity index.
- the polydispersity index (PDI) is a measure of the distribution of molecular mass in a given polymer sample. PDI can be calculated by dividing the weight average molecular weight and the number average molecular weight.
- the scaffold structures have a PDI of greater than or equal to about: 1.05, 1.1, 1.2, 1.3, 1.5, 1.7, 1.8, 1.9, 2.0, or ranges including and/or spanning the aforementioned values.
- Representative polymers include those disclosed in each of U.S. Patent Application No. 62/441,742, U.S. Patent Application No. 62/483,505 International Application No. PCT/IB2018/050051, U.S. Patent Application No. 62/447,564, International Application No. PCT/IB2018/052144, U.S. patent application Ser. No. 14/421,525, U.S. Patent Application No. 62/639,119, and U.S. Patent Application No. 62/737,603 are used. Each of these applications and publications is incorporated by reference in its entirety for all purposes.
- the compositions may be water soluble and/or mutually miscible.
- the compositions are soluble in water (at about 20° C.) at a concentration of greater than or equal to about: 1 mg/ml, 10 mg/ml, 20 mg/ml, 50 mg/ml, 100 mg/ml, 200 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, or ranges including and/or spanning the aforementioned values.
- the NO donor can be formulated within a pharmaceutical formulation at a concentration equal to or at least about: 100 ⁇ g/mL, and can be higher, e.g. about 1 mg/ml, about 5 mg/ml, about 10 mg/ml, about 20 mg/ml, 25 mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml or about 200 mg/ml or higher.
- a polymeric species can be formulated within a pharmaceutical formulation at a concentration equal to or at least about: 100 ⁇ g/mL, and can be higher, e.g.
- the amount of the polymer in the aqueous composition can be at least about 10% by weight, based on the weight of the NO donor, and may be higher, e.g., at least about 20% by weight, at least about 30% by weight, or at least about 50% by weight, same basis. Any combinations of NO donors and polymers in an aqueous composition are selected to be mutually miscible.
- the NO donor and the polymer are considered mutually miscible if at least about 90% of the polymeric components remain mutually soluble 24 hours after mixing and maintaining at room temperature in water at a concentration of each polymer of 1 mg/ml, upon visible examination.
- Such mutual miscibility of the water-soluble polymers with the NO donors can be achieved, despite an expectation of phase separation at the 1 mg/ml concentrations and molecular weights described herein.
- the aqueous compositions described herein can be prepared by intermixing the individual formulation components with water, e.g., at room temperature with stirring.
- the composition disclosed herein have properties characteristic of a viscous fluid and/or of a gel.
- a composition has a gelling point at room temperature (in water or PBS) at a concentration (in w/w %) of less than or equal to about: 0.5%, 1%, 2.5%, 5%, 10%, or ranges including and/or spanning the aforementioned values.
- the composition may have a gelling point in water.
- the composition gels in water (at about 20° C.) at a concentration of greater than or equal to about: 0.5 mg/ml, 1 mg/ml, 10 mg/ml, 20 mg/ml, 50 mg/ml, 100 mg/ml, 250 mg/ml, or ranges including and/or spanning the aforementioned values.
- the polymers at a concentration of 5% w/w solution, have a viscosity (in cPa ⁇ s at 20° C.) of equal to or at least about: 10, 50, 100, 1,000, 2,000, 5,000, 10,000, or ranges including and/or spanning the aforementioned values.
- the polymers have an intrinsic viscosity of equal to or greater than about: 0.5 m 3 /kg, 1.0 m 3 /kg, 2.0 m 3 /kg, 4.0 m 3 /kg, 8.0 m 3 /kg, or ranges including and/or spanning the aforementioned values.
- the compositions have a firmness of equal to or at least about: 1.0 mN, 2.5 mN, 5 mN, 10 mN, 15 mN, 20 mN, 30 mN, 50 mN, or ranges including and/or spanning the aforementioned values.
- the formulations have a work of adhesion (in mN*mm) of equal to or at least about: 1.0, 2.5, 5, 10, 15, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values.
- the compositions at a concentration of 5% w/w solution, have a storage modulus (G′) in Pa of equal to or at least about: 250, 500, 1,000, 2,000, 4,000, 5,000, 10,000, or ranges including and/or spanning the aforementioned values. In several embodiments, at a concentration of 5% w/w solution, the compositions have an elastic modulus (G′′) in Pa of equal to or at least about: 25, 50, 100, 200, 400, 500, 1,000, 2,000, 5,000, 10,000, or ranges including and/or spanning the aforementioned values. In several embodiments, the aqueous composition is characterized by a barrier activity, as measured by a decrease in the diffusion rate of an anionic dye of more than 2 logs at a total scaffold concentration of 40 mg/ml or less.
- the formulation is a gel and the gel are stable at a variety of temperatures 20° C. (e.g., 40° C., 45° C., 55° C., 60° C., 80° C., etc.) and are stable for prolonged storage periods (e.g., 10 hours, 20 hours, 22 hours, 25 hours, 30 hours, etc., days such as 1 day, 3 days, 5 days, 6 days, 7 days, 15 days, 30 days, 45 days, etc., weeks such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, etc., months such as 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc., or even years (1 year or greater)).
- temperatures 20° C. e.g., 40° C., 45° C., 55° C., 60° C., 80° C., etc.
- prolonged storage periods e.g., 10 hours, 20 hours, 22 hours, 25 hours, 30 hours, etc., days such as 1 day, 3 days, 5 days,
- the viscosity of the composition increases with increasing temperature, or decreases with decreasing temperature. For example, if the composition is above the gelling temperature, then the composition has a relatively high viscosity, such as in the form of a gel, and if cooled to below the gelling temperature, then the composition decreases in viscosity, such as in the form of a liquid.
- the polymers as disclosed herein may be reversible polymers (e.g., thermoreversible polymers), where the transition from liquid to gel may be reversed upon exposure to appropriate conditions.
- compositions of the present disclosure include thermoreversible polymers, where the viscosity of the composition may be changed depending on the temperature of the composition.
- the tunability of the viscosity enables a tailored composition profile upon delivery (e.g., more liquid at a delivery temperature and more viscous at, for example, body temperature).
- the compositions are characterized by a degree of swelling when exposed to water.
- the swelling degree % of the composition disclosed herein is equal to or at least about: 100, 250, 500, 1,000, 2,000, 5,000, or ranges including and/or spanning the aforementioned values.
- the composition may swell or otherwise expand by 2 ⁇ , 4 ⁇ , 5 ⁇ , 10 ⁇ , 20 ⁇ , 50 ⁇ , 100 ⁇ , or more.
- the compositions disclosed herein have a gelling temperature similar to the normal body temperature of a subject, such as similar to human body temperature, or 37° C.
- gelling temperature is meant the point on intersection between the plot for the elastic modulus and the plot for the viscous modulus.
- the composition if the composition is below the gelling temperature, then the composition has a relatively low viscosity, such as in the form of a liquid.
- the composition if the composition is above the gelling temperature, then the composition increases in viscosity (e.g., polymerizes), such that the composition is in the form of a gel.
- compositions that transition from a liquid to a gel may facilitate administration of the composition to the subject, for example by facilitating injection of a low viscosity (e.g., liquid) composition at a temperature below the gelling temperature.
- a low viscosity e.g., liquid
- the temperature of the composition may increase due to absorption of heat from the surrounding body tissue, such that the composition increases in viscosity (e.g., transitions from a liquid to a gel, or polymerizes), thus providing structural and/or geometric support to the body tissue at the target treatment site.
- gelling of the composition at the target treatment site may also facilitate retention of the composition at the treatment site by reducing the diffusion and/or migration of the composition away from the treatment site.
- the composition has a gelling temperature of 30° C. to 40° C., such as from 32° C. to 40° C., including from 35° C. to 40° C. In certain instances, the composition has a gelling temperature of 37° C.
- the compounds described herein can be combined with active agents conventionally used to treat the disorders being treated using the compounds described herein.
- active agents conventionally used to treat the disorders being treated using the compounds described herein.
- a patient in addition to administering one or more of the compounds described herein, a patient can also be administered a conventional agent.
- the compounds described herein can be combined with additional compounds useful for treating the disease states also treated by the release ofNO.
- the compounds discussed below can be used in combination therapy to treat Covid-19 infections, or other respiratory infections with similar pathology.
- a disease state is selected from the group consisting of baldness, ischemia/reperfusion injury, thrombosis/restenosis, a fibrotic disease, a cancer, a cardiovascular disease, a microbial, fungal, or viral infection, a disease of platelet aggregation and platelet adhesion, a disease caused by or characterized by low nitric oxide levels, a metabolic disease, pathological conditions resulting from abnormal cell proliferation, autoimmune diseases, inflammation, vascular diseases, scar tissue, wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases. Reducing implant-related infections.
- an effective amount refers to that amount of a recited compound that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, prevention or delay of the onset of the disorder, and/or change in clinical parameters, disease or illness, etc., as would be well known in the art.
- an effective amount can refer to the amount of a composition, compound, or agent that improves a condition in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
- Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired response for a particular subject and/or application.
- the selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the composition, formulation, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated.
- a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein.
- Treat” or “treating” or “treatment” refers to any type of action that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, and/or change in clinical parameters, disease or illness, curing the illness, etc.
- the “patient” or “subject” treated as disclosed herein is, in some embodiments, a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications.
- the term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), monkeys, etc.
- Human subjects include neonates, infants, juveniles, adults and geriatric subjects.
- the subject “in need of” the methods disclosed herein can be a subject that is experiencing a disease state and/or is anticipated to experience a disease state, and the methods and compositions of the invention are used for therapeutic and/or prophylactic treatment.
- Some embodiments provide a method for treating a tissue defect comprising positioning any of the compounds or compositions described herein, i.e., compound of Formula I-III, at, over, or into the tissue defect.
- the tissue defect is a wound.
- Several embodiments provide a method for treating a wound, for performing tissue repair, and/or for providing tissue and organ supplementation.
- the first step of treating a tissue defect, wound, and/or supplementing and replacing tissue involves identifying a patient in need of an antimicrobial compound or composition to aid in the remedying and healing of a tissue defect, healing of a wound, or in need of a tissue supplement.
- a non-limiting list of patients in need of an antimicrobial compound or composition includes patients suffering tissue defects.
- the patients in need of an antimicrobial compound or composition suffer from wounds including those from burns, skin ulcers, lacerations, bullet holes, animal bites, and other wounds prone to infection.
- Antimicrobial compounds or compositions can also be used in the treatment of diabetic foot ulcers, venous leg ulcers, pressure ulcers, amputation sites, in other skin trauma, or in the treatment of other wounds or ailments.
- Patients in need of an antimicrobial scaffold also include patients in need of repair and supplementation of tendons, ligaments, fascia, and dura mater.
- Degradable antimicrobial compounds or compositions can be used in supplement tissue in procedures including, but not limited to, rotator cuff repair, Achilles tendon repair, leg or arm tendon or ligament repair (e.g., torn ACL), vaginal prolapse repair, bladder slings for urinary incontinence, breast reconstruction following surgery, hernia repair, staple or suture line reinforcement, bariatric surgery repair, pelvic floor reconstruction, dural repair, gum repair, bone grafting, and reconstruction. Further, a patient in need of an antimicrobial compound or composition also includes one in need of tissue or organ replacement.
- the antimicrobial compounds or polymers described herein can be used as fillers and/or to supplement and/or replace tissue by acting as an artificial extracellular matrix.
- an antimicrobial compound or composition can be used to support cell and tissue growth. Briefly, cells can be taken from a patient or a viable host and seeded on an antimicrobial scaffold either in vivo or ex vivo. Then as the patient's natural tissues invade the material, it is tailored to degrade and leave only naturally occurring tissues and cells free of bacterial infection.
- the compounds and/or compositions discussed herein may be administered by direct injection or application to, for example, an injured tissue. Suitable routes also include injection or application to a site adjacent to the injured tissue. Administration may include parenteral administration (e.g., intravenous, intramuscular, or intraperitoneal injection), subcutaneous administration, administration into vascular spaces, and/or administration into joints (e.g., intra-articular injection). Additional routes of administration include intranasal, topical, vaginal, rectal, intrathecal, intraarterial, and intraocular routes.
- the compounds and compositions disclosed herein can be applied as a gel to a site of treatment. In several embodiments, the compounds and compositions can be applied as a liquid.
- NO is the endothelium-derived relaxing factor responsible for vasodilation and blood pressure regulation, and that NO plays key physiological roles in the cardiovascular (1) and nervous (2 and 3) systems, and as a signaling molecule capable of modulating cytokine production (4) in the immune response (5).
- Organic nitrates such as isosorbide mononitrate and glyceryl trinitrate, are widely used to treat angina, heart failure, and pulmonary hypertension, but are disadvantaged by the risk of hypotension, headaches and evolving tolerance (Miller and Megson, Br. J. Pharmacol., 2007, 151, 305-321).
- the metal nitrosyl sodium nitroprusside is also a potent vasodilator but requires co-administration with other drugs to prevent cyanide poisoning.
- the compounds described herein are low molecular weight NO-donor compounds, with a relatively long half-life. As such, they can deliver precise NO doses to cardiac tissues, providing an improved therapeutic output and reduced side effects relative to the organic nitrate drugs.
- Nitric oxide is also intricately involved in cancer biology where both NO concentration and lifetime governs whether it acts as a tumor progressor or suppressor (Mocellein, et al., Med. Res. Rev., 2007, 27, 317-352).
- NO oxidative and nitrosative stress
- nitrosylation of enzymes impaired cellular function
- enhanced inflammatory reactions inhibited mitochondrial respiration and cell apoptosis
- Lower NO concentrations i.e., picomolar
- the main advantage of NO over other antitumor therapies is a decreased toxicity toward healthy cells, particularly at concentrations toxic to tumor cells.
- any NO-based drug depends strongly on the concentration and duration of NO delivered. For example, micromolar NO concentrations are required to inhibit the growth of tumor cells, while picomolar NO concentrations have an angiogenic effect leading to cell proliferation (Mocellein, et al., Med. Res. Rev., 2007, 27, 317-352).
- NO-donor compounds must be capable of delivering high concentrations of NO specifically to the tumor site without the possibility of residual low concentrations that promote tumor growth.
- NO-based therapies must store and deliver only relevant NO doses for specific durations.
- NO delivery is selective, due to NO's short half-life (seconds) (Ignarro, Nitric Oxide: Biology and Pathobiology, Academic Press, San Diego, Calif., 2000).
- Pro-NO cancer therapies aim to increase NO concentrations at the tumor site to initiate apoptosis and/or necrosis of cancer cells (Hirst and T. Robson, Curr. Pharm. Des., 2010, 16, 411-420).
- Many LMW NO donors have shown anti-tumor efficacy, including diethylenetriamine NONOate, GTN, sodium nitroprusside, furoxan-based derivatives, and NO-releasing aspirin.
- LMW low molecular weight
- the compounds described herein have a relatively high NO concentration, due to their having three diazeniumdiolate moieties per molecule, and due to the relatively small size of the molecules (i.e., 200-500 g/mol), so overcome the limitations of prior low molecular weight (LMW) NO-donor compounds. While not wishing to be bound to a particular theory, it is believed that the NO-donor compounds disclosed herein have an improved effect on cancer cells, relative to other LMW NO-donor compounds that have been tried, because the NO-release is relatively slow. This can allow for a delay of NO release until the compounds have reached their intended target (i.e., tumor cells). Accordingly, it is advantageous to use the NO-donors disclosed herein, both for thei relatively long NO half-lives, and their relatively high NO storage capacity.
- LMW low molecular weight
- the compounds can be encapsulated, for example, in small unilamellar vesicles (SULVs), with an average diameter of around 30 nm to around 120 nm. These vesicles are small enough to travel through arteries and veins, but are trapped in capillary beds surrounding tumors.
- SULVs small unilamellar vesicles
- the compounds described herein can be effectively delivered to tumors in these vesicles before they release all of their NO payload.
- targeting approaches can also be used, for example, particles that encapsulate the compounds described herein, and which include targeting ligands, such as antibodies, for receptors which are overexpressed by certain tumors.
- the compounds described herein can be used to treat or prevent certain types of cancers, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas,
- NO alone for cancer treatment can be complicated by its dual role as a tumor promoter and repressor, so in some embodiments, the NO-based antitumor therapy disclosed herein involve co-administration with other therapies.
- Anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of formula 1 and pharmaceutical compositions described herein.
- MMP-2 matrix-metalloproteinase 2
- MMP-9 matrix-metalloproteinase 9
- COX-II cyclooxygenase II
- Examples of useful COX-II inhibitors include CELEBREX (alecoxib), valdecoxib, and rofecoxib.
- Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul.
- MMP inhibitors are those that do not demonstrate arthralgia.
- MMP-2 and/or MMP-9 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
- MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13 are examples of MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
- the compounds described herein can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors, such as VEGF receptors and molecules that can inhibit VEGF; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, Calif., USA).
- EGFR epidermal growth factor receptor
- VEGF vascular endothelial growth factor
- erbB2 receptor inhibitors such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, Calif., USA).
- EGFR inhibitors are described in, for example in WO 95/19970 (published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), and such substances can be used as described herein.
- EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C 225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y., USA), ABX-EGF (Abgenix/Cell Genesys), EMD-7200 (Merck KgaA), EMD-5590 (Merck KgaA), MDX-447/H-477 (Medarex Inc.
- VEGF inhibitors for example CP-547,632 (Pfizer Inc., N.Y.), AG-13736 (Agouron Pharmceuticals, Inc. a Pfizer Company), SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), and SH-268 (Schering) can also be combined with the compound of the present invention.
- VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov.
- VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic rib ozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be used in the present invention as described herein.
- ErbB2 receptor inhibitors such as CP-358,774 (OSI-774) (Tarceva) (OSI Pharmaceuticals, Inc.), GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with the compound of the invention, for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul.
- the compounds can also be used with other agents useful in treating abnormal cellular proliferation or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and antiproliferative agents such as other farnesyl protein transferase inhibitors, and the like.
- CTLA4 cytotoxic lymphocite antigen 4
- antiproliferative agents such as other farnesyl protein transferase inhibitors, and the like.
- Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used.
- anti-angiogenesis agents including, but not limited to, other COX-II inhibitors, other MMP inhibitors, other anti-VEGF antibodies or inhibitors of other effectors of vascularization can also be used.
- Abnormal cell proliferation can occur either due to abnormal cell division or by abnormal cell differentiation.
- Abnormal cell proliferation results in the formation of neoplasms, which are abnormal masses of tissue where the growth and division of the cells are uncoordinated and continue in the same excessive manner even after the cessation of the stimuli that caused it. Like cancers, these neoplasms can also be treated using NO-donor compounds.
- NO is generated to maintain proper blood flow and pressure (Loscalzo and J. A. Vita, Nitric oxide and the cardiovascular system, Humana Press, Inc., Totowa, N.J., 2000).
- NO When NO is produced from vascular endothelial cells, it influences the cellular activities of smooth muscle cells, platelets, and immune cells. After generation, NO diffuses into vascular smooth muscle cells and reacts with the iron of soluble guanylate cyclase. This activation of guanylate cyclase results in the production of cyclic guanosine monophosphate (cGMP), leading to relaxation of the smooth muscle cells and an overall dilation of blood vessels.
- cGMP cyclic guanosine monophosphate
- NO-donor compounds can be used to treat these disorders.
- LMW organic nitrates and nitrites have been used for centuries as cardiovascular therapeutics, particularly to initiate dilation of vascular smooth muscle (Loscalzo and Vita, Nitric oxide and the cardiovascular system, Humana Press, Inc., Totowa, N.J., 2000).
- GTN Glyceryl trinitrate
- GTN bioactivation desensitization of vascular soluble guanylate cyclase
- oxidative stress desensitization of mitochondrial aldehyde dehydrogenase inactivation.
- Sodium nitroprusside has also been used clinically, but its success is limited by cyanide toxicity.
- the compounds described herein provide not only a sustained release of nitric oxide, due to their relatively long NO half-lives, but also have relatively large payloads of nitric oxide precursors. As such, they can offer distinct advantages over nitrates and nitrites for these indications.
- Nitric oxide release from the NO donor compounds described herein allows for much longer and continuous delivery of NO at therapeutic levels than the nitrates and nitrites in use today, and thus represents a promising alternative to those NO donors for blood pressure regulation.
- pegylated liposomes also known as “stealth” liposomes
- Stealth liposomes are liposomes that evade detection by the immune system, hence, they are also known as immunoliposomes.
- Conventional liposomes are not stable for long periods of time, especially when injected into a body, but stealth liposomes use poly-(ethylene glycol) as a steric stabilizer.
- the stealth liposomes are not fully inert vesicles; they can eventually become detected by the immune system, just more slowly than non-pegylated liposomes. As such, stealth liposomes tend to provide relatively slow release of therapeutic compounds in vivo.
- the relatively slow release coupled with the NO-donor compounds' relatively long NO half-life and large NO capacity, can improve the efficacy of the compounds described herein, for example, in providing a more sustained reduction in mean arterial pressure.
- the compounds can be used to obtain decreased blood pressure over an extended period of time.
- Prolonged circulation and proper regulation of blood pressure with minimal negative side-effects are some of the advantages the compounds described herein can provide when used to treat circulatory disorders.
- I/R injury ischemia/reperfusion
- endogenous NO is known to be a mediator/protector of I/R injury, and can be used to treat this cardiovascular dysfunction.
- targeted NO delivery is necessary for reducing I/R injury, as the cytoprotective activity is only relevant at the compromised tissue.
- the compounds can be targeted to the liver, for example, by incorporating them in particles, and attaching appropriate targeting ligands to the particles.
- the compounds can be used to reduce I/R injury in a heart.
- the amount of infarcted (i.e., necrotic) tissue can be significantly reduced upon pretreatment (i.e., before the onset of ischemia) with the NO-releasing compounds.
- pretreatment i.e., before the onset of ischemia
- NO diffusion to intracellular organelles leads to cardioprotective effects.
- I/R injuries are seen in the carotid artery.
- Ischemic Stroke occurs as a result of a clot in the artery blocking the flow of blood to the brain leading to dysfunction or death of the brain tissue.
- Carotid artery disease is caused by a buildup of plaque in carotid arteries that deliver blood to the brain. These disorders can also be treated using the compounds described herein.
- Blood clots can cause heart attacks and strokes, and while the compounds of Formulas I-III can minimize ischemic damage, it can also be advantageous to administer an anti-coagulant/blood thinner, such as tissue plasminogen activator, integrilin, coumarin or heparin.
- an anti-coagulant/blood thinner such as tissue plasminogen activator, integrilin, coumarin or heparin.
- thrombosis i.e., blood clots within a vessel
- restenosis i.e., re-narrowing of vessels.
- endothelial cells generate NO to prevent thrombosis and platelet activation/adhesion.
- interventional procedures such as angioplasty and stenting often cause damage to, or removal of the endothelial cells lining the artery.
- normal NO production from the endothelium required for vascular homeostasis is disrupted with thrombosis resulting as activated platelets aggregate and adhere along with proteins (i.e., fibrin) to the device and/or injured site.
- smooth muscle cells migrate to the site, and their proliferation results in neointimal hyperplasia (i.e., proliferation of the cells of the inner most lining of an artery) ultimately leading to restenosis.
- vascular device implantation Due to NO's innate role in the cardiovasculature, application of exogenous NO can address problems arising at the site of vascular device implantation and vascular injury.
- implanted devices such as drug-loaded stends, may be coated with a sustained release polymer that incorporates the NO-releasing compounds described herein.
- the resulting NO release can effectively decrease platelet adhesion and activation on the interior walls of excorporeal blood circulatory tubes.
- lumen surfaces coated with NO-releasing compounds exhibit decreased platelet adhesion.
- thrombosis may also prove problematic by initiating excessive platelet activation and aggregation.
- Stasko et al. reported the ability of NO-releasing dendrimers (G4-SNAP) to inhibit platelet aggregation relative to the LMW NO donor SNAP (Stasko, et al., Biomacromolecules, 2008, 9, 834-841).
- G4-SNAP NO-releasing dendrimers
- the LMW NO donor compounds described herein provide enhanced NO half-lives, and have relatively large NO payloads, they can be as advantageous, or more so, as the polymeric NO donors, as they can provide a large, localized concentration of NO.
- vascular smooth muscle cells vascular smooth muscle cells
- endothelial cells may lead to neointimal hyperplasia following thrombosis in the restenosis cascade.
- NO vascular smooth muscle cells
- the prevention of restenosis with exogenous NO is achieved by decreasing platelet activation/aggregation and reducing neointimal hyperplasia.
- Optimal treatment requires that NO is delivered directly to the vascular injury either by direct application or by some NO release trigger.
- Site-specific delivery may be achieved using NO-release vehicles capable of targeted NO release.
- NO-based therapies have a long history in cardiovascular diseases.
- Compounds that release NO have a positive effect on blood flow regulation, ischemia/reperfusion injury, thrombosis and restenosis.
- Nitric oxide is an intercellular messenger that performs a number of functions, including neurotransmission, vasodilatation, inhibition of platelet aggregation, and modulation of leukocyte adhesion. NO has recently been shown to act as a potent cytotoxic effector molecule as well as to play an important role in the pathogenesis of organ-specific autoimmunity. NO may also modulate the immune response by interfering with Th1/Th2 balance in autoimmune diseases.
- Autoimmune disorders include multiple organ-specific to systemic disorders, including type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, scleroderma, thyroiditis, and others. There are also implications of autoimmune pathology in common health problems such as arteriosclerosis, inflammatory bowel diseases, psoriasis, schizophrenia, and certain types of infertility.
- iNOS inducible nitric oxide synthase
- the NO-donor compounds described herein can be used to treat a variety of autoimmune disorders, including type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, scleroderma, thyroiditis, and psoriasis.
- topical formulations When used to treat psoriasis, local delivery of the compounds via topical formulations may be preferable to systemic delivery, as the local concentration of NO on the tissue of interest can be enhanced.
- intra-articular delivery of the compounds may be beneficial, as NO release will occur directly in the affected joint.
- Nitric oxide acts as an anti-inflammatory, and can help inflamed joints and muscles, and help reduce the severity of symptoms from certain ailments.
- Nitric oxide is a signaling molecule that plays a key role in the pathogenesis of inflammation. It gives an anti-inflammatory effect under normal physiological conditions. However, on the other hand, NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations. Accordingly, NO can be used to treat inflammation, but care must be taken to avoid abnormally large concentrations of NO that might induce inflammation.
- the NO-donor compounds described herein have a relatively long NO half-life, so can provide sustained release of NO at therapeutically effective concentrations that can control inflammation. This can help avoid relatively high concentrations, as might be observed using NO-donor compounds with significantly shorter NO half-lives, and the corresponding higher concentrations of NO resulting from faster release from compounds with shorter NO half-lives. Thus, the compounds are uniquely suited for treating inflammatory disorders.
- representative inflammatory disorders include CNS encephalitis, myelitis, meningitis arachnoiditis, PNS neuritis, eye dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, ear otitis externa, otitis media, labyrinthitis, and mastoiditis.
- representative inflammatory disorders include carditis, endocarditis, myocarditis, pericarditis, vasculitis arteritis, phlebitis, and capillaritis.
- representative inflammatory disorders include chronic obstructive pulmonary disorder (COPD), upper sinusitis, rhinitis, pharyngitis, laryngitis, lower tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritic, and mediastinitis.
- COPD chronic obstructive pulmonary disorder
- representative inflammatory disorders include stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis/parotitis, cheilitis, pulpitis, and gnathitis.
- representative inflammatory disorders include esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, caecitis, appendicitis and proctitis.
- hepatitis such as non-alcoholic steatohepatitis, ascending cholangitis, cholecystitis, pancreatitis and peritonitis.
- representative inflammatory disorders include dermatitis folliculitis, cellulitis, and hidradenitis.
- representative inflammatory disorders include arthritis, dermatomyositis, soft tissue myositis, synovitis/tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, osteitis/osteomyelitis, spondylitis, periostitis, and chondritis.
- representative inflammatory disorders include nephritis glomerulonephritis, pyelonephritis, ureteritis, cystitis and urethritis.
- inflammatory disorders include oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, and mastitis.
- inflammatory disorders a pregnant woman might experience include chorioamnionitis, funisitis, and omphalitis.
- representative inflammatory disorders include orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, and balanoposthitis.
- representative inflammatory disorders include insulitis, hypophysitis, thyroiditis, parathyroiditis, and adrenalitis.
- representative inflammatory disorders include lymphangitis and lymphadenitis.
- Systemic sclerosis is a multisystem, connective tissue disease of unknown aetiology characterized by vascular dysfunction, autoimmunity, and enhanced fibroblast activity resulting in fibrosis of the skin, heart, and lungs, and ultimately internal organ failure, and death.
- oxidative stress One of the most important and early modulators of disease activity is thought to be oxidative stress.
- NO free radical nitric oxide
- Animal models and human studies have also identified dietary antioxidants, such as epigallocatechin-3-gallate (EGCG), to function as a protective system against oxidative stress and fibrosis.
- EGCG epigallocatechin-3-gallate
- targeting EGCG may prove a possible candidate for therapeutic treatment aimed at reducing both oxidant stress and the fibrotic effects associated with SSc.
- Peripheral neuropathy occurs when the part of the nervous system that carries signals from the brain to the muscles, skin, and other tissues begins to weaken and die.
- One of the conditions that can cause the peripheral nerves to die is neuropathy.
- Neuropathy often occurs when the tissues around nerves fail to get sufficient circulation, and this is a common condition in diabetic patients. The nerves begin to die when tissues become starved of oxygen and nutrients.
- Nitric oxide causes blood vessels to open, increasing the volume of blood that is able to move through them. Along with this increased blood flow, tissues get access to the greater supply of oxygen and vital nutrients. Enhanced levels of nitric oxide can therefore be used to treat neuropathy, so the NO-releasing compounds described herein can treat neuropathy, including peripheral neuropathy.
- Nitric Oxide offers pain relief in a number of ways, and NO is the mediator of the analgesic effect of opioids such as morphine. Accordingly, the NO-donor compounds described herein can be used to provide pain relief.
- Nitric oxide has a role in thermoregulation and fever.
- An elevated level of NO in the central nervous system can prevent fever, possibly via positive feedback action of NO on presynaptic glutaminergic neurons (Riedel W. Antipyretic role of nitric oxide during endotoxin-induced fever in rabbits. Int J Tissue React).
- Steiner and Branco “Nitric oxide in the regulation of body temperature and fever,” Journal of Thermal Biology, Volume 26, Issues 4-5, September 2001, Pages 325-330. Accordingly, the NO-donor compounds described herein can help reduce fevers.
- nitric oxide is the principal agent responsible for relaxation of penile smooth muscle (Cartledge et al., “The role of” nitric oxide in penile erection, Expert Opin. Pharmacother., 2001 January; 2(1):95-107. For this reason, NO-releasing compounds like sildenafil are used to treat impotence. More recently, nitroglycerin lotions/creams have been topically applied in order to provide erections.
- the NO-donor compounds release NO, so can be used orally, like Viagra, or topically, such as in a gel, to induce smooth muscle relaxation and erection.
- Baldness has been treated using helmets that emit light at wavelengths that promote the production or the release of endogenous NO.
- Revian has an FDA-cleared all-LED hair loss treatment for men and women, clinically proven to grow more hair in less time than other hair loss products.
- Topical administration of the compounds described herein to the scalp can also promote hair growth, as the local administration of NO to the tissue surrounding hair follicles can increase blood flow to the hair follicles.
- CNS disorders particularly those with an inflammatory component, and/or those associated with poor vascularization in one or more regions of the brain, that can be treated using the compounds described herein. These disorders include cognitive disorders, motor disorders, and behavioral/mood disorders.
- nitric oxide In disorders with an inflammatory component, the anti-inflammatory properties of nitric oxide can be leveraged to treat these disorders. In disorders with a vascular component, the release of nitric oxide can help promote increased vascularization.
- the treatments described herein can be used to treat a number of different disorders, including neurocognitive disorders, movement disorders, and emotional/behavioral/mood disorders.
- the treatments can also increase the flow of drugs across the blood brain barrier, so can be used to treat disorders of the brain, such as cancer, or disorders associated with an impaired blood brain barrier.
- Alzheimer's disease van de Haar H J, et al., “Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease”. Radiology. 282 (2): 615 (February 2017)
- anxiety and depression Gal Z, Huse R J, Gonda X, Kumar S, Juhasz G, Bagdy G, Petschner P (March 2019). “[Anxiety and depression—the role of blood-brain barrier integrity]”.
- Neuropsychopharmacologia Hungarica the role of blood-brain barrier integrity
- De Vivo disease also known as GLUT1 deficiency syndrome, resulting from inadequate transportation of the sugar glucose across the blood—brain barrier, typically caused by genetic defects in glucose transporter type 1 (GLUT1), HIV encephalitis (Ivey N S, MacLean AG, Lackner A A (April 2009). “Acquired immunodeficiency syndrome and the blood-brain barrier”. Journal of Neurovirology. 15 (2): 111-22), Meningitis (associated with inflammation of the membranes that surround the brain and spinal cord, i.e., meninges), multiple sclerosis (Waubant E (2006). “Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis”. Disease Markers. 22 (4): 235-44), and neuromyelitis optica, also known as Devic's disease, which is similar to multiple sclerosis.
- Brain cancers such as astrocytomas, including gliomas, glioblastoma multiforme, and meningiomas, ependymomas, pituitary tumors, such as pituitary adenomas and pituitary carcinomas, craniopharyngiomas, germ cell tumors, such as germinomas, pineal region tumors, including slow growing (pineocytoma) and fast growing (pineoblastoma) tumors, medulloblastomas, and primary CNS lymphomas, can also be treated.
- astrocytomas including gliomas, glioblastoma multiforme, and meningiomas, ependymomas
- pituitary tumors such as pituitary adenomas and pituitary carcinomas
- craniopharyngiomas craniopharyngiomas
- germ cell tumors such as germinomas, pineal region tumors, including slow growing (pineocytoma)
- anticancer drugs When used to treat brain cancers, conventional anticancer drugs can be coadministered, and their passage across the blood brain barrier can be enhanced, thus maximizing treatment efficiency.
- Representative anticancer drugs include SFC, Accutane, AEE788 (Novartis), AMG-102, Anti Neoplaston, AQ4N (Banoxantrone), AVANDIA (Rosiglitazone Maleate), Avastin (Bevacizumab) BCNU, BiCNU, Carmustine, Carboplatin, CC-223, CC223, CCI-779, CCNU, CCNU Lomustine, Celecoxib (Systemic), Chloroquine, Cilengitide (EMD 121974), Cisplatin, CPT-11 (CAMPTOSAR, Irinotecan), Cytoxan, Dasatinib (BMS-354825, Sprycel), Etoposide (Eposin, Etopophos, Vepesid), GDC-0449, Gle
- Thalomid thalidomide
- Toca 511 Topotecan (Systemic)
- VEGF Trap VEGF-Trap
- Velcade Vincristine
- Vorinostat SAHA
- XL 765 XL-184, XL184, XL765
- Zarnestra tipifarnib
- Zocor sirolimus
- Dexamethasone and furosemide can be used to decrease swelling.
- Central nervous system (CNS) vasculitis is inflammation of blood vessel walls in the brain or spine, which make up the central nervous system.
- CNS vasculitis is often accompanied by other autoimmune diseases such as systemic lupus erythematosus, dermatomyositis, and, rarely, rheumatoid arthritis. It is often caused by a viral or bacterial infection and can be systemic.
- PACNS primary angiitis of the CNS
- the compounds described herein can treat these disorders, due to the ability of NO to treat inflammation, and also to treat the underlying viral or bacterial infection.
- neurocognitive disorders also known as cognitive disorders
- Examples include Alzheimer's disease, amnesia, Binswanger's disease, cerebellar cognitive affective syndrome, clinical dementia rating, clouding of consciousness, cognitive deficit, cognitive slippage, cognitive vulnerability, corticobasal degeneration, corticobasal syndrome, delirium, dementia, disabilities affecting intellectual abilities, frontal assessment Battery, frontotemporal dementia, frontotemporal dementia and parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, HIV-associated neurocognitive disorders, learning problems in childhood cancer, Lewy body dementia association, Lewy body dementia, logopenic progressive aphasia, mild cognitive impairment, paratonia, Pick's disease, post-chemotherapy cognitive impairment, postoperative cognitive dysfunction, primary progressive aphasia, progressive nonfluent aphasia, progressive supranuclear palsy, pseudosenility, REM sleep behavior disorder, semantic dementia, severe cognitive impairment, subcor
- Neurocognitive disorders can have numerous causes, including genetics, brain trauma, stroke, and heart issues.
- the main causes are neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease because they affect or deteriorate brain functions.
- Other diseases and conditions that cause NDCs include vascular dementia, frontotemporal degeneration, Lewy body disease, prion disease, normal pressure hydrocephalus, and dementia/neurocognitive issues due to HIV infection. They may also include dementia due to substance abuse or exposure to toxins.
- Neurocognitive disorders also include brain trauma, including concussions and traumatic brain injuries, as well as post-traumatic stress and alcoholism. This is referred to as amnesia, and is characterized by damage to major memory encoding parts of the brain such as the hippocampus. Difficulty creating recent term memories is called anterograde amnesia and is caused by damage to the hippocampus part of the brain. Retrograde amnesia is also caused by damage to the hippocampus, but the memories that were encoded or in the process of being encoded in long-term memory are erased.
- Movement disorders are clinical syndromes with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity, and are typically divided into two major categories—hyperkinetic and hypokinetic.
- Hyperkinetic movement disorders refer to dyskinesia, or excessive, often repetitive, involuntary movements that intrude upon the normal flow of motor activity.
- Hypokinetic movement disorders refer to akinesia (lack of movement), hypokinesia (reduced amplitude of movements), bradykinesia (slow movement), and rigidity.
- the abnormal movement is the primary manifestation of the disorder.
- secondary movement disorders the abnormal movement is a manifestation of another systemic or neurological disorder.
- Representative movement disorders include hypokinetic movement disorders, Parkinson's disease (Primary or Idiopathic Parkinsonism), secondary Parkinsonism, Parkinson plus syndromes, Hallevorden-Spatz Disease, progressive supranuclear ophthalmoplegia, striatonigral deneneration, hyperkinetic movement disorders, dystonia, including drug-induced dystonia, idiopathic familial dystonia, idiopathic non-familial dystonia, ideopathic orofacial dystonia, spasmodic torticollis, blepharospasm, and other other dystonias, extrapyramidal movement disorders, essential tremors, drug induced tremors, myoclonus, opsoclonus, chorea (rapid, involuntary movement), including drug-induced chorea, rheumatic chorea (Sydenham's chorea), and Huntington's Chorea, ballismus (violent involuntary rapid and irregular movements), hemiballismus (affecting only one side
- Emotional and behavioral disorders (EBD; also known as behavioral and emotional disorders (ICD-10)) refer to a disability classification used in educational settings that allows educational institutions to provide special education and related services to students who have displayed poor social and/or academic progress.
- Disruptive behavior disorders include attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorders (CD). Schizophrenia is also included in this definition.
- Anxiety disorders are also included.
- Representative anxiety disorders include generalized anxiety disorder, specific phobia, social anxiety disorder, separation anxiety disorder, agoraphobia, panic disorder, and selective mutism.
- Anxiety disorders often occur with other mental disorders, particularly major depressive disorder, personality disorder, and substance use disorder.
- Depressive disorders include major depressive disorder (MDD, also known as major depression, unipolar depression, or clinical depression), and there are several subtypes or course specifiers, including atypical depression (AD), melancholic depression, psychotic major depression (PMD, or simply psychotic depression), catatonic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), dysthymia, double depression, depressive personality disorder (DPD), recurrent brief depression (RBD), minor depressive disorder (minor depression), and depressive disorder not otherwise specified (DD-NOS), which encompasses “any depressive disorder that does not meet the criteria for a specific disorder.”
- AD atypical depression
- PMD psychotic major depression
- PMDD psychotic major depression
- catatonic depression postpartum depression
- PMDD premenstrual dysphoric disorder
- SAD seasonal affective disorder
- DPD depressive personality disorder
- RBD recurrent brief depression
- minor depressive disorder minor depression
- DD-NOS
- Bipolar disorders also called manic depression or manic-depressive disorder
- BD also called manic depression or manic-depressive disorder
- bipolar I bipolar I
- bipolar II bipolar II
- cyclothymia bipolar disorder not otherwise specified
- BD-NOS bipolar disorder not otherwise specified
- Certain mood disorders are substance-induced, including alcohol-induced and benzodiazepine-induced.
- Medications such as antidepressants, benzodiazepines, or beta blockers, may be used in combination with the treatments described herein.
- Parkinson's Disease Although there is no cure for Parkinson's disease, a number of different types of medications provide some relief.
- the main families of drugs useful for treating motor symptoms are levodopa (typically combined with a dopa decarboxylase inhibitor and sometimes also with a COMT inhibitor), dopamine agonists and MAO-B inhibitors.
- Representative dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.
- Representative MAO-B inhibitors include safinamide, selegiline and rasagiline.
- Carbidopa and benserazide are dopa decarboxylase inhibitors which do not cross the blood-brain barrier and inhibit the conversion of levodopa to dopamine outside the brain, reducing side effects and improving the availability of levodopa for passage into the brain.
- One of these drugs is usually taken along with levodopa, often combined with levodopa in the same pill.
- Duodopa Intestinal infusions of levodopa (Duodopa) can also be used, and can reduce dosage fluctuations relative to oral levodopa.
- Catechol-O-methyltransferase (COMT) inhibitors such as opicapone, entacapone and tolcaponecan be used in combination with levodopa and dopamine dearecarboxylase (DDC) inhibitors to inhibit peripheral levodopa metabolism, increasing the amount of levodopa delivered to the brain.
- DDC dopamine dearecarboxylase
- Other drugs such as amantadine, anticholinergics, quetiapine, cholinesterase inhibitors, modafinil, pimavanserin, doxepin and rasagline can also be used.
- various drugs have been developed for use with Alzheimer's patients, and these can be used in combination with the treatments.
- Representative compounds that can be administered include memantine, Solanezumab, aducanumab, compounds which reduce beta-amyloid levels, such as apomorphine and aducanumab, vaccines that train the immune system to recognize, attack, and reverse deposition of amyloid, such as ACC-001 and bapineuzumab, and antisense therapies, neuroprotective agents, such as AL-108, metal-protein interaction attenuation agents, such as PBT2, TNF ⁇ receptor-blocking compounds, such as the fusion protein, etanercept, tau aggregation inhibitors, such as methylthioninium chloride and its prodrug LMTX, antihistamines, such as dimebon, and beta-secretase protein inhibitors, such as verubecestat, which reduced amyloid beta concentrations.
- Medications that reduce oxidative stress can improve memory, and can therefore be co
- amyloid precursor protein As discussed elsewhere herein, in animal models, such as the senescence accelerated mouse (SAMP8) model, amyloid precursor protein (APP) is overproduced.
- SAMP8 senescence accelerated mouse
- APP amyloid precursor protein
- the blood—brain barrier is damaged, causing a decreased expulsion of amyloid- ⁇ protein from the brain, and causing an increase in oxidative stress in the brain.
- the use of the treatments described herein can increase the ability of agents to cross the blood brain barrier, so can enhance the effectiveness of these agents, as well as accelerate expulsion of amyloid- ⁇ protein from the brain.
- Sickle cell anemia is one of them.
- Low levels of both oxygen and nitric oxide appear to have an unfortunate synergy for patients with sickle cell disease. These two conditions, common in sickle cell disease, dramatically increase red blood cells' adhesion to the lining of blood vessels walls and the debilitating pain crises that can result.
- the compounds disclosed herein can be used to treat sickle cell disease, as the release of nitric oxide can minimize adhesion of red blood cells to the lining of blood vessel walls, and relieve the pain that otherwise would result.
- Methemoglobinemia can also be reduced by the administration of low-dose nitric oxide releasing compounds.
- NO nitric oxide
- CKD chronic kidney disease
- Other disorders associated with low NO levels include glomerular hypertension, glomerular ischemia, glomerulosclerosis, tubulointerstitial injury, and proteinuria (Baylis, American Journal of Physiology-Renal Physiology, 2008, Vol. 294, No. 1).
- Metabolic syndrome is a cluster of metabolic disorders that collectively increase the risk of cardiovascular disease. Mitochondrial dysfunction is closely associated with obesity, metabolic syndrome and type 2 diabetes mellitus. Impaired nitric oxide synthase (NOS) activity is closely associated with insulin resistance.
- NOS paired nitric oxide synthase
- Nitric oxide therefore plays a crucial role in the pathogeneses of MS components and is involved in different mitochondrial signaling pathways that control respiration and apoptosis (Litvinova, et al., “Nitric oxide and mitochondria in metabolic syndrome.” Frontiers in Physiology, 6 (1): 20 (2015)).
- Administration of the compounds described herein can increase nitric oxide levels, and therefore treat metabolic syndrome and other metabolic disorders.
- the compounds described herein can be used to treat or prevent restenosis, which often occurs after stents are inserted into blood vessels.
- the compounds are administered using drug-loaded stents.
- the compounds and/or compositions discussed herein can be administered by inhalation, nebulization, intranasal delivery, direct injection or application to, for example, an infected tissue.
- Administration can also include parenteral administration (e.g., intravenous, intramuscular, or intraperitoneal injection), subcutaneous administration, administration into vascular spaces, and/or administration into joints (e.g., intra-articular injection).
- the compounds can also be administered via topical, vaginal, rectal, buccal, intrathecal, and intraarterial administration, or applied as a liquid or gel to a site of treatment.
- the compounds can be administered to the mouth, nasal passages, throat, esophagus, larynx, pharynx, trachea, bronchioles, bronchi, upper airways, lower airways, subcutaneously or via an implant (for example, up under the ribs and into the chest cavity), and combinations thereof.
- the compounds are nebulized, inhaled, or delivered intranasally.
- the methods comprise inhalation of particles including one or more of the compounds described herein aerosolized via nebulization.
- Nebulizers generally use compressed air or ultrasonic power to create inhalable aerosol droplets of the particles or suspensions thereof.
- the nebulizing results in pulmonary delivery to the subject of aerosol droplets of the particles or suspension thereof.
- the methods comprise inhalation of particles aerosolized via a pMDI, wherein the particles or suspensions thereof are suspended in a suitable propellant system (including but not limited to hydrofluoroalkanes (HFAs) containing at least one liquefied gas in a pressurized container sealed with a metering valve. Actuation of the valve results in delivery of a metered dose of an aerosol spray of the particles or suspensions thereof.
- a suitable propellant system including but not limited to hydrofluoroalkanes (HFAs) containing at least one liquefied gas in a pressurized container sealed with a metering valve.
- the compounds are administered during lung lavage, which can be whole lung lavage or bronchoalveolar lavage (BAL).
- BAL also known as bronchoalveolar washing
- a bronchoscope is passed through the mouth or nose into the lungs and fluid is squirted into a small part of the lung and then collected for examination.
- the compounds can travel through the fluid, and treat the entire fluid-coated portion of the lung.
- Bronchoalveolar lavage is commonly used to diagnose infections in people with immune system problems, pneumonia in people on ventilators, some types of lung cancer, and scarring of the lung (interstitial lung disease). It is the most common method used to sample the epithelial lining fluid (ELF) and to determine the protein composition of the pulmonary airways. It is often used in immunological research as a means of sampling cells (for example, T cells) or pathogen levels (for example, influenza virus) in the lung.
- Whole lung lavage (WLL; or “lung washing”) is a treatment for pulmonary alveolar proteinosis. While the lung is washed, therapy with the compounds can also be administered, and the fluid allows the compounds to contact the entire fluid-coated surface of the lung.
- This example pertains to the synthesis and identification of one embodiment of the compound of Formula III. This embodiment has the following features, advantages, and/or uses.
- the methane trisdiazeniumdiolate, sodium salt was prepared according to the following procedure in Table 1:
- reaction solution was filtered via vacuum filtration using 110 mm GF/F filter paper.
- FIG. 1 the FTIR spectrum is shown of the compound of Formula III according to the present disclosure.
- the UV absorbance spectrum of the analyte retained for approximately 6 minutes, the UV absorbance spectrum of the analyte retained for approximately 10 minutes, and the UV absorbance spectrum of the analyte retained for approximately 11 minutes are shown in the insets.
- FIG. 3 shows the 1 H NMR of the compound of Formula III. The peak at 7.5 ppm is assigned to the single proton on the compound of Formula III.
- FIG. 4 shows the 13 C NMR of the compound of Formula III. The peak at 100 ppm is assigned to the single carbon on the compound of Formula III.
- FIG. 5 shows 2D NMR of the compound of Formula III.
- FIG. 6 shows A) HPLC chromatograms (IEX-UV) with the top chromatogram (red) showing the separation of components prior to acid degradation of the compound of Formula III (referenced as MD3), the middle chromatogram (blue) showing the separation of components after 5 h of acid degradation, and the bottom chromatogram (black) showing the separation of components after 24 h of acid degradation, B) the 1 H NMR spectrum of the acid degraded components, C) a table of NOA Totals for the compound of Formula III before and after acid degradation.
- FIG. 7 is a 1 H NMR spectrum and FIG. 8 is 13 C NMR spectrum of a composition comprising the products of the compound of Formula III after degraded at neutral pH at room temperature.
- the NO release of the compound of Formula III at pH 7.4 is shown in FIG. 9 .
- the release profile was measured by chemiluminescence, showing 6.7 ⁇ mol NO/mg material releasing with a T 1/2 of approximately 3.75 h.
- 2 moles of NO are released per 1 mole of Formula III which converts to a theoretical yield of 7.6 ⁇ mol NO/mg.
- the synthesis of the compound of Formula III also generated an impurity, referred to herein as MD2, or methane bis-diazeniumdiolate, which has the following formula:
- bactericidal activity is a reasonable measure of nitric oxide release. Accordingly, the activity of mixtures of these compounds was evaluated against P. aeruginosa (PAK), with the goal of determining how the percentage of the compound of Formula III (referenced as MD3 in the table) relative to MD2 in different samples affected the activity of the mixture against P. aeruginosa .
- PAK P. aeruginosa
- MIC MBC TA Strain: (mg/ml) (mg/ml) Run #1, vial 7 (97% MD3) N0049 0.0625 0.125 Run #3, vial 7 (50% MD3) N0049 0.125 0.25 Run #3, vial 4 (5% MD3) N0049 0.25 0.5
- the efficacy of the compound of Formula III against PAK was evaluated at various pHs, 6.4, 7.6, and 8.4, all of which are physiological pHs, though at different places in the human body.
- tuminal pH in the proximal small bowel ranges from 5.5 to 7.0 and gradually rises to 6.5-7.5 in the distal ileum.
- luminal pH from the terminal ileum to the caecum ranges from 7.9 to 8.5.
- a normal blood pH level is 7.40, and this is approximately the pH in the lung.
- the pH of saliva is ranges from 6.5 to 7.5.
- the data (not shown) demonstrated that the release of NO from the compound of Formula III is pH-dependent, with higher rates of NO-release at a pH of around 6.5 than around 7.5, and relatively little NO release at a pH of around 8.4.
- the compound of Formula III can be prepared using acetone, ethanol or acetonitrile as a starting material as well as other compound with similar functional groups, though when prepared from ethanol or acetonitrile (or any other compound), the impurity profiles for each will be unique.
- a set of chromatograms are shown of samples of the compound of Formula III prepared from acetone, ethanol, and acetonitrile. In each case a different set of impurities were observed. While the material prepared from ethanol was comparable in purity to the material prepared from acetone (>90% area), the material prepared from acetonitrile was significantly less pure ( ⁇ 40% area).
- the methods disclosed herein include certain actions taken by a practitioner; however, they can also include any third-party instruction of those actions, either expressly or by implication.
- actions such as “administering an NO-donating composition” include “instructing the administration of an NO-donating composition.”
- administering an NO-donating composition include “instructing the administration of an NO-donating composition.”
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Agronomy & Crop Science (AREA)
- Dentistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/797,776 US20230108186A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062971624P | 2020-02-07 | 2020-02-07 | |
PCT/US2021/016869 WO2021158954A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/797,776 US20230108186A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230108186A1 true US20230108186A1 (en) | 2023-04-06 |
Family
ID=77199389
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/797,776 Pending US20230108186A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/797,899 Pending US20230337678A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/312,321 Pending US20220160736A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/542,124 Active US11813270B2 (en) | 2020-02-07 | 2021-12-03 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/797,899 Pending US20230337678A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/312,321 Pending US20220160736A1 (en) | 2020-02-07 | 2021-02-05 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
US17/542,124 Active US11813270B2 (en) | 2020-02-07 | 2021-12-03 | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto |
Country Status (4)
Country | Link |
---|---|
US (4) | US20230108186A1 (ja) |
EP (1) | EP4093205A4 (ja) |
JP (1) | JP2023513106A (ja) |
WO (3) | WO2021158954A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023211932A1 (en) * | 2022-04-28 | 2023-11-02 | Know Bio, Llc | Buffering agent-containing compositions and methods of using same |
WO2023230486A2 (en) * | 2022-05-23 | 2023-11-30 | Inhalon Biopharma, Inc. | Compositions and methods for inhalable therapeutics |
WO2023239801A1 (en) * | 2022-06-08 | 2023-12-14 | Know Bio, Llc | Multi-component pharmaceutical compositions and kits containing nitric oxide releasing compounds and methods of using same |
WO2024112512A1 (en) * | 2022-11-26 | 2024-05-30 | Sterile State Llc | Thiol-containing alcohols for generating nitric oxide and methods of forming the same |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5910316A (en) | 1992-08-24 | 1999-06-08 | The United States Of America, As Represented By The Department Of Health And Human Services | Use of nitric oxide-releasing agents to treat impotency |
US6203822B1 (en) * | 1996-09-03 | 2001-03-20 | University Of Iowa Research Foundation | Gallium-containing compounds for the treatment of infections caused by intracellular pathogens and pathogens causing chronic pulmonary infection |
US20020182162A1 (en) * | 2002-08-07 | 2002-12-05 | Mohsen Shahinpoor | Nitric oxide (NO) donor+cGMP-PDE5 inhibitor as a topical drug for enhanced hair growth |
US7569559B2 (en) * | 2004-02-09 | 2009-08-04 | Noxilizer, Inc. | Nitric oxide-releasing molecules |
US8557300B2 (en) * | 2005-05-19 | 2013-10-15 | University Of Cincinnati | Methods for treating bacterial respiratory tract infections in an individual using acidified nitrite |
ES2731298T3 (es) * | 2005-05-27 | 2019-11-14 | Univ North Carolina Chapel Hill | Partículas de liberación de óxido nítrico para agentes terapéuticos de óxido nítrico y aplicaciones biomédicas |
EP1942942A2 (en) * | 2005-10-31 | 2008-07-16 | Government of the United States of America, Represented by the Secretary, Department of Health and Human Services | Polysaccharide-derived nitric oxide-releasing carbon-bound diazeniumdiolates |
US8236341B2 (en) * | 2009-04-02 | 2012-08-07 | Medtronic Vascular, Inc. | Poly(tetrafluoroethylene) polymer with nitric oxide donating surface |
WO2018127819A1 (en) * | 2017-01-03 | 2018-07-12 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing alginates as biodegradable antibacterial scaffolds and methods pertaining thereto |
WO2019173539A1 (en) * | 2018-03-06 | 2019-09-12 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing cyclodextrins as biodegradable antibacterial scaffolds and methods pertaining thereto |
-
2021
- 2021-02-05 WO PCT/US2021/016869 patent/WO2021158954A1/en active Application Filing
- 2021-02-05 US US17/797,776 patent/US20230108186A1/en active Pending
- 2021-02-05 EP EP21750343.2A patent/EP4093205A4/en active Pending
- 2021-02-05 JP JP2022547051A patent/JP2023513106A/ja active Pending
- 2021-02-05 US US17/797,899 patent/US20230337678A1/en active Pending
- 2021-02-05 WO PCT/US2021/016841 patent/WO2021158930A1/en active Application Filing
- 2021-02-05 US US17/312,321 patent/US20220160736A1/en active Pending
- 2021-02-05 WO PCT/US2021/016854 patent/WO2021158941A1/en unknown
- 2021-12-03 US US17/542,124 patent/US11813270B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
WO2021158941A1 (en) | 2021-08-12 |
WO2021158930A1 (en) | 2021-08-12 |
US11813270B2 (en) | 2023-11-14 |
US20230337678A1 (en) | 2023-10-26 |
WO2021158954A1 (en) | 2021-08-12 |
JP2023513106A (ja) | 2023-03-30 |
US20220152063A1 (en) | 2022-05-19 |
EP4093205A4 (en) | 2024-02-21 |
US20220160736A1 (en) | 2022-05-26 |
EP4093205A1 (en) | 2022-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230108186A1 (en) | Nitric oxide-releasing antibacterial compounds, formulations, and methods pertaining thereto | |
US11931363B2 (en) | Triazolopyrimidine compounds and uses thereof | |
JP6823067B2 (ja) | 生体直交型組成物 | |
AU2020200979A1 (en) | New substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs | |
AU2018250312B2 (en) | Bioorthogonal compositions | |
JP6936007B2 (ja) | Chk1阻害剤とatr阻害剤との組み合わせを使用してがんを処置する方法 | |
ES2959419T3 (es) | Formulaciones secas por aspersión | |
US10689378B2 (en) | Triazolopyridine compounds and uses thereof | |
TW200918542A (en) | Sirtuin modulating compounds | |
WO2019141254A1 (zh) | 一种mTOR抑制剂、药物组合物及其应用 | |
US9650359B2 (en) | Modulators of resistant androgen receptor | |
TW201018688A (en) | Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) | |
CN110730664A (zh) | 含谷氨酰胺酶抑制剂的组合疗法 | |
CN109846884A (zh) | 用tor激酶抑制剂治疗癌症 | |
JP2016528174A (ja) | 治療的送達用のシクロデキストリンベースのポリマー | |
TW201236683A (en) | Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives as JAK inhibitors | |
US20210246120A1 (en) | Method of preparation and use of phosphoinositide 3-kinase inhibitors in treating cancer | |
WO2017114260A1 (zh) | 色胺酮及其衍生物在制备hIDO2抑制剂中的用途 | |
JP2015505557A (ja) | 治療的送達のためのシクロデキストリンに基づく重合体 | |
JP2022527451A (ja) | Pkm2モジュレーターおよびその使用方法 | |
WO2017114261A1 (zh) | N-芳基、苄基色胺酮及其衍生物在制备hIDO2抑制剂中的用途 | |
CA3232856A1 (en) | Kras antagonists | |
CN113710660B (zh) | Dot1l降解剂及其用途 | |
JP2005536467A (ja) | 選択的iNOS阻害剤を用いる呼吸器の疾患および状態の治療方法 | |
US20220184041A1 (en) | (AZA)Benzothiazolyl Substituted Pyrazole Compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |