EP3917507A1 - Tumescent infiltration drug delivery of cannabinoids - Google Patents
Tumescent infiltration drug delivery of cannabinoidsInfo
- Publication number
- EP3917507A1 EP3917507A1 EP20747957.7A EP20747957A EP3917507A1 EP 3917507 A1 EP3917507 A1 EP 3917507A1 EP 20747957 A EP20747957 A EP 20747957A EP 3917507 A1 EP3917507 A1 EP 3917507A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tumescent
- cannula
- subcutaneous
- infiltration
- delivery
- 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
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 49
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 48
- 230000008595 infiltration Effects 0.000 title claims description 215
- 238000001764 infiltration Methods 0.000 title claims description 215
- 238000012377 drug delivery Methods 0.000 title description 56
- 229940065144 cannabinoids Drugs 0.000 title description 15
- 238000001990 intravenous administration Methods 0.000 claims abstract description 212
- 238000012384 transportation and delivery Methods 0.000 claims abstract description 173
- 206010033675 panniculitis Diseases 0.000 claims abstract description 77
- 210000004304 subcutaneous tissue Anatomy 0.000 claims abstract description 72
- 239000003589 local anesthetic agent Substances 0.000 claims abstract description 60
- 239000000203 mixture Substances 0.000 claims abstract description 56
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 46
- 239000005526 vasoconstrictor agent Substances 0.000 claims abstract description 38
- 238000007918 intramuscular administration Methods 0.000 claims abstract description 22
- 230000001988 toxicity Effects 0.000 claims abstract description 20
- 231100000419 toxicity Toxicity 0.000 claims abstract description 20
- 239000003937 drug carrier Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims description 218
- 229940079593 drug Drugs 0.000 claims description 204
- 238000007920 subcutaneous administration Methods 0.000 claims description 128
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 123
- 229960004194 lidocaine Drugs 0.000 claims description 123
- 230000009885 systemic effect Effects 0.000 claims description 95
- 210000001519 tissue Anatomy 0.000 claims description 86
- 208000002193 Pain Diseases 0.000 claims description 76
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims description 60
- 230000036407 pain Effects 0.000 claims description 60
- 229930182837 (R)-adrenaline Natural products 0.000 claims description 59
- 229960005139 epinephrine Drugs 0.000 claims description 59
- 208000007514 Herpes zoster Diseases 0.000 claims description 57
- 238000010521 absorption reaction Methods 0.000 claims description 55
- 238000001356 surgical procedure Methods 0.000 claims description 51
- 230000002035 prolonged effect Effects 0.000 claims description 48
- 238000011282 treatment Methods 0.000 claims description 47
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 44
- 229960004150 aciclovir Drugs 0.000 claims description 43
- 238000001802 infusion Methods 0.000 claims description 34
- 210000003722 extracellular fluid Anatomy 0.000 claims description 32
- 208000004296 neuralgia Diseases 0.000 claims description 29
- 208000021722 neuropathic pain Diseases 0.000 claims description 27
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 20
- 239000003443 antiviral agent Substances 0.000 claims description 20
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 20
- 229960004242 dronabinol Drugs 0.000 claims description 20
- 206010061218 Inflammation Diseases 0.000 claims description 17
- 230000004054 inflammatory process Effects 0.000 claims description 17
- 230000001839 systemic circulation Effects 0.000 claims description 15
- 230000000840 anti-viral effect Effects 0.000 claims description 12
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims description 11
- 229950011318 cannabidiol Drugs 0.000 claims description 11
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims description 11
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims description 11
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims description 11
- 206010006187 Breast cancer Diseases 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 206010047700 Vomiting Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000007908 nanoemulsion Substances 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 5
- 239000004530 micro-emulsion Substances 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 206010028813 Nausea Diseases 0.000 claims description 4
- 230000004596 appetite loss Effects 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 230000008693 nausea Effects 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 3
- 206010019909 Hernia Diseases 0.000 claims description 2
- 238000011542 limb amputation Methods 0.000 claims description 2
- 230000008439 repair process Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 191
- 238000000034 method Methods 0.000 description 179
- 230000003115 biocidal effect Effects 0.000 description 165
- 239000012530 fluid Substances 0.000 description 134
- 239000003242 anti bacterial agent Substances 0.000 description 93
- 229940088710 antibiotic agent Drugs 0.000 description 74
- 229960001139 cefazolin Drugs 0.000 description 71
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 70
- 208000031650 Surgical Wound Infection Diseases 0.000 description 58
- 238000002690 local anesthesia Methods 0.000 description 53
- 206010028980 Neoplasm Diseases 0.000 description 51
- 210000002966 serum Anatomy 0.000 description 51
- 208000015181 infectious disease Diseases 0.000 description 49
- -1 but not limited to Substances 0.000 description 44
- 230000000694 effects Effects 0.000 description 42
- 210000003491 skin Anatomy 0.000 description 42
- 229960000282 metronidazole Drugs 0.000 description 40
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 40
- 230000003444 anaesthetic effect Effects 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 34
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 33
- 230000000845 anti-microbial effect Effects 0.000 description 33
- 208000014674 injury Diseases 0.000 description 33
- 201000011510 cancer Diseases 0.000 description 32
- 230000006378 damage Effects 0.000 description 27
- 239000007924 injection Substances 0.000 description 27
- 238000002347 injection Methods 0.000 description 27
- 238000007443 liposuction Methods 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 229920003023 plastic Polymers 0.000 description 24
- 239000004033 plastic Substances 0.000 description 24
- 230000001154 acute effect Effects 0.000 description 23
- 230000008901 benefit Effects 0.000 description 23
- 230000006870 function Effects 0.000 description 22
- 238000002695 general anesthesia Methods 0.000 description 22
- 208000032843 Hemorrhage Diseases 0.000 description 21
- 208000034158 bleeding Diseases 0.000 description 21
- 230000000740 bleeding effect Effects 0.000 description 21
- 206010047139 Vasoconstriction Diseases 0.000 description 20
- 230000002980 postoperative effect Effects 0.000 description 20
- 230000025033 vasoconstriction Effects 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 229940090044 injection Drugs 0.000 description 19
- 238000003780 insertion Methods 0.000 description 19
- 230000037431 insertion Effects 0.000 description 19
- 208000001435 Thromboembolism Diseases 0.000 description 18
- 230000007423 decrease Effects 0.000 description 18
- 230000008733 trauma Effects 0.000 description 18
- 208000005189 Embolism Diseases 0.000 description 17
- 230000000844 anti-bacterial effect Effects 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 206010002091 Anaesthesia Diseases 0.000 description 16
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 16
- 208000027418 Wounds and injury Diseases 0.000 description 16
- 230000037005 anaesthesia Effects 0.000 description 16
- 210000001772 blood platelet Anatomy 0.000 description 16
- 238000002637 fluid replacement therapy Methods 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 230000002265 prevention Effects 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 15
- 210000004003 subcutaneous fat Anatomy 0.000 description 15
- 206010040047 Sepsis Diseases 0.000 description 14
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 229940124597 therapeutic agent Drugs 0.000 description 14
- 241000894006 Bacteria Species 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 230000003110 anti-inflammatory effect Effects 0.000 description 12
- 210000001736 capillary Anatomy 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- 239000002260 anti-inflammatory agent Substances 0.000 description 11
- 239000004599 antimicrobial Substances 0.000 description 11
- 229940044683 chemotherapy drug Drugs 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 11
- 238000002483 medication Methods 0.000 description 11
- 238000011321 prophylaxis Methods 0.000 description 11
- 208000036142 Viral infection Diseases 0.000 description 10
- 230000036592 analgesia Effects 0.000 description 10
- 230000005484 gravity Effects 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 210000000689 upper leg Anatomy 0.000 description 10
- 210000003462 vein Anatomy 0.000 description 10
- 230000009385 viral infection Effects 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000012829 chemotherapy agent Substances 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 9
- 229960005015 local anesthetics Drugs 0.000 description 9
- 230000002572 peristaltic effect Effects 0.000 description 9
- 230000010118 platelet activation Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000012385 systemic delivery Methods 0.000 description 9
- 239000003071 vasodilator agent Substances 0.000 description 9
- 208000004550 Postoperative Pain Diseases 0.000 description 8
- 208000002847 Surgical Wound Diseases 0.000 description 8
- 210000000577 adipose tissue Anatomy 0.000 description 8
- 229940035674 anesthetics Drugs 0.000 description 8
- 230000002303 anti-venom Effects 0.000 description 8
- 238000002512 chemotherapy Methods 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- 239000003193 general anesthetic agent Substances 0.000 description 8
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- 230000000069 prophylactic effect Effects 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 231100000331 toxic Toxicity 0.000 description 8
- 230000002588 toxic effect Effects 0.000 description 8
- 230000003639 vasoconstrictive effect Effects 0.000 description 8
- 229940124549 vasodilator Drugs 0.000 description 8
- 201000004624 Dermatitis Diseases 0.000 description 7
- 241001560589 Hemitaurichthys zoster Species 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 208000005298 acute pain Diseases 0.000 description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 7
- 239000003862 glucocorticoid Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 230000033001 locomotion Effects 0.000 description 7
- 230000003211 malignant effect Effects 0.000 description 7
- 210000005036 nerve Anatomy 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 7
- 231100000611 venom Toxicity 0.000 description 7
- 241001535291 Analges Species 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 6
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 6
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 208000005156 Dehydration Diseases 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound 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)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 208000010201 Exanthema Diseases 0.000 description 6
- 208000000453 Skin Neoplasms Diseases 0.000 description 6
- 206010048038 Wound infection Diseases 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 230000000843 anti-fungal effect Effects 0.000 description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 6
- 229940125385 biologic drug Drugs 0.000 description 6
- 210000000481 breast Anatomy 0.000 description 6
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 238000006297 dehydration reaction Methods 0.000 description 6
- 201000005884 exanthem Diseases 0.000 description 6
- 229960004396 famciclovir Drugs 0.000 description 6
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 230000002631 hypothermal effect Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 210000001165 lymph node Anatomy 0.000 description 6
- 210000001365 lymphatic vessel Anatomy 0.000 description 6
- 239000002581 neurotoxin Substances 0.000 description 6
- 231100000618 neurotoxin Toxicity 0.000 description 6
- 235000013824 polyphenols Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 206010037844 rash Diseases 0.000 description 6
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000007929 subcutaneous injection Substances 0.000 description 6
- 238000010254 subcutaneous injection Methods 0.000 description 6
- 238000007910 systemic administration Methods 0.000 description 6
- 239000002435 venom Substances 0.000 description 6
- 210000001048 venom Anatomy 0.000 description 6
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 5
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 5
- 208000000094 Chronic Pain Diseases 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 229930182566 Gentamicin Natural products 0.000 description 5
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 208000028389 Nerve injury Diseases 0.000 description 5
- 208000004983 Phantom Limb Diseases 0.000 description 5
- 208000010378 Pulmonary Embolism Diseases 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 239000012984 antibiotic solution Substances 0.000 description 5
- 208000002352 blister Diseases 0.000 description 5
- 229960003150 bupivacaine Drugs 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229960004755 ceftriaxone Drugs 0.000 description 5
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 5
- 230000003533 narcotic effect Effects 0.000 description 5
- 230000008764 nerve damage Effects 0.000 description 5
- 230000002981 neuropathic effect Effects 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- 244000052769 pathogen Species 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 201000000849 skin cancer Diseases 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- 238000012549 training Methods 0.000 description 5
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 4
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 201000006082 Chickenpox Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 206010051055 Deep vein thrombosis Diseases 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 description 4
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical class [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 206010028851 Necrosis Diseases 0.000 description 4
- PPEKGEBBBBNZKS-UHFFFAOYSA-N Neosaxitoxin Natural products N=C1N(O)C(COC(=O)N)C2N=C(N)NC22C(O)(O)CCN21 PPEKGEBBBBNZKS-UHFFFAOYSA-N 0.000 description 4
- 206010056238 Phantom pain Diseases 0.000 description 4
- 206010039897 Sedation Diseases 0.000 description 4
- 206010053879 Sepsis syndrome Diseases 0.000 description 4
- 241000270295 Serpentes Species 0.000 description 4
- 206010046980 Varicella Diseases 0.000 description 4
- 206010070995 Vascular compression Diseases 0.000 description 4
- 206010047249 Venous thrombosis Diseases 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000003246 corticosteroid Substances 0.000 description 4
- 229960001334 corticosteroids Drugs 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 229960002518 gentamicin Drugs 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 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 4
- 210000003205 muscle Anatomy 0.000 description 4
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 4
- 230000017074 necrotic cell death Effects 0.000 description 4
- PPEKGEBBBBNZKS-HGRQIUPRSA-N neosaxitoxin Chemical compound N=C1N(O)[C@@H](COC(=O)N)[C@@H]2NC(=N)N[C@@]22C(O)(O)CCN21 PPEKGEBBBBNZKS-HGRQIUPRSA-N 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 230000000737 periodic effect Effects 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 230000036280 sedation Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 229940037128 systemic glucocorticoids Drugs 0.000 description 4
- 231100000057 systemic toxicity Toxicity 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000000472 traumatic effect Effects 0.000 description 4
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- HYKGUEIYMKVUSR-NPULLEENSA-N 2-(diethylamino)-n-(2,6-dimethylphenyl)acetamide;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1.CCN(CC)CC(=O)NC1=C(C)C=CC=C1C HYKGUEIYMKVUSR-NPULLEENSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- 206010008631 Cholera Diseases 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 3
- 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 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 101710138657 Neurotoxin Proteins 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 208000008765 Sciatica Diseases 0.000 description 3
- 208000036064 Surgical Blood Loss Diseases 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 244000269722 Thea sinensis Species 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 239000003929 acidic solution Substances 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 229960004821 amikacin Drugs 0.000 description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 3
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 230000000842 anti-protozoal effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 3
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 3
- 229960002100 cefepime Drugs 0.000 description 3
- 229960002682 cefoxitin Drugs 0.000 description 3
- 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 3
- 230000022131 cell cycle Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000010878 colorectal surgery Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000004880 explosion Methods 0.000 description 3
- 229920002457 flexible plastic Polymers 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 208000012410 herpes zoster dermatitis Diseases 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000002706 hydrostatic effect Effects 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 150000002605 large molecules Chemical class 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000000394 mitotic effect Effects 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 210000000578 peripheral nerve Anatomy 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 210000003594 spinal ganglia Anatomy 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000008718 systemic inflammatory response Effects 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 229960000707 tobramycin Drugs 0.000 description 3
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 3
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 3
- 230000008736 traumatic injury Effects 0.000 description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 description 3
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- 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 3
- 230000003612 virological effect Effects 0.000 description 3
- 229940107931 zovirax Drugs 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 2
- VFMMPHCGEFXGIP-UHFFFAOYSA-N 7,8-Benzoflavone Chemical compound O1C2=C3C=CC=CC3=CC=C2C(=O)C=C1C1=CC=CC=C1 VFMMPHCGEFXGIP-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- 206010003011 Appendicitis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 2
- 241000218236 Cannabis Species 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 208000028399 Critical Illness Diseases 0.000 description 2
- 208000003311 Cytochrome P-450 Enzyme Inhibitors Diseases 0.000 description 2
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 206010011951 Decompression Sickness Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 206010018852 Haematoma Diseases 0.000 description 2
- 208000001688 Herpes Genitalis Diseases 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 102100037907 High mobility group protein B1 Human genes 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010021137 Hypovolaemia Diseases 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 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 2
- 108010051335 Lipocalin-2 Proteins 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 206010029174 Nerve compression Diseases 0.000 description 2
- 102100035405 Neutrophil gelatinase-associated lipocalin Human genes 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 208000012868 Overgrowth Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 206010067268 Post procedural infection Diseases 0.000 description 2
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000004078 Snake Bites Diseases 0.000 description 2
- 229910000831 Steel Inorganic materials 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
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 description 2
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 2
- 108010004977 Vasopressins Proteins 0.000 description 2
- 102000002852 Vasopressins Human genes 0.000 description 2
- 206010058874 Viraemia Diseases 0.000 description 2
- 238000012084 abdominal surgery Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 206010069351 acute lung injury Diseases 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 229940013181 advil Drugs 0.000 description 2
- 229940060515 aleve Drugs 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 230000001407 anti-thrombic effect Effects 0.000 description 2
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000003904 antiprotozoal agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 230000003190 augmentative effect Effects 0.000 description 2
- 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 2
- 230000004888 barrier function Effects 0.000 description 2
- 229960005274 benzocaine Drugs 0.000 description 2
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 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 2
- 229960001169 brivudine Drugs 0.000 description 2
- 229960003585 cefmetazole Drugs 0.000 description 2
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 2
- 229960005495 cefotetan Drugs 0.000 description 2
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 2
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 description 2
- 229950004259 ceftobiprole Drugs 0.000 description 2
- 229940047495 celebrex Drugs 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 230000007969 cellular immunity Effects 0.000 description 2
- 208000025997 central nervous system neoplasm Diseases 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000011461 current therapy Methods 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 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 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 2
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- 229950010160 dimethocaine Drugs 0.000 description 2
- OWQIUQKMMPDHQQ-UHFFFAOYSA-N dimethocaine Chemical compound CCN(CC)CC(C)(C)COC(=O)C1=CC=C(N)C=C1 OWQIUQKMMPDHQQ-UHFFFAOYSA-N 0.000 description 2
- 208000028659 discharge Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229960000735 docosanol Drugs 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 239000002621 endocannabinoid Substances 0.000 description 2
- 238000002692 epidural anesthesia Methods 0.000 description 2
- 229960002770 ertapenem Drugs 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
- 210000003414 extremity Anatomy 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000002594 fluoroscopy Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 208000027700 hepatic dysfunction Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960004716 idoxuridine Drugs 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- FABUFPQFXZVHFB-PVYNADRNSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-PVYNADRNSA-N 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 2
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 208000037819 metastatic cancer Diseases 0.000 description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 238000001690 micro-dialysis Methods 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 229940072709 motrin Drugs 0.000 description 2
- 229940090008 naprosyn Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- 239000004081 narcotic agent Substances 0.000 description 2
- 229940086322 navelbine Drugs 0.000 description 2
- 210000004126 nerve fiber Anatomy 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 229940072711 nuprin Drugs 0.000 description 2
- 230000000399 orthopedic effect Effects 0.000 description 2
- 229940052264 other local anesthetics in atc Drugs 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 229960001019 oxacillin Drugs 0.000 description 2
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 2
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 2
- 238000006213 oxygenation reaction Methods 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 229960002036 phenytoin Drugs 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 201000003144 pneumothorax Diseases 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229960002957 praziquantel Drugs 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 230000002250 progressing effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 2
- 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 2
- 238000005070 sampling Methods 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000007390 skin biopsy Methods 0.000 description 2
- 206010040872 skin infection Diseases 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 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 2
- 229940063683 taxotere Drugs 0.000 description 2
- 229960002372 tetracaine Drugs 0.000 description 2
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- 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 2
- 238000012546 transfer Methods 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 229960003962 trifluridine Drugs 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 229940093257 valacyclovir Drugs 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 2
- 230000002227 vasoactive effect Effects 0.000 description 2
- 229960003726 vasopressin Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 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 2
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 2
- 210000000707 wrist Anatomy 0.000 description 2
- 229940053867 xeloda Drugs 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- GEFQWZLICWMTKF-CDUCUWFYSA-N (-)-alpha-Methylnoradrenaline Chemical compound C[C@H](N)[C@H](O)C1=CC=C(O)C(O)=C1 GEFQWZLICWMTKF-CDUCUWFYSA-N 0.000 description 1
- YKSVGLFNJPQDJE-YDMQLZBCSA-N (19E,21E,23E,25E,27E,29E,31E)-33-[(2R,3S,4R,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-17-[7-(4-aminophenyl)-5-hydroxy-4-methyl-7-oxoheptan-2-yl]-1,3,5,7,37-pentahydroxy-18-methyl-9,13,15-trioxo-16,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid Chemical compound CC(CC(C)C1OC(=O)CC(=O)CCCC(=O)CC(O)CC(O)CC(O)CC2(O)CC(O)C(C(CC(O[C@@H]3O[C@H](C)[C@@H](O)[C@@H](N)[C@@H]3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\C1C)O2)C(O)=O)C(O)CC(=O)C1=CC=C(N)C=C1 YKSVGLFNJPQDJE-YDMQLZBCSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- XUSXOPRDIDWMFO-CTMSJIKGSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[[(2s,3r)-3-amino-6-[(1s)-1-aminoethyl]-3,4-dihydro-2h-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(O2)[C@H](C)N)N)[C@@H](N)C[C@H]1N XUSXOPRDIDWMFO-CTMSJIKGSA-N 0.000 description 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- CNPVJJQCETWNEU-CYFREDJKSA-N (4,6-dimethyl-5-pyrimidinyl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-1-piperazinyl]-4-methyl-1-piperidinyl]methanone Chemical compound N([C@@H](COC)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)N=CN=C1C CNPVJJQCETWNEU-CYFREDJKSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- XSPUSVIQHBDITA-KXDGEKGBSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(5-methyltetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-KXDGEKGBSA-N 0.000 description 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 description 1
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 1
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- JRYYVMDEUJQWRO-UHFFFAOYSA-N 2-methylnicotinamide Chemical compound CC1=NC=CC=C1C(N)=O JRYYVMDEUJQWRO-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- PYSICVOJSJMFKP-UHFFFAOYSA-N 3,5-dibromo-2-chloropyridine Chemical compound ClC1=NC=C(Br)C=C1Br PYSICVOJSJMFKP-UHFFFAOYSA-N 0.000 description 1
- JRJGKUTZNBZHNK-UHFFFAOYSA-N 3-phenylpropyl acetate Chemical compound CC(=O)OCCCC1=CC=CC=C1 JRJGKUTZNBZHNK-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound 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)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- YLDCUKJMEKGGFI-QCSRICIXSA-N 4-acetamidobenzoic acid;9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one;1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C.CC(O)CN(C)C.CC(O)CN(C)C.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC=NC2=O)=C2N=C1 YLDCUKJMEKGGFI-QCSRICIXSA-N 0.000 description 1
- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 description 1
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010001526 Air embolism Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- QTGIAADRBBLJGA-UHFFFAOYSA-N Articaine Chemical compound CCCNC(C)C(=O)NC=1C(C)=CSC=1C(=O)OC QTGIAADRBBLJGA-UHFFFAOYSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000031872 Body Remains Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 241000197194 Bulla Species 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 description 1
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 1
- 206010064012 Central pain syndrome Diseases 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000766026 Coregonus nasus Species 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 101150073133 Cpt1a gene Proteins 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- OJLOPKGSLYJEMD-LNQMSSPSSA-N Cyotec Chemical compound CCCCC(C)(O)CC=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-LNQMSSPSSA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 description 1
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 206010069808 Electrical burn Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- 206010059284 Epidermal necrosis Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 1
- 208000012468 Ewing sarcoma/peripheral primitive neuroectodermal tumor Diseases 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 208000004929 Facial Paralysis Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 229930183931 Filipin Natural products 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 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
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 108700010013 HMGB1 Proteins 0.000 description 1
- 101150021904 HMGB1 gene Proteins 0.000 description 1
- 229930195098 Hamycin Natural products 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 208000003809 Herpes Zoster Ophthalmicus Diseases 0.000 description 1
- 206010019972 Herpes viral infections Diseases 0.000 description 1
- 206010063491 Herpes zoster oticus Diseases 0.000 description 1
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 101001025337 Homo sapiens High mobility group protein B1 Proteins 0.000 description 1
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 208000003367 Hypopigmentation Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- XAGMUUZPGZWTRP-ZETCQYMHSA-N LSM-5745 Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1C1(N)CC1 XAGMUUZPGZWTRP-ZETCQYMHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010024774 Localised infection Diseases 0.000 description 1
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101710151321 Melanostatin Proteins 0.000 description 1
- JCYZMTMYPZHVBF-UHFFFAOYSA-N Melarsoprol Chemical compound NC1=NC(N)=NC(NC=2C=CC(=CC=2)[As]2SC(CO)CS2)=N1 JCYZMTMYPZHVBF-UHFFFAOYSA-N 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- WJAJPNHVVFWKKL-UHFFFAOYSA-N Methoxamine Chemical compound COC1=CC=C(OC)C(C(O)C(C)N)=C1 WJAJPNHVVFWKKL-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 241000192041 Micrococcus Species 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010050031 Muscle strain Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 description 1
- LUCQSVLCPJUJRN-UHVRHXOTSA-N Naringerin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](C)O1)c1cc(O)c2C(=O)C[C@H](c3ccc(O)cc3)Oc2c1 LUCQSVLCPJUJRN-UHVRHXOTSA-N 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030302 Oliguria Diseases 0.000 description 1
- 206010030865 Ophthalmic herpes zoster Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102100023472 P-selectin Human genes 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- YQKAVWCGQQXBGW-UHFFFAOYSA-N Piperocaine Chemical compound CC1CCCCN1CCCOC(=O)C1=CC=CC=C1 YQKAVWCGQQXBGW-UHFFFAOYSA-N 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 206010048737 Poor venous access Diseases 0.000 description 1
- 206010057751 Post procedural discharge Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 description 1
- 239000005822 Propiconazole Substances 0.000 description 1
- CAJIGINSTLKQMM-UHFFFAOYSA-N Propoxycaine Chemical compound CCCOC1=CC(N)=CC=C1C(=O)OCCN(CC)CC CAJIGINSTLKQMM-UHFFFAOYSA-N 0.000 description 1
- PWNMXPDKBYZCOO-UHFFFAOYSA-N Prulifloxacin Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC=1OC(=O)OC=1C PWNMXPDKBYZCOO-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- AQXXZDYPVDOQEE-MXDQRGINSA-N Pyrantel pamoate Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1.C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 AQXXZDYPVDOQEE-MXDQRGINSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- LUJAXSNNYBCFEE-UHFFFAOYSA-N Quercetin 3,7-dimethyl ether Natural products C=1C(OC)=CC(O)=C(C(C=2OC)=O)C=1OC=2C1=CC=C(O)C(O)=C1 LUJAXSNNYBCFEE-UHFFFAOYSA-N 0.000 description 1
- PUTDIROJWHRSJW-UHFFFAOYSA-N Quercitrin Natural products CC1OC(Oc2cc(cc(O)c2O)C3=CC(=O)c4c(O)cc(O)cc4O3)C(O)C(O)C1O PUTDIROJWHRSJW-UHFFFAOYSA-N 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 208000032831 Ramsay Hunt syndrome Diseases 0.000 description 1
- 206010037876 Rash papular Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- AWGBZRVEGDNLDZ-UHFFFAOYSA-N Rimocidin Natural products C1C(C(C(O)C2)C(O)=O)OC2(O)CC(O)CCCC(=O)CC(O)C(CC)C(=O)OC(CCC)CC=CC=CC=CC=CC1OC1OC(C)C(O)C(N)C1O AWGBZRVEGDNLDZ-UHFFFAOYSA-N 0.000 description 1
- AWGBZRVEGDNLDZ-JCUCCFEFSA-N Rimocidine Chemical compound O([C@H]1/C=C/C=C/C=C/C=C/C[C@H](OC(=O)[C@@H](CC)[C@H](O)CC(=O)CCC[C@H](O)C[C@@]2(O)O[C@H]([C@@H]([C@@H](O)C2)C(O)=O)C1)CCC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O AWGBZRVEGDNLDZ-JCUCCFEFSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 208000003837 Second Primary Neoplasms Diseases 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000032383 Soft tissue cancer Diseases 0.000 description 1
- 208000000017 Solitary Pulmonary Nodule Diseases 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- HEYZWPRKKUGDCR-QBXMEVCASA-N Swertiamarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](C=C)[C@]2(O)CCOC(=O)C2=CO1 HEYZWPRKKUGDCR-QBXMEVCASA-N 0.000 description 1
- HEYZWPRKKUGDCR-WRMJXEAJSA-N Swertiamarin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@H]1[C@@H](C=C)[C@@]2(O)C(C(=O)OCC2)=CO1 HEYZWPRKKUGDCR-WRMJXEAJSA-N 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000000728 Thymus Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102400000731 Tumstatin Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 1
- 101710099833 Venom protein Proteins 0.000 description 1
- XUSXOPRDIDWMFO-UHFFFAOYSA-N Verdamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(O2)C(C)N)N)C(N)CC1N XUSXOPRDIDWMFO-UHFFFAOYSA-N 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- DLGSOJOOYHWROO-WQLSENKSSA-N [(z)-(1-methyl-2-oxoindol-3-ylidene)amino]thiourea Chemical compound C1=CC=C2N(C)C(=O)\C(=N/NC(N)=S)C2=C1 DLGSOJOOYHWROO-WQLSENKSSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- TYBHXIFFPVFXQW-UHFFFAOYSA-N abafungin Chemical compound CC1=CC(C)=CC=C1OC1=CC=CC=C1C1=CSC(NC=2NCCCN=2)=N1 TYBHXIFFPVFXQW-UHFFFAOYSA-N 0.000 description 1
- 229950006373 abafungin Drugs 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- OXGUCUVFOIWWQJ-XIMSSLRFSA-N acanthophorin B Natural products O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OXGUCUVFOIWWQJ-XIMSSLRFSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940060198 actron Drugs 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 229940108553 acyclovir injection Drugs 0.000 description 1
- 229940008235 acyclovir sodium Drugs 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- UHIXWHUVLCAJQL-MPBGBICISA-N albaconazole Chemical compound C([C@@](O)([C@H](N1C(C2=CC=C(Cl)C=C2N=C1)=O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 UHIXWHUVLCAJQL-MPBGBICISA-N 0.000 description 1
- 229950006816 albaconazole Drugs 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229940110282 alimta Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical compound CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 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
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229940059275 anacin Drugs 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940072359 anaprox Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940089918 ansaid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000000398 anti-amebic effect Effects 0.000 description 1
- 230000001136 anti-cestodal effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 238000011861 anti-inflammatory therapy Methods 0.000 description 1
- 230000003127 anti-melanomic effect Effects 0.000 description 1
- 230000001679 anti-nematodal effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000573 anti-seizure effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000011203 antimicrobial therapy Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940036589 antiprotozoals Drugs 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000007486 appendectomy Methods 0.000 description 1
- 229950006334 apramycin Drugs 0.000 description 1
- XZNUGFQTQHRASN-XQENGBIVSA-N apramycin Chemical compound O([C@H]1O[C@@H]2[C@H](O)[C@@H]([C@H](O[C@H]2C[C@H]1N)O[C@@H]1[C@@H]([C@@H](O)[C@H](N)[C@@H](CO)O1)O)NC)[C@@H]1[C@@H](N)C[C@@H](N)[C@H](O)[C@H]1O XZNUGFQTQHRASN-XQENGBIVSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960005397 arbekacin Drugs 0.000 description 1
- MKKYBZZTJQGVCD-XTCKQBCOSA-N arbekacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)CC[C@H]1N MKKYBZZTJQGVCD-XTCKQBCOSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940097776 arthrotec Drugs 0.000 description 1
- 229960003831 articaine Drugs 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- BIDUPMYXGFNAEJ-APGVDKLISA-N astromicin Chemical compound O[C@@H]1[C@H](N(C)C(=O)CN)[C@@H](OC)[C@@H](O)[C@H](N)[C@H]1O[C@@H]1[C@H](N)CC[C@@H]([C@H](C)N)O1 BIDUPMYXGFNAEJ-APGVDKLISA-N 0.000 description 1
- 229950004074 astromicin Drugs 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960002699 bacampicillin Drugs 0.000 description 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 1
- 201000005008 bacterial sepsis Diseases 0.000 description 1
- 229960001192 bekanamycin Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OUGIDAPQYNCXRA-UHFFFAOYSA-N beta-naphthoflavone Chemical compound O1C2=CC=C3C=CC=CC3=C2C(=O)C=C1C1=CC=CC=C1 OUGIDAPQYNCXRA-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone 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-DVTGEIKXSA-N 0.000 description 1
- 229960003169 biapenem Drugs 0.000 description 1
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229960005074 butoconazole Drugs 0.000 description 1
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229960004348 candicidin Drugs 0.000 description 1
- 229940121376 cannabinoid receptor agonist Drugs 0.000 description 1
- 239000003537 cannabinoid receptor agonist Substances 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000005518 carboxamido group Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940047475 cataflam Drugs 0.000 description 1
- 229960003972 cefacetrile Drugs 0.000 description 1
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- 229950004030 cefaloglycin Drugs 0.000 description 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 1
- 229960003866 cefaloridine Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960004350 cefapirin Drugs 0.000 description 1
- 229950004359 cefazaflur Drugs 0.000 description 1
- HGXLJRWXCXSEJO-GMSGAONNSA-N cefazaflur Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(F)(F)F)[C@H]2SC1 HGXLJRWXCXSEJO-GMSGAONNSA-N 0.000 description 1
- 229960005312 cefazedone Drugs 0.000 description 1
- VTLCNEGVSVJLDN-MLGOLLRUSA-N cefazedone Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3C=C(Cl)C(=O)C(Cl)=C3)[C@H]2SC1 VTLCNEGVSVJLDN-MLGOLLRUSA-N 0.000 description 1
- 229960003408 cefazolin sodium Drugs 0.000 description 1
- 229960001817 cefbuperazone Drugs 0.000 description 1
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 description 1
- 229960002966 cefcapene Drugs 0.000 description 1
- HJJRIJDTIPFROI-NVKITGPLSA-N cefcapene Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 HJJRIJDTIPFROI-NVKITGPLSA-N 0.000 description 1
- JUVHVMCKLDZLGN-TVNFHGJBSA-N cefclidin Chemical compound N([C@@H]1C(N2C(=C(C[N+]34CCC(CC3)(CC4)C(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 JUVHVMCKLDZLGN-TVNFHGJBSA-N 0.000 description 1
- HOGISBSFFHDTRM-GHXIOONMSA-N cefdaloxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/O)\C1=CSC(N)=N1 HOGISBSFFHDTRM-GHXIOONMSA-N 0.000 description 1
- 229950006550 cefdaloxime Drugs 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- 229960004041 cefetamet Drugs 0.000 description 1
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- XAKKNLNAJBNLPC-MAYKBZFQSA-N cefluprenam Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)/C=C/C[N+](C)(CC)CC(N)=O)C([O-])=O)C(=O)C(=N/OCF)\C1=NSC(N)=N1 XAKKNLNAJBNLPC-MAYKBZFQSA-N 0.000 description 1
- 229950001334 cefluprenam Drugs 0.000 description 1
- 229960003791 cefmenoxime Drugs 0.000 description 1
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 description 1
- 229960001958 cefodizime Drugs 0.000 description 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- ZINFAXPQMLDEEJ-GFVOIPPFSA-N cefoselis Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1C=CC(=N)N1CCO ZINFAXPQMLDEEJ-GFVOIPPFSA-N 0.000 description 1
- 229950001580 cefoselis Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960003391 cefovecin Drugs 0.000 description 1
- ZJGQFXVQDVCVOK-MSUXKOGISA-N cefovecin Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1[C@@H]1CCCO1 ZJGQFXVQDVCVOK-MSUXKOGISA-N 0.000 description 1
- QDUIJCOKQCCXQY-WHJQOFBOSA-N cefozopran Chemical compound N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 QDUIJCOKQCCXQY-WHJQOFBOSA-N 0.000 description 1
- 229960002642 cefozopran Drugs 0.000 description 1
- LNZMRLHZGOBKAN-KAWPREARSA-N cefpimizole Chemical compound N1=CNC(C(=O)N[C@@H](C(=O)N[C@@H]2C(N3C(=C(C[N+]=4C=CC(CCS(O)(=O)=O)=CC=4)CS[C@@H]32)C([O-])=O)=O)C=2C=CC=CC=2)=C1C(=O)O LNZMRLHZGOBKAN-KAWPREARSA-N 0.000 description 1
- 229950004036 cefpimizole Drugs 0.000 description 1
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 1
- 229960000466 cefpirome Drugs 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- 229950009592 cefquinome Drugs 0.000 description 1
- 229960003844 cefroxadine Drugs 0.000 description 1
- RDMOROXKXONCAL-UEKVPHQBSA-N cefroxadine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)OC)C(O)=O)=CCC=CC1 RDMOROXKXONCAL-UEKVPHQBSA-N 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 229950000679 cefteram Drugs 0.000 description 1
- 229960004366 ceftezole Drugs 0.000 description 1
- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 description 1
- 229960004086 ceftibuten Drugs 0.000 description 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 1
- 229960005229 ceftiofur Drugs 0.000 description 1
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 1
- WJXAHFZIHLTPFR-JLRJEBFFSA-N ceftiolene Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C\SC1=NNC(=O)C(=O)N1CC=O WJXAHFZIHLTPFR-JLRJEBFFSA-N 0.000 description 1
- 229950008880 ceftiolene Drugs 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000014564 chemokine production Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960002688 choline salicylate Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229960001747 cinchocaine Drugs 0.000 description 1
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 description 1
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 description 1
- 229950001320 clinafloxacin Drugs 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 201000010918 connective tissue cancer Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229950008484 corbadrine Drugs 0.000 description 1
- 230000036757 core body temperature Effects 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 229960004741 cyclomethycaine Drugs 0.000 description 1
- YLRNESBGEGGQBK-UHFFFAOYSA-N cyclomethycaine Chemical compound CC1CCCCN1CCCOC(=O)C(C=C1)=CC=C1OC1CCCCC1 YLRNESBGEGGQBK-UHFFFAOYSA-N 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- 229940070230 daypro Drugs 0.000 description 1
- 229940026692 decadron Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 229960003807 dibekacin Drugs 0.000 description 1
- JJCQSGDBDPYCEO-XVZSLQNASA-N dibekacin Chemical compound O1[C@H](CN)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N JJCQSGDBDPYCEO-XVZSLQNASA-N 0.000 description 1
- 229960004515 diclofenac potassium Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- 229940105576 disalcid Drugs 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229960001089 dobutamine Drugs 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 229940072701 dolobid Drugs 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 210000003027 ear inner Anatomy 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 229940073063 ecotrin Drugs 0.000 description 1
- 229960002030 edoxudine Drugs 0.000 description 1
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 238000002283 elective surgery Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960003976 etidocaine Drugs 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229940085392 excedrin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229940065410 feldene Drugs 0.000 description 1
- RDJGLLICXDHJDY-UHFFFAOYSA-N fenoprofen Chemical compound OC(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-UHFFFAOYSA-N 0.000 description 1
- 229960005341 fenoprofen calcium Drugs 0.000 description 1
- VHUXSAWXWSTUOD-UHFFFAOYSA-L fenoprofen calcium (anhydrous) Chemical compound [Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 VHUXSAWXWSTUOD-UHFFFAOYSA-L 0.000 description 1
- 229950000152 filipin Drugs 0.000 description 1
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 1
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 229960002878 flomoxef Drugs 0.000 description 1
- UHRBTBZOWWGKMK-DOMZBBRYSA-N flomoxef Chemical compound O([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC(F)F)OC)CC=1CSC1=NN=NN1CCO UHRBTBZOWWGKMK-DOMZBBRYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- RIKPNWPEMPODJD-UHFFFAOYSA-N formononetin Natural products C1=CC(OC)=CC=C1C1=COC2=CC=CC=C2C1=O RIKPNWPEMPODJD-UHFFFAOYSA-N 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 229940112424 fosfonet Drugs 0.000 description 1
- 229960003704 framycetin Drugs 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 229960003883 furosemide Drugs 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
- 229960002870 gabapentin Drugs 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 238000011902 gastrointestinal surgery Methods 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 201000011349 geniculate herpes zoster Diseases 0.000 description 1
- 208000003884 gestational trophoblastic disease Diseases 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229960000642 grepafloxacin Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 229950006942 hamycin Drugs 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 description 1
- 229960001587 hesperetin Drugs 0.000 description 1
- AIONOLUJZLIMTK-UHFFFAOYSA-N hesperetin Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-UHFFFAOYSA-N 0.000 description 1
- 235000010209 hesperetin Nutrition 0.000 description 1
- 229940025878 hesperidin Drugs 0.000 description 1
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 description 1
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- FTODBIPDTXRIGS-UHFFFAOYSA-N homoeriodictyol Natural products C1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 FTODBIPDTXRIGS-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 229940096120 hydrea Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000003425 hypopigmentation Effects 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- CFUQBFQTFMOZBK-QUCCMNQESA-N ibazocine Chemical compound C12=CC(O)=CC=C2C[C@H]2N(CC=C(C)C)CC[C@]1(C)C2(C)C CFUQBFQTFMOZBK-QUCCMNQESA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000013394 immunophenotyping Methods 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 229940089536 indocin Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 210000005061 intracellular organelle Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 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 1
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 description 1
- 229960000788 isavuconazole Drugs 0.000 description 1
- 229960000798 isepamicin Drugs 0.000 description 1
- UDIIBEDMEYAVNG-ZKFPOVNWSA-N isepamicin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)O)[C@@H](N)C[C@H]1NC(=O)[C@@H](O)CN UDIIBEDMEYAVNG-ZKFPOVNWSA-N 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- 229940111707 ixempra Drugs 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229930182824 kanamycin B Natural products 0.000 description 1
- SKKLOUVUUNMCJE-FQSMHNGLSA-N kanamycin B Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SKKLOUVUUNMCJE-FQSMHNGLSA-N 0.000 description 1
- SKKLOUVUUNMCJE-UHFFFAOYSA-N kanendomycin Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)C(O)C(CO)O2)O)C(N)CC1N SKKLOUVUUNMCJE-UHFFFAOYSA-N 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 229960004891 lapatinib Drugs 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
- 229960000433 latamoxef Drugs 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- 229960004288 levobupivacaine Drugs 0.000 description 1
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229940063718 lodine Drugs 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 1
- 229960000570 luliconazole Drugs 0.000 description 1
- 208000026807 lung carcinoid tumor Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940072082 magnesium salicylate Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001728 melarsoprol Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 229960005192 methoxamine Drugs 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960003152 metisazone Drugs 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940112801 mobic Drugs 0.000 description 1
- 229940101984 mobidin Drugs 0.000 description 1
- 208000008588 molluscum contagiosum Diseases 0.000 description 1
- 229960005389 moroxydine Drugs 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960003808 nadifloxacin Drugs 0.000 description 1
- JYJTVFIEFKZWCJ-UHFFFAOYSA-N nadifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCC(O)CC1 JYJTVFIEFKZWCJ-UHFFFAOYSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229940089466 nalfon Drugs 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229940100605 naprelan Drugs 0.000 description 1
- 229960003940 naproxen sodium Drugs 0.000 description 1
- 208000018795 nasal cavity and paranasal sinus carcinoma Diseases 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 208000020588 necrotizing soft tissue infection Diseases 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 230000030626 negative regulation of ion transmembrane transport Effects 0.000 description 1
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 231100000878 neurological injury Toxicity 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940101771 nexavir Drugs 0.000 description 1
- 229960001920 niclosamide Drugs 0.000 description 1
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 230000037000 normothermia Effects 0.000 description 1
- 229940053973 novocaine Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 229960004031 omoconazole Drugs 0.000 description 1
- JMFOSJNGKJCTMJ-ZHZULCJRSA-N omoconazole Chemical compound C1=CN=CN1C(/C)=C(C=1C(=CC(Cl)=CC=1)Cl)\OCCOC1=CC=C(Cl)C=C1 JMFOSJNGKJCTMJ-ZHZULCJRSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229940053544 other antidepressants in atc Drugs 0.000 description 1
- 231100000199 ototoxic Toxicity 0.000 description 1
- 230000002970 ototoxic effect Effects 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- 229960000321 oxolinic acid Drugs 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 229940124583 pain medication Drugs 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229950011346 panipenem Drugs 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
- 229960005065 paromomycin sulfate Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229960002625 pazufloxacin Drugs 0.000 description 1
- 229960004236 pefloxacin Drugs 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229960001045 piperocaine Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 229960003342 pivampicillin Drugs 0.000 description 1
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960000471 pleconaril Drugs 0.000 description 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 description 1
- 210000004910 pleural fluid Anatomy 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940072710 ponstel Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960003981 proparacaine Drugs 0.000 description 1
- STJLVHWMYQXCPB-UHFFFAOYSA-N propiconazole Chemical compound O1C(CCC)COC1(C=1C(=CC(Cl)=CC=1)Cl)CN1N=CN=C1 STJLVHWMYQXCPB-UHFFFAOYSA-N 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 229950003255 propoxycaine Drugs 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229960001224 prulifloxacin Drugs 0.000 description 1
- 229960000996 pyrantel pamoate Drugs 0.000 description 1
- OEKUVLQNKPXSOY-UHFFFAOYSA-N quercetin 3-O-beta-D-glucopyranosyl(1->3)-alpha-L-rhamnopyranosyl(1->6)-beta-d-galactopyranoside Natural products OC1C(O)C(C(O)C)OC1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OEKUVLQNKPXSOY-UHFFFAOYSA-N 0.000 description 1
- QPHXPNUXTNHJOF-UHFFFAOYSA-N quercetin-7-O-beta-L-rhamnopyranoside Natural products OC1C(O)C(O)C(C)OC1OC1=CC(O)=C2C(=O)C(O)=C(C=3C=C(O)C(O)=CC=3)OC2=C1 QPHXPNUXTNHJOF-UHFFFAOYSA-N 0.000 description 1
- OXGUCUVFOIWWQJ-HQBVPOQASA-N quercitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OXGUCUVFOIWWQJ-HQBVPOQASA-N 0.000 description 1
- 238000009803 radical hysterectomy Methods 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 1
- 229950004154 ravuconazole Drugs 0.000 description 1
- 229950000381 razupenem Drugs 0.000 description 1
- XFGOMLIRJYURLQ-GOKYHWASSA-N razupenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)SC(SC=1)=NC=1C1=C[C@H](C)NC1 XFGOMLIRJYURLQ-GOKYHWASSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229940087462 relafen Drugs 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229930184609 rhodostreptomycin Natural products 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960003485 ribostamycin Drugs 0.000 description 1
- 229930190553 ribostamycin Natural products 0.000 description 1
- NSKGQURZWSPSBC-NLZFXWNVSA-N ribostamycin Chemical compound N[C@H]1[C@H](O)[C@@H](O)[C@H](CN)O[C@@H]1O[C@@H]1[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](CO)O2)O)[C@H](O)[C@@H](N)C[C@H]1N NSKGQURZWSPSBC-NLZFXWNVSA-N 0.000 description 1
- NSKGQURZWSPSBC-UHFFFAOYSA-N ribostamycin A Natural products NC1C(O)C(O)C(CN)OC1OC1C(OC2C(C(O)C(CO)O2)O)C(O)C(N)CC1N NSKGQURZWSPSBC-UHFFFAOYSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960001549 ropivacaine Drugs 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 229960004062 rufloxacin Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical compound NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 description 1
- RPQXVSUAYFXFJA-UHFFFAOYSA-N saxitoxin hydrate Natural products NC(=O)OCC1N=C(N)N2CCC(O)(O)C22NC(N)=NC12 RPQXVSUAYFXFJA-UHFFFAOYSA-N 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000011270 sentinel node biopsy Methods 0.000 description 1
- 208000021043 septic peritonitis Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229960005429 sertaconazole Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 229960003177 sitafloxacin Drugs 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229940125794 sodium channel blocker Drugs 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000011421 subcutaneous treatment Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002607 sulconazole Drugs 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products 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
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)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-XAZOAEDWSA-N 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
- 229940116411 terpineol Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 1
- 229950010357 tetrodotoxin Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 201000009377 thymus cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960004214 tioconazole Drugs 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- QGUALMNFRILWRA-UHFFFAOYSA-M tolmetin sodium Chemical compound [Na+].C1=CC(C)=CC=C1C(=O)C1=CC=C(CC([O-])=O)N1C QGUALMNFRILWRA-UHFFFAOYSA-M 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229950008187 tosufloxacin Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- IALIDHPAWNTXOK-UHFFFAOYSA-N tricosanal Chemical compound CCCCCCCCCCCCCCCCCCCCCCC=O IALIDHPAWNTXOK-UHFFFAOYSA-N 0.000 description 1
- 229940078279 trilisate Drugs 0.000 description 1
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 1
- 229940086984 trisenox Drugs 0.000 description 1
- UXQDWARBDDDTKG-UHFFFAOYSA-N tromantadine Chemical compound C1C(C2)CC3CC2CC1(NC(=O)COCCN(C)C)C3 UXQDWARBDDDTKG-UHFFFAOYSA-N 0.000 description 1
- 229960000832 tromantadine Drugs 0.000 description 1
- 229960000497 trovafloxacin Drugs 0.000 description 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010012374 type IV collagen alpha3 chain Proteins 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229960002004 valdecoxib Drugs 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
- 229940108442 valtrex Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 229950009860 vicriviroc Drugs 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 102000008538 voltage-gated sodium channel activity proteins Human genes 0.000 description 1
- 108040002416 voltage-gated sodium channel activity proteins Proteins 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Definitions
- the present embodiments relate to compositions, kits and methods of use of a solution comprising an anesthetic component, a vasoconstrictor component, and an active agent such as an antiviral component, an anti-inflammatory agent and/or a chemotherapy agent for use in medical procedures involving tumescent delivery of high doses of actives for local subcutaneous treatment.
- liposuction may be performed entirely by tumescent local anesthesia, which was invented by Jeffrey A. Klein. Dr. Klein first published the description of tumescent local anesthesia to perform liposuction in 1987 (Klein JA. The tumescent technique for liposuction surgery. J Am Acad Cosmetic Surg 4: 263- 267, 1987). The tumescent technique was developed in order to eliminate the dangers of liposuction surgery under general anesthesia and the associated excessive bleeding. With proper technique, tumescent infiltration permits liposuction totally by local anesthesia with virtually no surgical blood loss.
- Infiltrators are known as sprinkler-tip or KleinTM needle infiltrators.
- These cannula are constructed out of a rigid stainless steel and have one or more apertures, which are typically round or oval, and are distributed about the distal end of the cannula. The apertures are distributed over about 15% to 25% or less than 5.0 cm of the distal end of the cannula needle.
- These traditional infiltration cannula are intended to be inserted through a small incision in the patient’s skm and then moved in and out through the subcutaneous tissue while a dilute solution of local anesthetic (or other pharmaceutical solution) is ejected through the distal apertures.
- the cannula needle Since the cannula needle is moved in and out, only the distal end (e.g., about 15% to 25%) of the cannula needle may have apertures. Otherwise, fluid may squirt out of the apertures and onto medical professionals when the cannula needle is moved out too much.
- Such infiltrators typically have a blunt tip and require the placement of a small hole (made by a one mm skin-biopsy punch or a small surgical blade) through which the blunt tipped cannula can be passed. Unfortunately, the piston-like in and out motion of the cannula causes the patient discomfort.
- infiltration cannula is the sharp tipped tumescent infiltration cannula which is available as 1) a single long sharp needle similar to a spinal needle and 2) a group of short sharp hypodermic needles each connected by separate plastic tube to a manifold that distributes Tumescent Local Anesthesia (TLA) solution.
- TLA Tumescent Local Anesthesia
- the first type of needle is inserted into subcutaneous fat and infiltration proceeds while the needle is continuously moved in and out along paths that radiate from the skin puncture site. A targeted area is eventually anesthetized after multiple skin punctures.
- the second type the group of short sharp needles, consists of a group of individual hypodermic needles each attached to an individual IV extension tube, which are in turn connected to a multi-port manifold which connected to a reservoir (IV bag) of tumescent fluid.
- IV bag a reservoir of tumescent fluid.
- PICC line a peripherally inserted central catheter
- IV intravenous
- a PICC line may be used when a patient needs to receive intravenous (IV) fluids, such as medication or nutrients over a prolonged period of time, such as a w3 ⁇ 4ek or more.
- the On-Q® Pain Management System marketed by I-Flow® Corporation employs a flexible plastic or silicone catheter system for continuously providing local anesthetic. This system provides prolonged local anesthesia by means of an elastomeric (elastic container) device that continuously infiltrates a solution of local anesthesia over many hours.
- the On-Q® device comprises a long soft flexible tube with many small holes arranged along a significant portion of the tube.
- the On-Q® device is designed to be initially positioned within a surgical wmund at the time of surgery. After the surgical wound is closed, the On-Q® device permits slow steady infiltration of a local anesthetic solution into the wound, thereby attenuating post-operative pam.
- the On-Q® device cannot be inserted through a tiny hole in the skin when there is a need. Therefore the On-Q device cannot achieve infiltration of local anesthesia and prevent post-operative pam in a preemptive fashion.
- a long flexible multi-holed catheter is inserted subcutaneously using an introducer wire and an introducer catheter. This device requires a large sterile field (an area upon which to lay all of the sterile devices used during the insertion process), a complicated insertion protocol, and either general anesthesia or careful pre-insertion infiltration of local anesthesia.
- the Massengale device is not intend for or capable of being repeatedly inserted in and out of different areas of subcutaneous tissue; it cannot be inserted quickly by untrained personnel in- the-field and far from a sophisticated medical facility. It has been shown that preemptive local anesthesia in the form of peripheral nerve blocks, can prevent nociception by the central nervous system (CNS) during general anesthesia, and thereby prevent chronic post-operative pain syndromes similar to "phantom-limb syndrome.”
- CNS central nervous system
- a simple device that can permit the direct percutaneous insertion of a multi-holed infiltration cannula into subcutaneous tissue for the localized delivery of medications such as local anesthetics, chemotherapeutic agents, or crystalloids for parenteral hydration.
- medications such as local anesthetics, chemotherapeutic agents, or crystalloids for parenteral hydration.
- a device that can easily provide localized fluid resuscitation to bum victims whereby fluid is infiltrated into the subcutaneous tissue directly sub
- a system for infiltration of a local anesthetic into intact subcutaneous tissue which decreases patient discomfort preemptively, and allows prolonged local anesthesia either by rapid (less than 10 to 15 minutes) bolus injections, extended infiltration (e.g. over intervals ranging from 15 minutes to several hours) or continuous slow infiltration over many hours to days.
- a device that can provide pre-emptive local anesthesia before a surgical wound is created.
- a percutaneously-insertable infiltration cannula with applications that are unrelated to the delivery of local anesthesia, which can be easily inserted by rescuers with minimal clinical skill or training.
- a cannula that permits emergency fluid resuscitation in situations where an IV cannot be established such as nighttime military' combat conditions where using a flash light to establish an IV access would be extremely dangerous.
- Another example is the need to provide emergency fluid resuscitation to large numbers of patients in acute epidemic diarrhea (dehydration) associated with biological warfare, or mass- trauma situations such as a natural disaster (earth quake) or terrorist attack.
- a device that can easily provide localized fluid resuscitation to burn victims whereby fluid is infiltrated into the subcutaneous tissue directly subjacent to burned skin.
- U.S. Pat. Pub. No. 2003/0009132 (Schwartz et al.) is directed to a micro- intravascular (never extra-vascular) catheter for infusing milliliter quantities of drugs for the lysis of intravascular blood clots (i.e., a micro target).
- Another embodiment of the Schwartz device is intended to improve the precision and safety of intra-myocardial delivery of micro- liter volumes of fluid for biologic gene therapy based angiogenesis.
- the Schwartz device requires a sterile high tech hospital environment and demands fluoroscopy and ultrasound guidance.
- the Schwartz device requires a highly trained, experienced and skilled medical professional to operate.
- the Schwartz infiltration catheter is defined by its obligatory guidewire and intravascular target.
- the intravascular insertion of the catheter via the guidewire is a complex procedure that requires significant clinical training, experience and skill.
- the method involves 1) preparation with a sterile surgical field, 2) making a skm incision and inserting an introducing catheter having coaxial stylet into the targeted vessel, 3) removing the stylet, 4) inserting the guidewire through the introducing catheter and into the vessel, 5) withdrawing the introducing catheter from the vessel without disturbing the intravascular location of the guidewire, 6) slipping the distal tip of the infiltration catheter over the proximal end of the guidewire, and advancing the infiltration catheter over the considerable length of the guidewire through the skin and into the intraluminal space of the targeted vessel, 7) withdrawing the guidewire and attaching the proximal end of the infiltration catheter to a source of the therapeutic fluid to be delivered into the targeted vessel.
- This insertion procedure is so specialized that a majority of physicians do not have the requisite expertise to qualify for hospital privileges for inserting an intravascular catheter using a guidewire. Locating a clotted blood vessel and inserting the Schwartz catheter into the vessel requires ultrasound guidance.
- an important feature of the Sclxwartz device is the shape, size, direction and pattern of the holes on the infiltration cannula.
- the Schwartz device is intended to improve directional control over the direction of injection of minute volumes of mjectate.
- the Schwartz device appears to be specifically designed to avoid vascular compression.
- vascular compression resulting from injecting excessive volume of drug into myocardium may precipitate infarction or arrhythmia.
- vascular compression appears to be contraindicated.
- the goal of infusing fluid into a vessel containing a blood clot is to open the vessel, and not compress it.
- the Schwartz device also appears to be incapable of large volume (e.g , multi liter) subcutaneous infiltration.
- the long plastic Schwartz catheter appears to be specifically intended for intravascular use.
- Schwartz cannula cannot have holes distributed along 100% of its entire length based on a contention that such situation will lead to a contradictory situation.
- the Schwartz device does have holes along its entire length then either the entire length of the cannula would have to be positioned inside a vessel (unlikely without ataching the cannula proximal ly to another catheter in winch case the bulky attachment mechanism would have to be passed through the wall of the vessel) or else some of the holes would have an extravascular loeation(unlikely because the therapeutic fluid would either leak onto the patient’s skin or extravasate into the perivascular and subcutaneous tissues). In either case, the potential for serious adverse effects would be significant.
- the Schwartz device does not appear to be capable of being reciprocated in and out of the subcutaneous tissue of the patient to locally anesthetize an entire compartment.
- the Schwartz infiltrator is intended for 1) intravascular insertion which demands a complex guidewire procedure involving several steps,
- Meglin device Another type of device for delivering fluid to a patient is described in U.S. Pat. No. 6,524,300, issued to Meglin. Similar to the Schwartz device, the Meglin device appears to be an intravascular device intended to inject a“medical agent into the target lumen of the body.” (see, Col. 2, ins. 41-48). Meglin is specifically intended to be inserted intraluminally into“a lumen of a blood vessel or another cavity within a patient’s body.” (see Col. 1 , Ins. 14-19). This is precisely opposite the goal of a tumescent infiltration cannula. A tumescent infiltration cannula is intended to deliver drugs to the subcutaneous space which excludes the vascular space and cavitary space.
- the Meglin device appears to be specifically designed to avoid vascular compression and to not induce vasoconstriction.
- An important aspect of the Meglin device appears to be the size and density of the apertures to control the rate of flow of fluidic medication.
- the medical professional utilizing the Meglin device requires a great deal of training, expertise and education based on a contention that the infusion segment of the device is located intravascularly by locating a radiopaque marker band with a fluoroscopy.
- Surgical site infections are a significant source of post-operative morbidity and mortality. They account for 17% of all hospital acquired infections, require prolonged hospital stays and contribute substantially to health care costs. The incidence of surgical site infection is a function of the type of surgical procedure, the surgeon, and the hospital. The risk of surgical site infection is significantly associated with a number of factors including anesthetic risk scores, wound class and duration of surgery.
- Antimicrobial prophylaxis with intravenous (IV) antibiotics is currently the most important clinical modality for preventing surgical site infection.
- the consensus recommendation for antimicrobial prophylaxis is for antimicrobial agents to be given as an IV infusion of antibiotics administered within the first 60 minutes before surgical incision and that prophylactic antimicrobial agents be discontinued within 24 hours of the end of surgery.
- An IV infusion of fluid is a common medical procedure to treat patients.
- an IV infusion is associated with an inherent expense, difficulty and risk.
- an IV line cannot be established in the patient.
- the patient may be burned such that a vein of the patient cannot be located to establish an IV access.
- the patient may have been traumatized in such a way that will not allow a doctor to perform an IV cut down procedure.
- the patient may be very obese such that the vein of the patient is difficult to locate. In other situations, occurring in remote locations where a trained medical professional is not available to establish the IV, such as the international space station or on an airplane.
- Other methods of delivering a drug to a patient other than IV administration may be oral delivery of the drug.
- oral delivery of the drug results in inconsistent absorption of the drug into the gastrointestinal tract.
- the drug may alternatively be delivered via periodic intramuscular injections.
- the fluidic drug serum may have varying levels of concentration at each of the periodic injections.
- Some embodiments relate to a method of subcutaneous deliver ' of a drug or a therapeutic agent to a subject including administering to said subject a tumescent composition that includes:
- infiltration of the tumescent composition achieves both prolonged local drug concentration within a tumescent subcutaneous tissue as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissue into a systemic circulation.
- a pharmacokinetic profile of the systemic absorption resembles a slow, constant, intravenous (IV) infusion.
- the subcutaneous concentration of the drug or therapeutic agent achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional IV, IM or oral delivery' of the drug or therapeutic agent.
- the tumescent composition further includes an anesthetic component.
- the anesthetic component is a local anesthetic.
- local and systemic blood viscosity are reduced in the subject and local and systemic oxygenation of tissues in the subject is increased.
- the local anesthetic is hdocaine.
- the concentration of lidocaine is approximately' 100 mg to 1,500 mg per L of solution.
- the tumescent composition further includes an anti- inflammatory' agent.
- the tumescent composition further includes an antibiotic component
- the antibiotic component includes cefazolin.
- the drug or therapeutic agent is an antiviral agent.
- the antiviral component is acyclovir.
- the vasoconstrictor component includes epinephrine.
- the concentration of epinephrine is approximately 0.2 to 1.5 mg/L
- the subject has a localized viral infection.
- the subject is infected by the varicella-zoster virus.
- the tumescent composition includes an agent that reduces neuropathic pain or the risk of developing neuropathic pain
- the neuropathic pain is selected from the group consisting of postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, diabetic neuropathy, carpal tunnel syndrome, sciatica, degenerative disk disease, spinal cord injury, post-surgical pain and cancer.
- the tumescent composition includes a chemotherapy agent, wherein the method treats a localized cancer.
- the localized cancer is selected from the group consisting of skin cancer, breast cancer, lymphoma, Pancreatic Adenocarcinoma, Insulinoma, lung cancer, colon cancer, prostate cancer, ovarian cancer and a metastatic cancer.
- the skin cancer is selected from the group consisting of Basal Cell Carcinoma, Squamous Cell Carcinoma, melanoma, Merkel Cell Carcinoma and Kaposi’s Sarcoma.
- Some embodiments relate to a method of treating or preventing sepsis or Systemic Inflammatory Response Syndrome (SIRS) in a subject including:
- tumescent composition acts as a reservoir for the drug or therapeutic agent, simultaneously providing a sustained high local interstitial drag concentration and a sustained systemic concentration of the drug or therapeutic agent resembling a slow constant IV infusion in the subject, thereby effectively treating or preventing sepsis or SIRS in the subject.
- a tumescent solution for treating a localized varicella-zoster viral infection (shingles) including:
- an antiviral agent selected from acyclovir, valacyclovir, famciclovir, brivudine, docosanol, idoxuridine, penciclovir or trifluridine, or combinations thereof;
- the antiviral agent is present at a concentration of 0.1 g/L-10 g/L
- the epinephrine is present at a concentration of 0.5 to 1 mg per L
- the local anesthetic is present at a concentration of 500 mg to 1,000 mg per L.
- the local anesthetic is an amide-type or an ester- type local anesthetic.
- the local anesthetic is selected from the group consisting of lidocaine, benzocaine and bupivacaine.
- the local anesthetic is a neurotoxin-type local anesthetic.
- the neurotoxin-type local anesthetic is neosaxitoxin.
- the local anesthetic includes an amide-type local anesthetic and/or an ester-type local anesthetic in combination with a neurotoxin-type local anesthetic
- kits for treating a localized varicella-zoster viral infection including:
- an IV-like bag including a pharmaceutically acceptable carrier selected from the group consisting of a saline solution, a lactated Ringer’s solution, and Hartmann’s solution;
- a sterile solution including a bicarbonate buffer in concentrated form
- an infusion cannula optionally an infusion cannula.
- Some embodiments relate to a tumescent composition
- a tumescent composition comprising a cannabinoid dissolved in a tumescent solution, wherein the tumescent solution consists of:
- the cannabinoid is a variant of cannabidiol (CBD) or tetrah y dr ocannabi nol (THC) .
- the cannabinoid is a variant of THC, wherein the alkyl side chain of thereof is derivatized.
- the cannabinoid is a variant of THC, wherein the phenolic hydroxyl group thereof is derivatized.
- the cannabinoid is an emulsion comprising CBD and/or THC.
- emulsion is a micro- or nano-emulsion.
- the local anesthetic is iidocame.
- the concentration of Iidocame is approximately 100 mg to 1,500 mg per L of solution.
- the vasoconstrictor component comprises epinephrine.
- the concentration of epinephrine is approximately 0.2 to 1.5 mg/L.
- Some embodiments relate to a tumescent composition including a cannabinoid dissolved in at least 500 ml of a tumescent solution, wherein the tumescent solution includes:
- a tumescent concentration of the cannabinoid is 1-2000 pg/kg and is simultaneously: 1) below a threshold for local, subcutaneous tissue toxicity,
- Some embodiments relate to a method of subcutaneous delivery of a cannabmoid to a subject including administering to said subject the tumescent composition as disclosed herein.
- infiltration of the tumescent composition achieves both prolonged local drug concentration within a tumescent subcutaneous tissue as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissue into a systemic circulation.
- a pharmacokinetic profile of the systemic absorption resembles a slow, constant, intravenous (IV) infusion.
- the subcutaneous concentration of the cannabinoid achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional IV, IM or oral delivery of the cannabinoid.
- the local anesthetic is hdocaine.
- the concentration of lidocame is approximately 100 mg to 1,500 mg per L of solution.
- the vasoconstrictor component includes epinephrine.
- the concentration of epinephrine is approximately 0.2 to 1.5 mg/L
- the subject is treated for a condition selected from the group consisting of surgically-induced neuropathic pain, shingles, inflammation, appetite loss, pain, multiple sclerosis, nausea, vomiting, and epilepsy.
- the surgically-induced neuropathic pain results from breast cancer surgery, limb amputation, thoracotomy or hernia repair.
- the breast cancer surgery is mastectomy or lumpectomy.
- the tumescent composition further comprises an antiviral drug.
- the antiviral drug is acyclovir.
- Figure 1 is a side elevation view of a stainless steel infiltration cannula with a closed tip shown inserted in subcutaneous tissue shown in partial cross section;
- Figure 2 is a section view of the infiltration cannula shown in Figure 1 ;
- Figure 3 is a side elevation view of a plastic infiltration cannula with a closed tip shown inserted m subcutaneous tissue shown in partial cross section;
- Figure 4 is an exploded view' of the infiltration cannula shown in Figure 3 with a closed end;
- Figure 5 is a flow diagram illustrating an exemplary procedure for using an infiltration cannula such as the one shown in Figure 1 or the one shown in Figure 3;
- Figure 6 is an exploded side elevation view of a plastic infiltration cannula through which a stylet can be inserted with an open end;
- Figure 7 is a side elevation view of a hollow sharp-tipped stylet with holes located along nearly the entire length of the stylet.
- Figure 8 shows the results of a comparison study of tumescent antibiotic delivery (TAD) versus IV delivery of Cefazolin.
- FIG. 9 Cefazolin log-linear concentration vs time profiles following one IV antimicrobial delivery (IV AD) and two tumescent antimicrobial deliveries (TAD).
- IV AD IV antimicrobial delivery
- TAD tumescent antimicrobial delivery
- the IV AD dose was lOOOmg.
- the TAD doses were both lOOOmg, but the cefazolin concentrations in the TAD solutions were different at 9Q0mg/L and 450mg/L.
- Doubling the cefazolin mg, A concentration in the tumescent solution, at a constant mg dose doubles the Cmax in TISF and increases the subsequent cefazolin concentrations in serum at every time point.
- FIG. 10 Cefazolin log-linear concentration vs time profiles following one IV antimicrobial delivery (IV AD) and two tumescent antimicrobial deliveries (TAD).
- IV AD IV antimicrobial delivery
- TAD tumescent antimicrobial delivery
- the IV AD dose was l OOOmg. Both TAD doses were 500mg, but cefazolin concentrations in the TAD solutions were different at 450mg/L and 225mg/L.
- the TAD solution contained equal 500mg doses and equal 413mg/L concentrations of metronidazole and cefazolin.
- C Log-linear concentration-time profiles of cefazolin and metronidazole. When equal 500mg doses of cefazolin (open circles) and metronidazole (open diamonds) were given by IV antimicrobial delivery, the concentration-time profiles in serum were significantly different. In contrast when equal doses and concentrations of cefazolin (closed squares) and metronidazole (closed triangles) were given by tumescent antimicrobial deliver ⁇ ', the concentration-time profiles in tumescent interstitial fluid were identical.
- FIG. 13 (A) Antibiotic log-linear concentration-time profiles of cefazolin comparing tumescent antimicrobial delivery (TAD) alone with IV antimicrobial delivery (IVAD) alone and with concomitant TAD+IVAD. When 1200mg of cefazolm was simultaneously delivered by TAD (800mg) and by IV AD (400mg), the Cmax for cefazolin in subcutaneous TISF was 9.2 times higher than in serum following 1200mg of cefazolin delivered by IV AD alone.
- concentration of antibiotic in the TAD solution is approximately equal to the antibiotic concentration within the subcutaneous tissue following tumescent infiltration.
- TI comprises a novel mode of drug delivery having a unique multi-compartment pharmacokinetic performance and presenting unique therapeutic opportunities. From a pharmacokinetic perspective, TI is functionally distinct from IV (intravenous), IM (intramuscular), PO (per os, oral), topical (percutaneous) and simple subcutaneous injection.
- ISF subcutaneous interstitial fluid
- TISF tumescent interstitial fluid
- TI drug delivery is the direct subcutaneous infiltration of drug(s) dissolved in a large volume of a physiologic crystalloid solution such as 0.9% physiologic saline or lactated Ringer’s solution.
- a TI solution may contain a dilute vasoconstrictor (e.g., epinephrine) for delayed systemic absorption or a dilute capillary vasodilator (e.g., lidocaine or niacin) for rapid systemic absorption (see, U.S. Patent No. 7,572,613).
- TI drug delivery provides unique subcutaneous and systemic concentration- time profile (bioavailability) of a wide range of drugs (antibiotic, antiviral, antifungal, anticancer, analgesic, local anesthetic, biologic, etc.) following subcutaneous tumescent infiltration ( ⁇ ) drug delivery. Specifically TI simultaneously produces:
- TI comprises a combination of a unique delivery vehicle with unique properties and a drug delivery method.
- TI drug delivery consists of a drug (D) dissolved in a dilute tumescent solution that typically consist of iidoeaine ( ⁇ Igm/L), epinephrine ( ⁇ lmg/L), sodium bicarbonate lOmEq/L in 0.9% physiologic saline.
- D drug
- ⁇ Igm/L iidoeaine
- ⁇ lmg/L epinephrine
- sodium bicarbonate lOmEq/L 0.9% physiologic saline.
- Alternative embodiments of TLA can involve higher or much lower concentrations of these components and/or alternative local anesthetics.
- TI drug delivery' permits safe and effective local (subcutaneous or deep tissue) infiltration of a large dose of a drug m a large volume of a dilute solution, which otherwise could not be injected because of dose-related systemic toxicity (typically manifested as pain, inflammation or necrosis.
- TI drug delivery consists of a large volume of dilute tumescent drugs injected subcutaneously.
- a small volume of dilute tumescent anti-tumor drugs is injected directly over a certain time interval, often prolonged, into a deep parenchymal tissue to target a malignant neoplasm.
- Examples of specific embodiments of ⁇ drug delivery include:
- tumescent antifungal deliver ⁇ ' for local treatment of cutaneous superficial or deep fungal infections with a relatively high local drug concentrations while significantly reducing the peak serum concentration associated with nephrotoxic, hepatotoxic and ototoxic drags
- tumescent anti-neoplastic delivery for treating cutaneous and subcutaneous malignancies or metastases, for example“in-vivo gene transfer” or biologic drug delivery targeting pancreatic adenocarcinoma,
- tumescent delivery of a biologic drug consisting of a large molecule snake antivenin for targeting the toxic venom proteins as they are absorbed via lymphatic vessels.
- Tumescent Infiltration Drug Delivery has a unique ability to achieve both a relatively high prolonged local drug concentration within the tumescent subcutaneous tissues as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissues into the systemic circulation, where the pharmacokinetic profile of the systemic absorption resembles a slow constant IV infusion.
- This unique feature of tumescent infiltration ( ⁇ ) cannot be matched by any other mode of drug delivery.
- TI is a novel mode of concomitant prolonged local and prolonged systemic drug delivery with unanticipated therapeutic benefits.
- TTAR The definition of TTAR: The tumescent therapeutic ambit range
- TTAE tumescent concentration of D
- the subcutaneous concentration of the drug, or therapeutic agent, achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug or therapeutic agent.
- the subcutaneous concentration of the drug or therapeutic agent achieved is from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug or therapeutic agent.
- Some drugs may not have a tumescent therapeutic ambit range.
- a sufficiently safe dilution may be too dilute to have a positive therapeutic effect; or the subcutaneous bioavailability of the drug by TI is equal to that of either IV, IM or PO delivery.
- Some drugs are inherently painful upon injection. Dilute Tumescent infiltration of a drug is less painful because dilute drug is less painful than more concentrated drug solutions and because dilute hdocaine in the solution eliminates the pain caused by subcutaneous delivery.
- tumescent lidocame In certain clinical situations tumescent lidocame (high prolonged wide spread local subcutaneous concentrations) provides important unanticipated therapeutic benefits that are not available with IV, IM or oral delivery. For example, tumescent lidocame (at concentrations that are significantly higher than can be safely achieved by IV, IM or PO delivery) has antibacterial, antithrombotic and anti-inflammatory properties. These are a unanticipated unique features of TI drug deliver ⁇ ' that IV, IM, and PO delivery do not provide.
- a lidocame component of ⁇ drug delivery can provide pain relief for pain associated with a disease being treated by TI.
- TLA can relieve the acute pain associated with Herpes zoster. This is a unique feature of TI drug delivery that IV, IM, and PO delivery do not provide.
- the subcutaneous bioavailability of D is often significantly greater by TI compared to IV, IM or oral delivery.
- TI drug deliver ⁇ An important pharmacokinetic advantages of TI drug deliver ⁇ is a prolonged local drug effect (e.g., prolonged T>MIC) in relatively avascular subcutaneous fat and concomitant prolonged systemic concentrations with relatively small Cmax in serum.
- the small serum Cmax is particularly advantageous with tumescent infiltration antibiotic deliver to prevent or treat a localized skin infection while simultaneously minimizing the peak antibiotic concentration within the gut and thus reducing the risk of antibiotic-associated C. difficile diarrhea.
- TI drug delivery can be performed by any primary care provider
- TI pharmacokinetic profiles include TI (antibiotic & lidocaine) delivery ? and TI (acyclovir & lidocaine) delivery:
- TI antibiotic & lidocaine drug deliver ⁇ prevents and treats systemic inflammatory response syndrome (SIRS) and bacterial sepsis.
- SIRS systemic inflammatory response syndrome
- bacterial sepsis a systemic inflammatory response syndrome
- local TI antibiotic & lidocaine delivery prevents SIRS by engulfing and isolating damaged (traumatized or infected) subcutaneous tissue within a persistent mass of vasoconstricted tumescent fluid.
- Systemic TI antibiotic & lidocaine delivery treats SIRS by significantly down regulating systemic inflammatory mediators.
- ⁇ lidocaine deliver ⁇ ' prevents platelet activation both locally and systemically and thereby and attenuates platelet-mediated inflammatory response. It is known that TI lidocame prevents thromboembolism (U.S. Patent No. 8,957,060 B2, Tumescent antibiotic solution).
- TI delivery achieves subcutaneous acyclovir concentrations that far exceed concentrations achievable by IV delivery; the result is decreased varicella zoster virus (VZV) replication, decreased extent, severity of VZV dermatitis, shortened duration of VZV dermatitis, decreased inflammatory' damage to nerves and decreased risk of chronic post-herpetic neuralgia.
- VZV varicella zoster virus
- systemic absorption of acyclovir following subcutaneous TI acyclovir delivery produces sustained therapeutic serum acyclovir concentrations and thereby reduces VZV viremia.
- TI allows direct subcutaneous infiltration of drugs which otherwise cannot be injected subcutaneously because of pain or tissue toxicity. Indeed, there are a number of drugs that are never injected subcutaneously because the Food and Drug Administration (FDA) approved package insert labeling states explicitly that the drug should NOT be injected subcutaneously.
- FDA Food and Drug Administration
- Acyclovir is a specific example of a drug for which the FDA countermands subcutaneous injection.
- the FDA-approved package insert labeling for IV acyclovir states, “Acyclovir Injection is intended for intravenous infusion only, and should not be administered topically, intramuscular ly, orally, subcutaneously, or in the eye.” Nevertheless, we have found that, in clinical practice, TI delivery of acyclovir is safe and effective.
- phenytoin calcium gluconate, potassium chloride, calcium chloride, dopamine, dextrose solutions, epinephrine, sodium bicarbonate, nafcillm, propofol, norepinephrine, arginine, promethazine, vancomycin, tetracycline, dobutamine, vasopressin, acyclovir, amphotericin, ampieiilin, cloxacillm, gentamicin, metronidazole, oxacillin, penicillin, amiodarone, albumin, furosemide, lorazepam, immunoglobulin, morphine, and sodium valproate. Careful formulation of dilute TI solutions of these drugs may allow safe and effective subcutaneous tumescent infiltration.
- Pharmacologic properties that contribute to cutaneous and subcutaneous tissue toxicity include pH, osmolality, diluent, vasoactive properties, and inactive ingredients. With appropriate formulation of the subcutaneous TI solution these drugs can be injected (delivered) subcutaneously in a manner that is safe, comfortable and uniquely effective.
- TI local and simultaneous systemic delivery
- TI provides therapeutic subcutaneous concentrations that are not achievable by any other mode of delivery and TI simultaneously provides therapeutic serum concentrations with a pharmacokinetic concentration-time profile resembling a slow continuous IV infusion. No previously described mode of drug delivery can achieve these results.
- the standard tumescent solution consisting of lgm of lidocaine, Img of epinephrine and lOmEq of sodium bicarbonate m a liter of 0.9% physiologic saline is the functional equivalent to a drug delivery vehicle.
- the epinephrine component of the tumescent solution determines the degree of local subcutaneous vasoconstriction. Reducing the epinephrine concentration in the tumescent solution attenuates pharmacologic capillary vasoconstriction. Infiltration of a tumescent solution with no epinephrine and a trace of lidocaine produce capillary vasodilation.
- the tumescent (augmented) interstitial pressure also accelerates trans-capillary fluid absorption into the systemic circulation and similarly accelerates systemic drug delivery.
- the lidocaine component of a tumescent solution has local anesthetic, local antibacterial and systemic anti-inflammatory effects. Locally, dilute lidocaine eliminates the pain associated with the subcutaneous injection of other drugs and provides rapid onset of prolonged widespread surgical local anesthesia.
- the continuous sy stemic absorption of 28mg/kg of tumescent lidocaine conveniently provides safe predictable therapeutic serum lidocaine concentrations (I pg/ml to 2pg/ml) for 12 hours or more.
- Epidural lidocaine may reduce bacterial growth at a surgical site (Igarashi T, Suzuki T, Mori K, Inoue K, Seki TI, Yamada T, Kosugi S, Minamishima S, Katori N, Sano F, Abe T, Morisaki H.
- Subcutaneous tumescent lidocaine at concentrations far exceeding the therapeutic serum concentrations of lidocaine following IV delivery, is anti-bacterial and provides pre-emptive, inter-operative and post-operative analgesia.
- Lidocaine local anesthesia reduces post-operati ve narcotic use with earlier return of normal bowl function and earlier postoperative ambulation (Sakuragi T, Ishino H, Dan K. Bactericidal activity of clinically used local anesthetics on Staphylococcus aureus. Reg Anesth. 21 : 239-42, 1996; Pan- AM, Zoutman DE, Davidson JS. Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection. Ann Plast Surg.
- lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol-remifentanil- based anaesthesia. Eur J Anaesthesiol. 2010; 27: 41-46).
- Lidocaine down regulates many inflammatory mediators and has significant pharmacologic anti-inflammatory properties (Hatakeyama N, Matsuda N. Alert cell strategy: mechanisms of inflammatory response and organ protection. Curr Pharm Des 2014; 20:5766-78; Berger C, Rossaint J, Van Aken H, Westphal M, Hahnenkamp K, Zarbock A. Lidocaine reduces neutrophil recruitment by abolishing chemokine-induced arrest and iransendothelial migration in septic patients. J Immunol.
- lidocaine Influence of lidocaine on endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo. Anesthesiology.1997; 87: 617-24).
- a tumescent solution of lidocaine and antibiotics engulfs large volumes of damaged tissue and prevents the spread of locally generated inflammatory cytokines, chemokines, histones and pathogens and blunts systemic inflammatory responses.
- Tumescent lidoeaine inhibits platelet function, limits platelet leukocyte aggregation, limits activated-platelet induced inflammation and may reduce the risk of thromboembolism.
- Tumescent lidoeaine decreases blood viscosity, resulting m increased oxygenation of local and systemic tissues.
- TI antimicrobial delivery is the direct subcutaneous infiltration of antimicrobial drug(s) dissolved in a large volume of a tumescent lidocaine anesthesia (TLA) solution.
- TLA tumescent lidocaine anesthesia
- the standard TLA solution consists lidocaine (lgm) and epinephrine (Img) and sodium bicarbonate (10 mEq) in a 1000ml bag of physiologic saline.
- a TLA solution consists of at least a 10-fold dilution of commercial 1% lidocaine with epinephrine 1 : 100,000 plus sodium bicarbonate (ImEq/ml) in a liter of normal saline.
- Wide spread subcutaneous vasoconstriction resulting from a large volume of dilute tumescent epinephrine produces prolonged local anesthesia and reduced surgical blood loss (Klein JA.
- Cefazolin and metronidazole were selected because they are water soluble, safe, well tolerated in subcutaneous tissue, effective and economical for prevention of SSIs (Meyer NL, Hosier KV, Scott K, Lipscomb GH. Cefazolin versus cefazolin plus metronidazole for antibiotic prophylaxis at cesarean section. South Med J. 2003; 96: 992-5; Morris WT, limes DB, Richardson RA, Lee AJ, Ellis-Pegler RB. The prevention of post- appendicectomy sepsis by metronidazole and cefazolin: a controlled double blind trial.
- Subcutaneous antibiotic delivery for systemic effect is commonly used for palliative therapy (Azevedo EF, Barbosa LA, DeBortoli Cassiani SH. Administration of antibiotics subcutaneously: an integrative literature review. Acta Paul Enfertn. 2012; 25: 817-22; Robelet A, Caruba T, Corvol A, Begue D, Gisselbrecht M, Saint- Jean (), Prognon P, Sabatier B. Antibiotics par intuitive sous-cutanee incurla vulgar agee Presse Med. 2009; 38: 366-76; Frasca D, Marchand S, Petitpas F, Dahyot-Fizelier C, Couet W, Mimoz O.
- Tumescent Infiltration ( ⁇ ) drug delivery is the slow rate of systemic absorption of antibiotic following TI produces a serum antibiotic concentrations-time profile resembling a slow constant IV infusion.
- the serum concentrations (at each time point after TI infiltration) increased with increasing total mg dose of antibiotic in the tumescent solution.
- the serum concentrations (at each time point after TI infiltration) increased with increasing mg/L concentration of antibiotic in the tumescent solution.
- Tumescent infiltration can safely provide prolonged relatively high drug concentration in subcutaneous TISF.
- achieving similar subcutaneous drug concentrations solely by IV infusion may be impossible or pose a significant risk of systemic toxicity and harm to the patient.
- the aminoglycoside antibiotics gentamicin and amikacin are associated with dose and concentration related potential ototoxicity' and nephrotoxicity.
- Achieving prolonged high subcutaneous concentrations by means of IV delivery' requires high-prolonged IV dosages with the inherent risk to hearing (inner ear) and kidney damage.
- TI of antibiotics for prevention of surgical site infection is optimally delivered with the use of either HK Monty stainless steel re-usable cannulas or HK SubQKath disposable catheters (U.S. Patent Nos. 7,572,613; 7,914,504; 8,105,310; 8,167,866; 8,246,587; 8,512,292; 8,529,541) and tumescent peristaltic infiltration pump and tubing.
- the present embodiments take advantage of the tumescent technique in order to provide intermittent or continuous, brief or prolonged multi-liter infiltration of local anesthetic, physiologic fluid, antibiotics or other therapeutic solution with a significant decrease in patient discomfort due to the elimination of the piston-like in and out motion of the cannula.
- Once the cannula is positioned in place there is no need to repeatedly move the cannula in and out through the tissue in order to deliver the fluid to a wide area.
- the time needed in order to complete the infiltration of a targeted anatomic area is reduced to nearly half of the time required when using traditional cannula.
- the device and method of the present embodiments can use multiple (e.g., two or more) infiltration cannula simultaneously. While one cannula is actively dispersing tumescent fluid into the subcutaneous tissue, the surgeon can reposition a second infiltration cannula. This allows the infiltration process to proceed without interruption, whereas prior art techniques of infiltration must be ceased each time the cannula is withdrawn from the skin and re-inserted into another direction.
- the flexible plastic cannula version of the present embodiments provides a means for relatively rapid fluid resuscitation in emergency situations such as when establishing an intravenous (IV) access is not feasible.
- a large volume of a tumescent crystalloid solution to treat intravascular fluid deficit may be delivered subcutaneously when an intravascular (IV) line cannot be started for fluid replacement (e.g., remote area, obese patient, burn/trauma victim, unavailable trained medical professional, etc.).
- rapid systemic absorption of physiologic saline can be achieved by adding a vasodilator drug to saline and using the tumescent technique to deliver the solution into subcutaneous tissue.
- the flexible cannula may also have important applications in treating a wounded soldier in night-time combat conditions when establishing an IV access in total darkness is nearly impossible or using a flashlight might attract enemy fire.
- the flexible cannula may similarly have important applications in other areas of use such as treating mass- casualty victims suffering hypovolemia as a result of epidemic infections, biologic warfare, or trauma such as explosions, burns or radiation exposure.
- the flexible cannula similarly has applications in surgical patients wherein the surgeon can provide localized pre-operative preemptive analgesia and simultaneously provide tumescent delivery of a prophylactic dose of an antibiotic aimed precisely at tissues targeted for surgical intervention.
- the tumescent technique was discovered by Jeffrey Alan Klein, M.D. (the present applicant) in 1985. Dr. Klein first published a description of the tumescent technique in 1987 when he described the use of dilute lidocaine and epinephrine to permit liposuction totally by local anesthesia. The technique for tumescent local anesthesia is well known in dermatologic and plastic surgery literature. A detailed description of the tumescent technique has not been published in anesthesiology literature, and therefore, the unique benefits of the tumescent technique are not recognized by anesthesiologists.
- the tumescent technique comprises a drug deliver system that takes advantage of a recently discovered reservoir effect of injecting a relatively large volume of relatively dilute solution of a drug into the subcutaneous tissue.
- the drug is isolated from the systemic circulation because only the drug on the outer boundary of the mass of drug is the available for absorption, whereas the portion of the drug located within the central portion of the mass of fluid is virtually isolated from the systemic circulation by virtue of profound capillary vasoconstriction.
- the tumescent fluid does not contain epinephrine there is no clinically significant vasoconstriction after tumescent infiltration, and the tumescent fluid is absorbed relatively rapidly. This has important clinical applications in situations where patients are hypovolemic or dehydrated and unable to be given fluids by mouth or intravenously.
- the tumescent technique permits rapid systemic hydration by direct subcutaneous or intramuscular injection of a large volume of fluid through a multi- fenestrated infiltration cannula described in this invention.
- hypodermoclysis involves the slow and continuous infiltration of fluid subcutaneously using a type of steel hypodermic needle, known as a butterfly needle, having a single distal aperture in order to provide fluid to patients who cannot be given fluids by mouth and for whom an IV access cannot be established, such as in the treatment of infants, or cancer patients.
- the technique of hypodermoclysis is typically used to deliver relatively small volumes of fluid, for example an adult might receive 70 ml per hour. At this small hourly volume hypodermoclysis is not an efficient method for the rapid systemic delivery of fluid in emergency situations that might require two to four liters per hour.
- the reason is that when using a cannula with only a single distal aperture, the local interstitial fluid pressure increases rapidly immediately adjacent to the single aperture as fluid infiltrates locally, which in turn dramatically slows the rate of subsequent fluid flow into the area.
- the multiple apertures formed along the length of the cannula as described in the present invention distribute the fluid throughout a much larger volume tissue before there can be a sufficient increase in the interstitial fluid to decrease the rate of additional infiltration. Also, the amount of pain is reduced because the rate of fluid flow through each of the apertures is less than the rate of fluid flow through the single aperture at the distal end.
- a preferred suitable peristaltic infiltration pump is described in pending United States Patent Application Number 10/811,733, filed March 29, 2004, entitled INFILTRATION PUMP HAVING INSULATED ROLLERS AND PROGRAMMABLE FOOT PEDAL, the disclosure of which is expressly incorporated herein by reference.
- the peristaltic pump provides a sufficient degree of pressure to easily overcome the localized increased interstitial pressure associated with the local effects of a tumescent infiltration.
- the present invention still permits relatively rapid tumescent infiltration by virtue of the multiple holes distributed along the length of the flexible cannula.
- external hydrostatic pressure can be applied to the fluid flowing into the flexible cannula from the fluid reservoir by means of gravitational force derived from elevating the reservoir one to two or more meters above the patient.
- the infiltration process can be continuous or intermittent in exemplary embodiments, the intermitent injections are administered at intervals ranging from every few minutes to eight to twelve hours or more.
- Figures 1 and 2 illustrate a stainless steel (reusable) infiltration cannula 10 and Figures 3-4 and 6 illustrate a (single use) plastic infiltration cannula 30.
- the cannula 10, 30 can be inserted under the skin 52 and into the subcutaneous tissue 50 and tumescent local anesthesia can be infiltrated either continuously until the clinical goal is achieved or intermittently (by way of example and not limitation, once every eight to twelve hours).
- Stainless steel infiltration cannula 10 such as the one shown in Figures 1 and 2, are formed having precision high quality and are preferably reusable. These cannula can be used to provide tumescent local anesthesia for surgical procedures, such as liposuction, which require tumescent local anesthesia over a relatively large area
- the cannula 10 includes a tubular needle portion 12 which has a proximal end 14 and a distal end 16.
- the proximal end 14 of the tubular needle 12 is attached to a hub 20 that is used by the anesthesiologist or surgeon to grasp and hold the cannula 10 during the infiltration procedure.
- the hub 20 is connected to the tubular needle 12 at a first end 22 and has a connector 24, such as a luer lock, at an opposing second end.
- the connector 24 is connected to a fluid source, such as tubing connected to an IV bag. Fluid enters the cannula 10 via the connector 24.
- the tip at the distal end 16 is closed.
- the local anesthetic is infiltrated into the patient via apertures 18 located proximate the distal end 16 of the tubular needle 12 of the cannula 10.
- the apertures 18, 38 and 54 discussed herein may have a helical, spiral, linear or any random or ordered pattern.
- the apertures 18 are disposed along the distal end 16 of the cannula 10 in a spiral or helical pattern and are distributed over the distal 33% to 100% of the tubular needle 12 of the cannula 10.
- the pattern of apertures of the cannula 10 are preferably distributed over 33% of the tubular needle 12 of the cannula 10.
- the size of the aperture and density of apertures on the tubular needle is limited by the structural integrity of the cannula. If the apertures 18 are too large or too close together then the cannula may bend or break during use (e.g., routine clinical applications).
- Prior art cannula wherein the apertures are limited to the distal 25% of the cannula eject the fluid into the subcutaneous tissue at a high rate so as to cause discomfort to the patient.
- the apertures 1 8 which are located along a greater length of the cannula compared to prior art cannula allows fluid fo flow out of each of the apertures at a slower rate but to achieve a greater amount of fluid flow as an aggregate so as to reduce the amount of discomfort to the patient due to the rate at which fluid flows out of each of the apertures.
- tumescent fluid When tumescent fluid is injected into subcutaneous tissue, tumescent fluid spreads by means of simple bulk-flow through the interstitial gel substance. This process is extremely rapid and unimpeded by fibrous tissue.
- the proximal portion 14 of the cannula 10 may be devoid of apertures in order to prevent fluid from leaking out of the cannula insertion site in the skin.
- the hub may be used to prevent fluid from leaking out of the cannula insertion site in the skin in the follower manner.
- the hub of the infiltration cannula serves as a connector. The distal end of the hub ataches to the cannula, while the proximal end of the huh detachably connects to the plastic tube set which carries tumescent solution to the cannula.
- the hub can also assist in reducing or virtually eliminating leakage of tumescent fluid out through the skin incision or adit site.
- An adit is a small round hole in the skin typically produced by a biopsy punch.
- the hub 20 may have a conical configuration.
- the hub 20 may become narrower from the proximal end of the hub to the distal end of the hub.
- the rate at which the hub 20 becomes narrow may be less than about fifteen degrees with respect to a centerline of the hub.
- the outer surface of the hub 20 may have a plurality of rounded circular ridges equally spaced apart.
- the adit may be formed so as to have a diameter which is less than a diameter of the cannula or the outer surface of the hub.
- the cannula may initially be inserted into the adit.
- the adit is slightly stretched to accommodate the cannula.
- the cannula may be fully inserted into the subcutaneous tissue of the patient such that the distal end of the hub contacts the adit.
- the hub may then be pushed into the adit such that the inner diameter of the adit expands and slides over the rounded circular ridges formed on the distal end of the hub.
- the hub is gently wedged into the adit until there is a snug fit between the infiltration cannula and the adit.
- Leakage of fluid out of the adit may also be minimized by placing the proximal most aperture on the cannula sufficiently deep within the subcutaneous tissue such that fluid injected from the most proximal hole produces localized interstitial tumescence and a snug fit of the tissue against the cannula. It is also contemplated that the hub has other shapes such as curved, linear, parabolic, or combinations thereof.
- Flexible plastic infiltration cannula 30, such as the one shown in Figures 3, 4 and 6 are single use cannula and can be used in one of several unique ways. First, an anesthesiologist, surgeon, untrained first responder, or even a victim can insert infiltration cannula 30 with stylet 46 into the subcutaneous tissue 50, remove the stylet 46, then attach IV tubing to the infiltrator and inject tumescent local anesthesia or other tumescent fluid into the targeted area without subsequent repositioning of the infiltration cannula 30.
- the plastic flexible nature of the tubular needle 32 of the disposable plastic cannula 30 allows the patient to move or change position of the body without risk of injury that might result if a patient moves while a rigid steel cannula is inserted.
- the stylet 46 is formed of a rigid material such as metal, stainless steel, or plastic material.
- the stylet 46 should be sufficiently rigid so as to guide the tubular needle 32 of the cannula 30 into the subcutaneous tissue 50.
- the stylet 46 may be solid (see Figure 4) or hollow (see Figure 7) through its center.
- the stylet may either be straight or curved.
- the plastic cannula 30 can be blunt-tipped with the metal stylet tip 48 covered by the rounded tip 39 of the plastic cannula 30, as shown in Figure 4.
- the plastic cannula 30 can be open-ended with the stylet 46 extending a short distance past the end 39 of the plastic cannula 30 as shown in Figure 6.
- the stylet 46 can be either blunt-tipped (see Figure 6; requiring a skin incision to permit insertion into the subcutaneous space), or sharp-tipped (see Figure 7; permitting the cannula to be inserted directly through the skin and into the subcutaneous space or muscle without requiring a preparatory' skin incision).
- the sharp-tipped stylet 46 can be formed in either a solid (see Figure 4) or hollow (see Figure 7) cross-sectional configuration.
- a sharp tipped hollow stylet is that it can be inserted directly through the skin and then advanced painlessly through the subcutaneous tissue by slowly injecting local anesthetic solution through the stylet as it is slowly advanced, thereby anesthetizing the tissue in advance of the stylet ’ s tip.
- apertures 54 may be formed along an entire length or along a portion (e.g., about 33% to 100%) of the length of the tubular needle 56 of the stylet 46, as shown in Figure 7.
- the hollow' stylet 46 may be utilized in a similar fashion as the cannula 10 shown in Figures 1 and 2 and described herein.
- the tubular needle 56 shown in Figure 7 may be inserted into the cannula 30.
- the combined tubular needle 56 and cannula 30 may be inserted through the subcutaneous tissue 50 of the patient.
- the tubular needle 56 may be removed from the patient and the cannula 30.
- the tubular needle 56 of the stylet 46 may now be reinserted into the patient at a different site and used as a rigid cannula similar to the cannula 10 discussed in relation to Figures 1 and 2.
- the stylet 46 shown in Figure 7 has apertures 54 about the periphery of tubular needle 56 of the stylet 46.
- the apertures 54 may have a pattern which is dissimilar to the pattern of apertures 38 formed m the tubular needle 32 of the cannula 30.
- the apertures 54 may have a pattern which is identical to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
- some of the apertures 54 may have a pattern which is identical to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
- some of the apertures 54 may have a pattern which is dissimilar to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
- the medical professional may insert the stylet 46 (see Figure 7) with apertures 54 into the cannula 30.
- the apertures 54 of the stylet 46 may be aligned or misaligned to the apertures 38 of the tubular needle by turning the stylet 46 within the cannula 30.
- the stylet 46 may have a hub with a similar configuration as hub 40.
- the hub of the stylet 46 may also be wedged into the adit of the patient to minimize or eliminate leakage of fluid, as discussed herein.
- the plastic cannula shown in Figures 3 and 4 is similar to an IV catheter except the sharp hollow stylet used for the insertion of an IV catheter can be replaced by a solid obturator/stylet 46 that can be either sharp or blunt tipped. Except for the removable stylet 46, the plastic cannula 30 is similar to the stainless steel cannula 10 shown in Figures 1 and 2 and described above.
- the plastic cannula 30 includes a flexible tubular needle 32 having a proximal end 34 and a distal end 36. The distal end has apertures 38 and the proximal end 34 may be devoid of apertures.
- the pattern of apertures 38 m the cannula 30 are distributed over the distal 33% to 100% (see Figure 4) of the tubular needle 32 of the cannula 30.
- the tubular needle 32 of cannula 30 shown in Figures 3 and 4 has a length D of 15 cm and the pattern of apertures are distributed over a length dl of 13.5 cm, then the apertures 38 are distributed over 90% of the cannula.
- the tubular needle 32 of cannula 30 shown in Figures 3 and 4 has a length D of 15 cm and the pattern of apertures are distributed over a length dl of 15 cm, then the apertures 38 are distributed over 100% of the cannula.
- the hub may be wedged into the adit site, as discussed above.
- a typical infiltration cannula 10, 30 may have a diameter equivalent to 20, 18, 16 or 14 gauge with small apertures 18, 38 placed every 5 mm along the cannula in a spiral or helical pattern.
- the infiltration cannula 10, 30 may be 20-14 cm in length.
- a typical infiltration cannula 10, 30 is 15 cm or 20 cm in length. It will be appreciated that the dimensions used herein are exemplary' and that the cannula dimensions, range of gauge, length range of cannula, relative size shape and pattern of apertures can vary greatly depending upon clinical preference.
- the proximal end 34 of the tubular needle 32 shown in Figures 3 and 4 is attached to a hub 40 that is used by the anesthesiologist or surgeon to hold the cannula 30 during the infiltration procedure.
- the hub 40 is connected to the tubular needle 32 at a first end 42 and has a connector 44 at an opposing second end.
- the connector 44 is connected to a fluid source.
- the stylet 46 can be inserted and removed from the cannula 30.
- infiltration using a plastic infiltration cannula 30, such as the one shown in Figures 3 and 4 can be accomplished using an infiltration pump.
- the force of gravity could be used to push the tumescent fluid into the tissues by hanging a reservoir plastic bag of tumescent local anesthesia (or other dilute drug, such as a chemotherapeutic agent or antibiotics) on an IV pole and connecting bag to the infiltration cannula by an IV line.
- Tumescent local anesthesia may be provided to a localized area through which a surgeon plans to make a surgical incision. Tumescent local anesthesia involves the administration of dilute anesthetic solutions into the subcutaneous fat compartment.
- a tumescent solution used m a liposuction procedure comprises a combination of 500-1 OOOmg of the anesthetic lidocaine per liter of solvent (typically normal saline or lactated Ringer’s solution) along with a vasoconstrictor such as epinephrine to control the rate of lidocaine absorption and reduce bleeding.
- Bicarbonate may be included to reduce patient discomfort from an otherwise acidic solution.
- Anti-inflammatory agents may also be included.
- tumescent local anesthesia converted liposuction from a hospital- based procedure requiring general anesthesia and often blood transfusions to an office-based procedure.
- the tumescent technique has subsequently been adapted for use in a variety of other surgical procedures including hair transplantation, phlebectomy, mastectomy, sentinel node biopsy, and others.
- a tumescent epinephrine induces profound local vasoconstriction resulting m significantly delayed systemic absorption of a tumescent antimicrobial drug from subcutaneous tissue.
- the systemic absorption of an aqueous solution of lidocaine requires approximately 2 to 4 hours.
- the systemic absorption of tumescent lidocaine requires 24 hours or more.
- a tumescent antibiotic can be expected to remain within the peri-incisional tissue at least 12 times longer than a routine aqueous antibiotic solution and the action would be far more effective.
- a tiny hematoma within an incision may be an isolated avascular space and a potential nidus for an infection.
- hypothermia is a major risk factor for postoperative surgical site infection. Mild perioperative hypothermia is common among patients having surgery under general anesthesia. The incidence of SSI w3 ⁇ 4s 5.8% in the normothemnc (core body temperature 37 degrees C) group and 18.8% in the hypothermic group (34.4 degrees C) in a randomized, double blind trial. (Kurtz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infections and shorten hospitalization. Study of wound infection and temperature group. N Eng J Med 334: 1209-15, 1996). Hypothermia also causes delays in moving the patient out of the recovery room. With surgery totally by tumescent local anesthesia there is no evidence of post-operative hypothermia.
- Some embodiments relate to infiltration of a tumescent solution comprising an anesthetic component, a vasoconstrictive component, and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising a vasoconstrictive component and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising an anesthetic component and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising an anesthetic component and a vasoconstrictive component. Some embodiments relate to infiltration of a tumescent solution comprising an anesthetic component. Some embodiments relate to infiltration of a tumescent solution comprising a vasoconstrictive component. Some embodiments relate to infiltration of a tumescent solution comprising an antibiotic component. Some embodiments relate to infiltration of a tumescent solution comprising crystalloid fluids/electrolytes.
- infiltration of a tumescent solution comprising iidocaine, epinephrine, and an antibiotic improves surgical site infection prophylaxis.
- Tumescent infiltration of antibiotics into peri-incisional skin and subcutaneous tissue offers the following advantages: prolonged local tissue concentrations of antibiotics and prolonged systemic delivery of antibiotic to tissues distant from the incision site.
- the systemic absorption of tumescent Iidocaine mimics IV delivery of iidocaine which is known to reduce postoperative pain and hasten postoperative discharge from the hospital.
- Embodiments of the infiltration cannula discussed herein may be used for tumescent delivery of antimicrobial drugs.
- tumescent technique to provide an easily accessible route for systemic administration of crystalloid fluids/electrolytes for systemic hydration or for other types of drug therapy.
- Potential clinical applications include emergency resuscitation with systemic fluids in situations where insertion of an IV catheter into a vein cannot he readily achieved. Examples of situations where emergency access for intravenous delivery' of fluids might not be possible include acute trauma or burn 'ound in civilian or military situations and very obese patients in which finding an accessible vein for IV access can be difficult even for a physician skilled in performing“IV cut-down” procedures.
- Embodiments of the infiltration cannula discussed herein may be a valuable adjunct to fluid resuscitation in an ambulance or an emergency room.
- Another application may be the emergency treatment of dehydration associated with pandemic influenza, prolonged vomiting or diarrhea as a result of chemical warfare or biological warfare (e.g., epidemic cholera among pediatric patients in rural third world settings) or other types of medical emergencies which overwhelm a medical center’s capacity to care for incoming victims.
- a subcutaneous infiltration catheter can easily be introduced by a layman, whereas inserting an IV catheter into a vein of a patient that is severely dehydrated can be difficult even for a skilled physician. Delivery of systemic fluids by subcutaneous infiltration is safer than an IV infusion in a zero gravity' ⁇ situation (for example, the Space Station).
- capillar vasodilator e.g., methylnicotinamide
- methylnicotinamide e.g., methylnicotinamide
- the continuous systemic drug delivery by tumescence has a similar therapeutic effect to continuous IV infusion but without the inherent expense, difficulties, and risk of an IV infusion.
- continuous systemic delivery is preferred in order to achieve prolonged and relatively uniform blood concentrations of the drug. This is especially true in critically ill patients.
- Tumescent delivery of a drug, placed in a tumescent solution containing epinephrine as a vasoconstrictor produces prolonged continuous system absorption of the drug over an interval of more than 24 hours.
- the simplicity and inexpensive equipment required to achieve continuous tumescent systemic drug delivery is clearly an advantage among medically impoverished populations, and in the demanding conditions of battlefield or at the scene of a mass casualty 7 .
- Yet another application is related to astronauts and systemic delivery of medication.
- the therapeutic options for treating an injured astronaut are limited.
- the fate of injured airplane pilots, passengers and astronauts are similar in that we presently have virtually no in-flight capability for treating an acute traumatic injury. If a pilot or astronaut survives the immediate effects of an explosion, burn, or decompression injury, or if there is an acute non-traumatic medical illness, it is assumed that the victim must return to terra firma for any significant therapeutic intervention such as providing systemic fluid replacement.
- the tumescent infiltrator is capable of providing systemic fluid and thus it is successfully solving a problem that has either never before been recognized, or has never before been solved by a simple device and technique.
- the present embodiments allow improved emergency medical care for an injured astronaut on-board the International Space Station Repeated and prolonged extra vehicular activities (EVA) expose astronauts to greater risk of physical trauma injury.
- Potential injuries to astronauts include decompression injury-induced neurological injury and coma, acute pneumothorax, bums, and radiation injury .
- Assembly and maintenance of the International Space Station requires an unprecedented number of spacewalks, which expose astronauts to the risk of decompression sickness (DeS).
- DeS decompression sickness
- the cannula 10, 30 is intended to be inserted far enough through the skin 52 so that all of the apertures 18, 38 are within the fat 50 or muscle of the patient. If the apertures 18, 38 are distributed over about 100% of the cannula, the hub may be wedged into the adit to prevent or minimize leakage of the tumescent fluid out of the adit.
- the cannula 10, 30 Once the cannula 10, 30 is properly positioned, it can remain stationary while the local anesthetic (or other pharmaceutical) solution is injected. Since the cannula remains stationary, the associated pam or discomfort typically caused by the reciprocating in and out movement of prior art cannula is reduced or eliminated. Accordingly, the cannula of the present invention permits infiltration of multi liter volumes of tumescent fluid into the patient m a safe and painless manner.
- the infiltration is briefly terminated (either by turning off the pump or by clamping the IV tubing) while the cannula 10, 30 is repositioned into another area of the subcutaneous tissue.
- the cannula is repositioned at the rate of about once per minute.
- the infiltration is then restarted with the cannula stationary' in its new position. Since the apertures are distributed over the distal 33% to 100% of the cannula, the apertures distribute tumescent fluid into the patient along the entire length of cannula insertion.
- the cannula does not have to be reciprocated in and out to infiltrate the subcutaneous tissue like prior art cannula.
- the infiltrator 10, 30 can also be used in the traditional mode whereby the cannula 10, 30 is moved through the targeted tissue while the fluid is simultaneously pumped through the cannula 10, 30 and into the subcutaneous tissue 50.
- Another unique aspect of the tumescent technique’s reservoir effect is that one can conveniently achieve a long, slow, steady absorption of a drug delivered to the subcutaneous space 50 using periodic injections of a tumescent solution.
- the alternative technique can achieve a slow systemic absorption of a drug but may be difficult require greater clinical expertise, be more expensive, and therefore, less practical than the technique described herein.
- FIG. 5 is a flow diagram illustrating steps performed in an exemplary infiltration procedure using a cannula 10, 30 such as the one shown in Figures 1 and 2 or the one shown in Figures 3 and 4, respectively.
- the procedure begins by inserting the tubular needle 12, 32 of the infiltration cannula 10, 30 into a desired subcutaneous tissue site 50, e.g., via an incision in the patient’s skin 52 (block 100). Fluid is then transported from the fluid source (e.g., an IV bag) into the cannula 10, 30 via the connector 24, 44 that is connected to the fluid source. The fluid is transported from the connector 24, 44 through the hub 20, 40 and to the tubular needle 12, 32 (block 102). The fluid is then ejected from the cannula 10, 30 into the subcutaneous tissue 50 of the patient via the apertures 18, 38 at the distal end 16, 36 of the tubular needle 12, 34 of the cannula 10, 30 (block 104).
- the fluid source e.g., an IV bag
- the fluid is transported from the connector 24, 44
- the fluid is transported (block 102) and ejected (block 104) until infiltration at the current site is completed (yes in decision block 106). Complete infiltration at the current site may take approximately one or two minutes.
- the fluid can be injected into multiple sites in order to distribute the solution over a greater area.
- Infiltration at a particular site may be deemed complete upon emptying of the fluid source or based on the anesthesiologist or surgeon’s decision to stop the infiltration at the current site.
- the infiltration can be briefly terminated (either by turning off the pump or by clamping the IV tubing) while the cannula 10, 30 is repositioned into another area of the subcutaneous tissue. The infiltration may then be restarted with the cannula stationary m its new position. If the infiltration at a site is complete (yes in decision block 106), the cannula is removed from the current site (block 108). If the infiltration at the current site is not complete (no in decision block 106), fluid is transported from the fluid source (block 102) and ejected into the subcutaneous tissue (block 104) until infiltration at the site is complete (yes in decision block 106).
- the tubular needle 12, 32 of the infiltration cannula 10, 30 is inserted into a new area of subcutaneous tissue 50.
- the tubular needle 12, 32 may be inserted into a new area adjacent the current site.
- the adjacent site may be partially anesthetized by infiltration of the anesthetic solution at the current site. As such, pain to the patient caused by insertion of the tubular needle 12, 32 is minimized, eliminated or greatly reduced.
- Tins process can be continuous or repeated intermittently. It is contemplated that infiltration of up to about 50% of the patient’s body may be achieved in the manner described herein.
- a second or additional cannula can be inserted (block 100) at the same time as a first cannula is being removed (block 108).
- the second cannula may be inserted parallel to the first cannula and into an area immediately adjacent to the area in which the first cannula is inserted.
- the pam usually associated with the insertion of the cannula into the patient’s fat tissue is reduced or eliminated because the first cannula has already at least partially anesthetized the area in which the second cannula is inserted.
- the second cannula is positioned adjacent the first cannula approximately every one or two minutes.
- the first cannula may then be removed from the patient’s body after the second cannula is inserted.
- the infiltration process need not be interrupted in order to reposition a single cannula. Progressing repeatedly in this fashion, eventually all the fat within a targeted area becomes tumescent and profoundly anesthetized. As such, such method can obviate the need for general anesthesia or heav IV sedation.
- the plastic infiltration cannula shown in Figures 3 and 4 may be used by either a lay person or a clinical professional for the delivery- of tumescent fluid for either tumescent local anesthesia, tumescent antimicrobial therapy, or emergency deliver of systemic fluids by tumescent infiltration.
- tumescent local anesthesia e.g., tumescent local anesthesia
- tumescent antimicrobial therapy e.g., tumescent antimicrobial therapy
- emergency deliver of systemic fluids by tumescent infiltration e.g., tumescent infiltration
- cannula 10, 30 may be utilized for continuous systemic tumescent delivery of a drug which produces continuous system absorption of the drug over nearly 24 hours in a fashion similar to a continuous IV infusion
- the infiltration cannula 10, 30 discussed herein is a subcutaneous device and not an intravascular device for infiltration of multi-liter volumes of fluid into areas of up to 50% of the total body surface area.
- the infiltration cannula 10, 30 infiltrates approximately 1,000 times the volume of fluid delivered by the Schwartz device discussed in the background.
- the tumescent technique may be used to deliver an antimicrobial solution by subcutaneous infiltration.
- the antimicrobial solution may comprise an antibiotic.
- the antimicrobial solution may also comprise a local anesthetic and/or a vasoconstrictor.
- the tumescent technique can be advantageously employed to deliver antibiotics and other agents to a surgical site or the sites of other medical procedures.
- Some embodiments relate to tumescent antibiotic delivery (TAD) to areas of infection. TAD may be employed prophylactically to prevent an infection or TAD may be employed to treat an existing infection.
- a large volume (> 1 L for example) of dilute antibiotic solution is provided to a site where antibiotic is needed, foregoing the disadvantages of systemic delivery ' .
- the antibiotics for tumescent delivery ' may be provided in a solution of tumescent local anesthetic or without combination with local anesthetic.
- TLAnti Tumescent Local Antibiotics
- the anesthetic component may be comprised of a mixture of 2 or more anesthetics.
- the vasoconstrictive component may be comprised of a mixture of 2 or more vasoconstrictors.
- the antibiotic component may be comprised of a mixture of 2 or more antibiotics.
- the anesthetic component may possess both anesthetic and antibiotic properties.
- TLAnti may additionally comprise an antiviral and/or an antifungal component.
- the TLAnti may comprise additional pharmacological agents, such as, but not limited to, anticonvulsants, stimulants, sedatives, antihistamines, retinoids, corticosteroids, calcium antagonists, chemotherapy agents, prostacyclins, and vasodilators.
- additional pharmacological agents such as, but not limited to, anticonvulsants, stimulants, sedatives, antihistamines, retinoids, corticosteroids, calcium antagonists, chemotherapy agents, prostacyclins, and vasodilators.
- TLAnti comprises a water-soluble antibiotic component.
- the water-soluble antibiotic may be Cefazolm.
- Cefazolin is a first generation cephalosporin that has been sold under the brand names Ancef and Kefzol. This medication is particularly effective against many varieties of gram-positive bacteria that are typically present on the epidermal surface such as Staphylococcus aureus. Antibiotic coverage for such ubiquitous organisms is particularly important in surgical procedures because they can enter the surgical site during the procedure and are therefore a likely cause of post-operative infection.
- cefazolin is used at a dosage of approximately 250 to 750mg per liter of solvent.
- cefazolin is used in 1 liter of TLAnti.
- cefazolm may be used at a dosage of approximately lOOmg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, BOOnig, 850mg, or 9Q0mg per liter of solvent.
- TLAnti may comprise a combination of two or more water-soluble antibiotics.
- penicillins, cephalosporins, carbapenems, aminoglycosides, sulfonamides, qumolones, rnacroiides, tetracyclines, lipopetides and oxazolidinones may be used.
- metronidazole is used m TLAnti.
- Suitable antibiotics can be substituted m cases wherein a patient has a known or suspected hypersensitivity to a class of antibiotics, such as cephalosporins, or if the procedure is being performed in an area where resistance to a particular antibiotic is prevalent.
- TLAnti may be used to treat an existing infection.
- the infective agent may be determined and tested for antibiotic resistance.
- the antibiotic or combination of antibiotics may be specifically selected based on the resistance profile of the bacterial flora.
- antibiotics include, but are not limited to: amoxicillin, ampicillin, bacampicillin, carbenicillm, cloxacillin, dicloxacillm, flucloxacii!in, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, Piperacillin, Pivampicillin, Pivrnecillinam, Ticarei!lin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, eefalonium, cefaioridine, cefalotin, cefamandole, cefapirin, cefatoxin, cefatrizme, cefazaflur, cephalexin, cefazedone, cefazolm, cefepime, cefradme, cefroxadine, ceftezole, cefaclor, cefomcid, cefprozil, cefuroxime, cefa
- TLAnti may also comprise an anesthetic component.
- the anesthetic component may comprise lidocaine.
- !idocaine may be provided at a concentration of between 30mg and 1500mg per liter of solvent.
- lidoeaine may be provided at a concentration of between 400mg and 1250mg per liter of solvent.
- lidoeaine may be provided at concentrations of 30mg to 40mg, 40mg to 50mg, 50mg to 60mg, 60mg to 70mg, 70mg to 80mg, 80mg to 90mg, 90mg to lOOmg, lOOmg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 800mg, 800mg to 900mg, 900mg to l ,000mg, l,000mg to 1, lOOmg, 1, lOOmg to l,200mg, ! ,200mg to l ,300mg, l,300mg to l,400mg, l ,400mg to l ,500mg, and 500mg to l,000mg per liter of solvent.
- anesthetics other than lidoeaine can be used.
- Traditional local anesthetics include amide-type or ester-type local anesthetics.
- Non- traditional anesthetics include neurotoxin-based local anesthetics.
- anesthetics that are used in tumescent compositions include, but are not limited to saxitoxm, tetrodotoxm, benzocame, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, propoxy caine, novocaine, proparacaine, tetracaine, amethocaine, articane, bupivacaine, carticaine, cmchocame, dibucaine, etidocaine, levobupivacaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecame. In some embodiments, combinations of two or more anesthetics may be used.
- Suitable concentrations of anesthetic are approximately 30mg to 40mg, 40mg to 50mg, 50mg to 60mg, 60mg to 70mg, 70mg to 80mg, 80mg to 90mg, 90mg to lOOmg, lOOmg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to BOOmg, 800mg to 900mg, 900mg to l,000mg, l,000mg to 1, lOOmg, 1 , lOOmg to l ,200mg, l ,200mg to l,300mg, l,300mg to l,400mg, l,400mg to l ,500mg, and 500mg to l,000mg per liter of solvent.
- the concentration of the anesthetic component can he varied depending on the sensitivity of the treatment area and the sensitivity of the patient to pain. If the TLAnti is to be used in sensitive areas such as the face or breasts, a higher concentration of anesthetic can be used. Lower concentrations of anesthetic can be used m the TLAnti solution for procedures in less-sensitive areas such as the hips.
- Neurotoxins are a varied group of compounds, both chemically and pharmacologically. They vary in both chemical structure and mechanism of action, and produce ver distinct biological effects. Neurotoxins act on various ion channels, e.g., sodium, potassium, calcium and chloride channels. Neurotoxins acting on voltage-gated sodium channels can bind to six different sites in the channels, distinguished both by binding site(s) on the ion channels and by effect(s) of a toxin’s action.
- ion channels e.g., sodium, potassium, calcium and chloride channels.
- Neurotoxins acting on voltage-gated sodium channels can bind to six different sites in the channels, distinguished both by binding site(s) on the ion channels and by effect(s) of a toxin’s action.
- Neosaxitoxin is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans (Lobo, K. et al. 2015 Anesthesiology 123(4): 873-885). Neosaxitoxin can be used in small doses.
- Other neurotoxin-based local anesthetics include tetrodotoxin, saxitoxin and conotoxins, such as w -conotoxin (Prasanna, C. et al. (2014 Int J Anesthesiology Res 2: 11-15).
- an anesthetic is efficacious for at least 6 hours, 12 hours, 1 8 hours, 24 hours, 30 hours, 36 hours or 48 hours.
- a local anesthetic solution that can last for 2 days is ideal for treating certain types of conditions, e.g., Herpes zoster (shingles).
- TLAnti may further comprise a vasoconstrictor component.
- a vasoconstrictor serves two functions. The first is to control the otherwise substantial bleeding resulting from the removal of adipose or other tissue. The second is to control the systemic distribution of the anesthetic and antibiotic components of TLAnti from the subcutaneous fat compartment into the systemic circulation. This helps to concentrate these medications in the area where they are needed for a prolonged period of time, thereby enabling them to exert sufficient anesthetic and antibiotic effects in the surgical site post-operatively or at the site of infection.
- the use of a vasoconstrictor limits the systemic absorption of other medications, which reduces the risk of sy stemic toxicity from elevated serum levels of these medications and thereby minimizes the risk of side effects.
- the vasoconstrictor component is epinephrine.
- Epinephrine may be provided at a concentration of ⁇ 1 mg/L.
- epinephrine is present in a concentration of 0 4 to 1.2mg per liter of solvent.
- epinephrine may be present in a concentration of 0.2 to 0.3mg, 0.3 to 0.4mg, 0.4 to 0.5mg, 0.5 to 0.6mg, 0.6 to Offing, 0.7 to 0.8mg, 0.8 to 0.9mg, 0.9 to Img, 1 to 1.1 mg, 1.1 to !
- TLAnti solutions containing epinephrine would be manufactured with a moderately acidic pH in the range of 3.8 to 5.0 in order to optimize the shelf life of the TLAnti solution.
- the TLAnti solution can be neutralized prior to subcutaneous infiltration by the addition of approximately 10-25 mEq of sodium bicarbonate.
- vasoconstrictors other than epinephrine can be used in some embodiments of TLAnti.
- suitable vasoconstrictors include, but are not limited to, methoxamine, metraminoi, ephedrine, noradrenaline, vasopressin, levonordefrin, prostaglandins, thromboxane A2, leukotriene D4, angiotensin II, neuropeptide Y, and endotheiin
- TLAnti other constituents may optionally be present in the TLAnti.
- bicarbonate can be present in the TLAnti. This helps to neutralize the otherwise acidic solution and reduce the burning sensation reported by many patients.
- the TLAnti can further comprise perf!uorocarbons. An example can be found in United States Patent No. 6,315,756, the disclosures of which are incorporated in their entirety by reference thereto.
- TLAnti can further comprise an anti-inflammatory component. Examples of anti-inflammatories include but are not limited to glucocorticoids and NSAIDS. Persons skilled in the art will note that there are a number of potential compounds that can be added to the TLAnti.
- TLAnti comprises lidocaine as the anesthetic component.
- Lidocaine has a synergistic effect with antibiotics m the prevention and/or treatment of infection at the surgical site. While primarily used as for anesthesia, lidocaine has also been found to have antibiotic properties. Lidocaine is well known to be bactericidal based on in-vitro studies although the precise mechanism has not been explained. Lidocaine is a trans-membrane anion (Na+, K+, Ca+) transport pump inhibitor in prokaryotic cells. Not to be bound by a particular theory, it is believed that lidocaine also acts as an antibiotic efflux pump inhibitor (inhibitor of multidrug resistant efflux systems in bacteria).
- Lidocaine can thus act synergistically at the local tissue level when both lidocaine and an antibiotic are delivered directly into the targeted tissue using the tumescent drug delivery technique.
- lidocaine By inactivating efflux pumps, lidocaine eliminates a mechanism of potential resistance to the cefazolin or other antibiotics used in TLAnti.
- tumescent antibiotic delivery of antibiotics together with tumescent lidocame provides a unique therapeutic benefit in preventing and treating biofilm infections.
- the IV delivery' of antibiotics is relatively ineffective against biofilm infections.
- Tumescent delivery of pharmaceutical agents can provide a highly localized and sustained dosage of the pharmaceutical agent to the delivery site.
- use of the tumescent technique to deliver TLAnti can provide a high, sustained dosage of antibiotics directly to a surgical site.
- IV intravenous
- the concentration of the antibiotic drug and the local anesthetic drug within the TLAnti (which equals the maximum concentrations of these drugs within the tissues infiltrated with the TLAnti) far exceed the concentrations of these drugs which can be safely achieved by intravenous delivery.
- the concentration of antibiotic in the subcutaneous tissue at the surgical site may be three times or more than the measured maximum serum concentration of the same drag when administered intravenously prior to the procedure.
- Another advantage is that the therapeutic dosage of antibiotics at the surgical site lasts significantly longer with tumescent administration of TLAnti as compared to IV antibiotics. The result is that any bacteria present at the surgical site are exposed to a higher dosage of antibiotics for a longer period of time when TLAnti is used in place of IV antibiotics.
- the bioavailability and effectiveness of an antibiotic can be assessed using the area under the curve (AUC) measurement of the tissue-concentration of the antibiotic as a function of time.
- AUC area under the curve
- the serum-antibiotic AUC may be more than 100 times greater than the serum-antibiotic AUC following tumescent antibiotic delivery.
- the subcutaneous tissue-antibiotic AUC following the IV delivery of an antibiotic is less than 1/100th the tissue-antibiotic AUC following tumescent antibiotic delivery.
- the peak serum concentrations of an antibiotic is higher after IV infusion compared to tumescent antibiotic, while the peak tissue concentration of antibiotic is lower after IV infusion compared to tumescent antibiotic. Tumescent antibiotic delivery produces significantly lower systemic concentrations of antibiotic while at the same time the local tissue concentration of antibiotic at the site of tumescent antibiotic infiltration is dramatically higher than that which can be achieved by IV antibiotic delivery.
- Some embodiments relate to a method of using TLAnti during various surgical procedures. For example, in a liposuction procedure, a therapeutic quantity of TLAnti is injected into the subcutaneous compartment. Once sufficient anesthesia is achieved, another cannula is inserted and adipose tissue removed. The cannula is subsequently removed and the surgical site dressed and/or closed as appropriate. The high levels of antibiotics that remain for some period of time in the surgical site can reduce the risk of postoperative infection. Similarly, a large number of general surgical procedures including, but not limited to, open gastrointestinal surgery, obstetric surgery, orthopedic surgery, and vascular surgery are appropriate for the use of subcutaneous TAD.
- Some embodiments relate to methods for using tumescent solutions in the subcutaneous space to treat a variety of medical conditions where systemic administration of medications is undesirable or impossible.
- Various embodiments include, but are not limited to, methods for using tumescent solutions as an anesthetic for medical procedures by clinicians, methods for using tumescent solutions in the administration of fluids to patients by medical professionals and first responders, methods for using tumescent antibiotic solutions to prevent and/or treat infections, methods for providing a chemotherapy agent to tissue after tumor removal and methods for using tumescent solutions in the controlled release of antibiotics and other pharmaceutical agents.
- Tumescent administration of anesthetics, antibiotics, vasoconstrictors, and/or other pharmaceutical agents can improve the outcome of surgical procedures to remove tumors.
- Tumors may be benign or malignant, cancerous. Benign tumors are well circumscribed and are generally treated by surgery alone. Malignant/cancerous tumors on the other hand are more difficult to treat. When malignant tumors are localized, surgical removal is a common treatment option. Approximately 40% of all cancers are treated with surgery alone. In most other cases where surgery is an option, it is combined with other treatments—usually radiation therapy or chemotherapy.
- One danger of the surgical removal of malignant tumors is the possibility of spreading or seeding the cancerous cells during the process of removing the tumor.
- Tumescent delivery of a vasoconstrictor to the surgical site can reduce the risk of malignant cells entering the bloodstream.
- the tumescent technique may also be used to locally deliver chemotherapy agents. Local administration of chemotherapy agents allows for higher localized dosages of the chemotherapy agents than would be tolerated systemically and a reduction of adverse side effects.
- chemotherapy agents include, but are not limited to: actinomycin D, adriamycin, alkeran, ara-C, arsenic trioxide (trisenox), avastin, BiCNU, busulfan, carboplatinum, CCNU, cisplatinum, cytoxan, daunorubicin, DTIC, 5 ⁇ FU, eriotinib, fludarabme, gemcitabine, herceptin, hydrea, idarubicin, ifosfamide, irinoteean, lapatinib, leustatm, 6-MP, methotrexate, mithramycin, mitomycin, mitoxantrone, navelbine, nitrogen mustard, rituxan, 6-TG, taxol, taxotere, topotecan, velban, vincristine, VP-16, and xeloda.
- angiogenesis inhibitors may also be tumescently delivered.
- angiogenesis inhibitors include, but are not limited to, angiostatin, endostatin, and tumstatin.
- the tumescent solutions can be premixed and packaged prior to being sent to the provider.
- one or more components of the tumescent solution can be added shortly before or during the medical procedure wherein they are to be used.
- the bulk of the tumescent solution comprises a physiologically compatible solvent.
- solvents can include, for example, saline solution comprising sterile water and 0.9% sodium chloride. More dilute saline solutions can also be used.
- a laetated Ringer’s solution may be used. This comprises a mixture of sterile water, sodium, chloride, lactate, potassium and calcium that is isotonic with blood. Hartmann’s solution can also be used as a solvent in some embodiments. Individuals skilled in the art will recognize that there are a wide variety of possible biologically compatible solvents for use in the solution.
- tumescent solution may be provided as a kit.
- the tumescent solution is TLAnti.
- TLAnti can be pre mixed at a manufacturing site and distributed to practitioners in a ready to use form.
- the TLAnti can be packaged in a form that allows easy interface with a tumescent reservoir or pumping system.
- packaging can come in a variety of sizes: however typical kits would include one liter or more of tumescent solution.
- the tumescent solution may require rehydration or dilution to an administrable concentration.
- a kit can comprise a one liter solution of .9% normal saline, 500mg of cefazolin, 500mg lidocaine 2%, I mg epinephrine, lOmEq bicarbonate.
- concentration of lidocaine can be used depending on the intended clinical use.
- embodiments comprising higher dosages of lidocaine, optionally buffered with additional bicarbonate can be used when a procedure is to be performed in a sensitive area.
- Variations on the type and concentration of antibiotic component are also possible.
- Some embodiments can also include various concentrations of epinephrine or different types of vasoconstrictors. Persons skilled in the art will recognize that many standardized variations are possible and the above example should not be deemed to be limiting.
- the tumescent solution or components for preparing the tumescent solution can be packaged along with a set of cannula, tubing and possibly other surgical instruments for performing liposuction.
- kits can include an appropriate mix of tumescent solution components for the body part where the procedure is to be performed along with appropriately sized, sterile instruments.
- the sterile instruments are capable of interacting with standardized liposuction equipment (i.e., peristaltic pumps, adipose tissue receptacles, etc.).
- Kits for TLAnti use in mastectomy procedures can be prepared comprising the tumescent solution along with any appropriate instruments.
- the tumescent solution can be provided in prefilled tumescent reservoir bags.
- Such bags could be manufactured by a pharmaceutical company and be sold as“ready to use.”
- Manufactured tumescent delivery bags are a more efficient and economical use of hospital staff than having to custom mix the tumescent solution for each surgical patient.
- commercially produced prefilled tumescent reservoir bags would eliminate pharmacist error in mixing and preparing tumescent solution.
- a TLAnti solution is provided in a prefilled tumescent reservoir bag comprising a dilute solution of local antibiotic such as lidocame ( ⁇ 1 g/L) or other water soluble antibiotic and a vasoconstrictor, such as epinephrine ( ⁇ 1 mg/L) in a physiologic electrolyte solution sodium chloride.
- TLAnti solutions containing epinephrine can be manufactured at a moderately acidic pH to optimize epinephrine stability.
- the TLAnti solution can be neutralized prior to administration by the addition of approximately 10-25 mEq of sodium bicarbonate. An appropriate amount of sodium bicarbonate can be included for addition to the prefilled tumescent reservoir bag.
- TLAnti solution is safe when infiltrated into subcutaneous tissue; rapid, systemic infusion of TLAnti may be lethal. There is thus a need to prevent inadvertent IV administration of tumescent solutions.
- Various safety features may be incorporated into the prefilled tumescent reservoir hags. Tumescent reservoir bags can be designed to be readily distinguishable from standard IV bags. Distinguishing features include, but are not limited to, unique shape, color-coding, and/or printed warnings.
- tumescent reservoir bags may be provided as kits in conjunction with a non-standard (non-luer) connector system to prevent inadvertent connection to an IV line.
- Tumescent solution can be injected into the subcutaneous space during surgical procedures using a variety of infiltration cannula that are well known to persons skilled in performing surgical procedures.
- the TLAnti can be injected into the treatment area using an infiltration cannula comprising a flexible cannula, a hub, and a rigid stylet.
- the flexible cannula has a proximal end and a distal end.
- the flexible cannula can also have a plurality of apertures disposed in a pattern about the distal end. The apertures are configured to infiltrate fluid into the subcutaneous tissue of a patient.
- the hub is configured to be held by a person performing the infiltration procedure.
- the hub has a first end and an opposing second end.
- the first end is attached to the proximal end of the flexible cannula and the second end includes a connector configured to connect to an input source for receiving the fluid to be infiltrated into the subcutaneous tissue of the patient.
- the fluid flows from the connector, through the hub and into the flexible cannula.
- the tumescent solution can also be delivered via a disposable catheter that can be used in emergency situations or under conditions when establishing intravenous access is difficult or impossible.
- the tumescent solution can be injected into the subcutaneous space via a flexile cannula with a rigid stylet that can be fabricated from stainless metal or rigid plastic.
- the distal end of the cannula can be closed to cover the tip of the rigid stylet or open with a hole allowing the tip of the rigid stylet to protrude.
- the tip of the rigid stylet can be sharp to facilitate the direct insertion through the skin of the patient.
- the stylet can be formed to have either a solid or hollow cross-sectional configuration.
- the hollow rigid stylet may have small holes distributed along its length in a pattern dissimilar or identical to the patern of holes placed along the flexible cannula into which the stylet is inserted.
- the stylet itself can be used as an infiltration cannula.
- Tumescent Infiltration Lidocaine Anesthesia has the ability to:
- systemic lidocame attenuates activity of inflammatory mediator associated with innate immunity and thus reduce the risk of sepsis and systemic inflammatory response syndrome.
- the tumescent technique may be used to treat localized viral infections. Surprisingly, while some antibiotics and antiviral agents are not recommended for subcutaneous use, the tumescent technique allows such agents to be safely used at relatively high, localized therapeutic dosages. For instance, the antibiotic gentamycin and the antiviral compound Acyclovir, which is commonly used to treat infections caused by herpes viruses, such as genital herpes, cold sores, shingles, and chicken pox, are not recommended for subcutaneous administration.
- the tumescent technique is amenable to treatment of localized viral infection, such as for treatment of viral diseases related to herpes virus (including Herpes Simplex I, Herpes Simplex II, herpes zoster (shingles), herpetic conjunctivitis, keratitis, and genital herpes).
- Herpes Simplex I Herpes Simplex II
- herpes zoster herpetic conjunctivitis
- keratitis heratitis
- genital herpes Other types of localized viral infection include Molluscum Contagiosum, a common skin infection caused by a pox virus that affects both children and adults and Kaposi's sarcoma (KS), a connective tissue cancer caused by human herpes virus 8.
- a non-exhaustive list of antiviral agents used to treat localized viral infection includes: Abacavir, Acyclovir, Adefovir, Amantadine, Amprenavir, Ampligen, Arbidol, Atazanavir, Atripla, Balavir, Brivudine, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Eeoliever, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Ganciclovir, Ibaeitabme, Imunovir, Idoxuridine, Imiquimod, Interferon type I, Interferon, Lamivudine, Lopinavir, Loviride, Maraviroc, Mor
- the subcutaneous concentration of the antiviral agent achieved is simultaneously; (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (li) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the antiviral agent.
- the subcutaneous concentration of the antiviral agent achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the antiviral agent.
- Acyclovir is used at a diluted concentration of 0.1 g/L-10 g/L, preferably 0.5g/L ⁇ 5g/L, more preferably l-2g/L, or at Ig/L.
- Gentamycm is used at a diluted concentration of 0.1 mg/L-lg/L, preferably 50-800 mg/L, more preferably 50-200 mg/L or at 80 mg/L.
- a tumescent composition used to treat localized viral infection typically contains an antiviral component and a vasoconstrictor.
- the tumescent composition may optionally comprise other components, such as antibiotic, anesthetic and anti inflammatory components.
- VZV Varicella-zoster virus
- varicella chickenpox
- herpes zoster shingles
- Varicella is highly contagious. It initially enters the host by penetrating the respirator ⁇ ' epithelium causing viremia and the classic vesicular chickenpox rash. From the skin, VZV migrates within cutaneous sensory neurons to arrive at sensoiy dorsal root ganglia (DRG). As the host develops a cellular immunity involving CD4 & CDS cells and a serologic immune response, the rash subsides and the VZV virus within the ganglion becomes latent.
- DDG sensoiy dorsal root ganglia
- the latent VZV can reactivate, proliferate and migrate along a sensory nerve from the dorsal root ganglion toward the skin of the corresponding dermatome.
- H zoster The initial manifestation of H zoster is abrupt onset of localized pain that extends over the next few days within a localized unilateral area of skin spanning 1 to 3 adjacent dermatomes. Patients often attribute the acute onset of the pain to be the result of muscle strain, back-muscle spasm, or a bacterial infection. Within 2-4 days there is the onset of. The host’s immune response produces an intense inflammatory reaction with a potential for permanent sensor ⁇ nerve injury. [0230] The area and intensity of painful skin tends to enlarge over the next 2 to 3 days.
- Zoster pain is intense, and has 3 clinically distinct components: a deep burning unremitting pain, sporadic acute sharp lancinating pain, and a paresthetic pain that is elicited by light touch or temperature change (mechanical aliodynia).
- Post herpetic neuralgia is the most common and perhaps the most dreaded complication of Herpes zoster. PHN is defined as pain that persists for more than 3 months after acute herpes zoster. PHN often does not respond well to narcotics or other analgesics. The incidence of post herpetic neuralgia (PHN) is approximately 10%, but among patients with hematologic malignancy it is at least 48%.
- Herpes zoster patients with greater pain and rash severity have greater risk of PHN. This suggests that greater neural damage (caused by more severe acute infection) contributes to risk of PHN. Indeed, acute pain seventy is a major risk factor for PHN (Dworkin RH, Boon RJ, Griffin DRG. Postherpetic neuralgia: Impact of Famciclovir, age, rash severity and acute pain in Herpes zoster patients. JID 1998; 178 (Suppl) S76-S80). Current approaches to acute zoster pain rely on aggressive analgesic intervention that merely attenuates zoster pain.
- TI acyclovir tumor lidocame and acyclovir
- TTAR tumescent therapeutic ambit range
- PHN is a neuropathic pain that is resistant to treatment, preventing PHN is of prime importance.
- TI of acyclovir delivers unprecedented high and prolonged subcutaneous concentrations of lidocame, eliminates 100% of pam for up to 12 hours or more without repeat dosing and thus reduces the risk of neuropathic pam and PHN.
- Tumescent lidocaine+ acyclovir is more effective than IV acyclovir at reducing the risk of
- the zoster blister contains large amounts of infectious VZV viral particles.
- the risk of severe H. zoster and the risk of PHN are closely correlated with the intensity of the host’s secondary inflammatory immune response to VZV, the degree of pathologic damage to sensory nerves, the total area of blistering, the intensity and duration of epidermal necrosis, and the intensity and duration of acute pain.
- Antiviral drugs do not provide anesthesia and do not eliminate acute zoster pain.
- the intensity and duration of any acute pain increases the risk of a permanent neuropathic pain syndrome.
- PHN is an example of neuropathic pain.
- Acyclovir, vaiacyclovir and famciclovir treat certain, but not all, aspects of H. zoster. They reduce the intensity and duration of zoster pain and decrease the risk of developing PHN.
- Tumescent iidocaine + acyclovir can both eliminate 100% of pain (for hours) and can decrease viral replication rate and the extent and intensity.
- the risk factors that have been shown to increase the incidence of PHN include: a) increasing age, b) intensity of pain upon initial presentation, c) duration of pain upon initial presentation, d) extent of the H. zoster rash upon presentation, e) intensity of pain one week after initiating antiviral therapy, f) progression of pain one week after initiating antiviral therapy and g) progression of dermatitis one week after initiating antiviral therapy.
- An important embodiment of the present invention is the safe and effective subcutaneous infiltration of an antiviral agent for the treatment of Herpes zoster.
- Herpes Zoster or Shingles is an unusually painful disease caused by 7 the varicella zoster virus that affects one million people in the United States annually. Among persons 85 years of age or older, 50% will eventually have herpes zoster. H. zoster can progress into chronic, potentially devastating, post-herpetic neuralgia (PHN).
- Methods disclosed herein involve the subcutaneous infiltration of a tumescent solution of dilute lidocaine and epinephrine and one or more zoster-specific antiviral drugs (e.g. acyclovir) and/or a broad-spectrum antiviral (e.g., cidofovir), with or without anti-inflammatory drugs (e.g., steroidal anti-inflammatory drugs such as triamcinolone, non-steroidal anti-inflammatories)), and with or without sodium bicarbonate.
- zoster-specific antiviral drugs e.g. acyclovir
- a broad-spectrum antiviral e.g., cidofovir
- anti-inflammatory drugs e.g., steroidal anti-inflammatory drugs such as triamcinolone, non-steroidal anti-inflammatories
- the antiviral drugs acyclovir (Zovirax®), valacycfovir (Valtrex ⁇ ) and famcyclovir (Farnvir®) effectively treat H. zoster. Only Acyclovir is available for IV deliver ⁇ ' . At present, oral deliver ⁇ ? is considered sufficient for most cases of H. zoster. IV delivery is usually reserved for patients requiring hospitalization, for example disseminated H.
- zoster in immunocompromised hematopoetic transplant patients or HIV (AIDS) patients, severe forms of zoster such as herpes zoster ophthalmicus that can cause blindness, herpes oticus (Ramsay-Hunt syndrome) which can cause unilateral facial paralysis and/or permanent hearing loss, CNS zoster and Zoster pneumonia.
- herpes zoster ophthalmicus that can cause blindness
- herpes oticus RVamsay-Hunt syndrome
- CNS zoster and Zoster pneumonia the sooner treatment begins, the less severe the intensity of the rash and pain and the shorter its duration.
- Subcutaneous tumescent drug delivery of acyclovir and lidocaine typically eliminates 100% of acute zoster pain for 12 hours or more. This is unique among ail forms of Herpes zoster treatments. Using an elastomeric pump to provide continuous subcutaneous infiltration, TI-acyclovir can eliminate zoster pain for days.
- Tumescent infiltration can also be used to treat local and systemic fungal infections.
- a partial list of antifungal drugs includes:
- Polyenes amphotericin B, candicidin, Filipin, Hamycin, Natamycin, Nystatin and Rimocidin;
- Imidazoles Bifonazole, Butoconazole, Clotrimazole, Econazole, Fentieonazoie, Isoconazole, Ketoconazole, Luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole and Tioconazole;
- Triazoles Albaconazole, Efmaeonazole, Epoxiconazo!e, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole and Voriconazole;
- Tumescent infiltration can also be used to treat local and systemic protozoa infections.
- a partial list of antiprotozoal drugs includes: Antinematodes: Mebendazole, Pyrantel pamoate, Thiabendazole, Diethylearbamazine, and Ivermectin;
- Anticestodes Niclosamide, Praziquantel, and Albendazole;
- Antitrematodes Praziquantel
- Antiamoebics Rifampin and Amphotericin B;
- Antiprotozoals Melarsoprol, Efl ornithine, Metronidazole, Timdazole and Miltefosine.
- Neuropathic pain is a complex, chronic pam state that is generally accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured. These damaged nerve fibers send incorrect signals to other pain centers.
- the clinical causes of neuropathic pain are diverse and include both trauma and disease. For example, traumatic nerve compression or crush and traumatic injury to the brain or spinal cord are common causes of neuropathic pain. Furthermore, most traumatic nerve injuries also cause the formation of neuromas, in which pam occurs as a result of aberrant nerve regeneration.
- cancer-related neuropathic pain is caused when tumor growth painfully compresses adjacent nerves, brain or spinal cord.
- Neuropathic pam can be caused by various diseases, such as viral infections and diabetes and alcoholism. For example, post herpetic neuralgia is caused by herpes viral infection and can cause moderate to severe chronic pain in the infected skin area to the subject.
- neuropathic pain often do not provide adequate pain relief.
- current therapies have serious side-effects including, for example, cognitive changes, sedation, nausea and, in the case of narcotic drugs, addiction.
- Many patients suffering from neuropathic pain are elderly or have other medical conditions that particularly limit their tolerance of the side-effects associated with available drug therapy.
- a number of anti-inflammatory, anxiolytic, narcotic and even anti-convulsants are currently used by the practitioners to treat neuropathic pain, but with limited success.
- SSRIs serotonin reuptake inhibitors
- other antidepressants ven!afaxine, bupropion
- Another common treatment of neuropathic pain includes anti-seizure medications (carbamazepine, phenytoin, gabapentin, lamotrigine, and others).
- Pregabalin and duloxetine can also be effective for nerve pain. Like amitriptyline, they may be given alongside other pain medications in the most troublesome nerve pain conditions.
- Duloxetme is licensed for pain from nerve damage resulting from diabetes, which most often starts in the feet.
- Neuropathic pain may be brought on by trauma, disease or irritation. There are countless types of neuropathic pain. Some of the common types include:
- Postherpetic neuralgia is neuropathic pain that is brought on by an outbreak of shingles, and persists after the condition has cleared.
- Trigeminal neuralgia is characterized by shooting neck and facial pam. The pam is often worse with light touch, and may make activities like shaving very painful.
- Phantom limb pain can occur in some people after a limb is amputated. This pain feels as if it is coming from part of the limb that is no longer there.
- Diabetic neuropathy causes burning or stabbing pain in the hands and feet of some people who suffer from diabetes.
- Carpal tunnel syndrome is caused by nerve compression in the wrists, and causes pain in the wrist, thumb and fingers.
- Sciatica is caused by compression or irritation of the sciatic nerve, and often results in shooting pain that radiates down the back of leg.
- Chronic neuropathic pain can also be caused by other chrome pain disorders. For instance, someone with degenerative disk disease, a form of arthritis, may experience neuropathic back pain if the condition causes damage to the nerves entering or exiting the spine. Some other conditions that may cause chronic neuropathic pain include spinal cord injury, post-surgical pam and cancer.
- the subcutaneous concentration of drug achieved is simultaneously: (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug.
- the subcutaneous concentration of the drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drag.
- the tumescent technique allows anti inflammatory agents to be safety administered at relatively high concentrations.
- anti-inflammatories include but are not limited to glucocorticoids and non-steroidal anti inflammatory drugs (NSAIDS).
- NSAIDS non-steroidal anti inflammatory drugs
- Example glucocorticoids include triamcinolone, dexamethsasone, prednisolone, methylprednisolone, budesonide betamethasone, hydrocortisone and cortisone.
- Example NSAIDS include Aspirin (Anacin®, Ascnptin®, Bayer®, Bufferm®, Ecotrin®, Excedrin®); choline and magnesium salicylates (choline magnesium trisalicylate (CMT), Tricosal®, Trilisate®); Choline salicylate (Arthropan®); Celecoxib (Celebrex®); Diclofenac potassium (Cataflam®); Diclofenac sodium (Voltaren®, Voltaren XR®); Diclofenac sodium with misoprostol (Arthrotec®); Diflumsal (Dolobid®); Etodolac (Lodine®, Lodine XL®); Fenoprofen calcium (Nalfon®); Flurbiprofen (Ansaid®); Ibuprofen (Advil®, Motrin®, Motrin IB®, Nuprin®); Indomethacin (Indocin®, Indocin , Indoc
- glucocorticoids remain at the forefront of anti inflammatory and immunosuppressive therapies. They are widely used to treat both acute and chronic inflammations, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis and eczema, as well as being used in treatment of certain leukaemias and in immunosuppressive regimes following organ transplant.
- the anti inflammatory effects are mediated either by direct binding of the glucocorticoid/glucocorticoid receptor complex to glucocorticoid responsive elements in the promoter region of genes, or by an interaction of this complex with other transcription factors, in particular activating protein- 1 or nuclear factor-kappaB.
- Glucocorticoids inhibit many inflammation-associated molecules such as cytokines, ehemokines, arachidomc acid metabolites, and adhesion molecules.
- NSAIDs comprise a large class of drugs with many different options.
- Ibuprofen e.g. brand names Advil®, Motrin®, Nuprin®
- Naproxen e.g. brand names Aleve®, Naprosyn®
- COX-2 inhibitors e.g., Celebrex®
- Tumescent drug delivery provides both local tissue effects and systemic effects.
- the concentration of the drug within the tumescent solution for example, a cannabinoid
- the primary intended effect of TDD of a drug may be a systemic effect.
- the TDD of a cannabinoid provides a subcutaneous depot of the cannabinoid, wherein the cannabinoid is slowly absorbed into the systemic circulation over a prolonged interval of time for up to 48 hours or more.
- the specified concentration of the cannabinoid within the tumescent solution can intentionally exceed the range of cannabinoid concentrations that are effective within local subcutaneous tissue.
- the maximal concentration of a cannabinoid within any tumescent solution should never exceed the clinically defined threshold for local tissue toxicity.
- the maximal total milligram dose of a cannabinoid should never exceed the clinically defined threshold for systemic toxicity.
- cannabinoids readily mixed into water, either as a suspension or a true solution, after soaking in cold water, or being soaked in hot water as a“cannabinoid tea”.
- a“aqueous tea solution” is pharmacologically active when delivered orally for systemic effect.
- a sterile aseptic cannabinoid tea can be added to a tumescent solution for local or systemic effect.
- Cannabinoid receptors include CBl, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system.
- CBl and CB2 receptors have been found on immune ceils suggests that cannabinoids play an important role in the regulation of the immune system.
- Administration of THC into mice triggers marked apoptosis in T ceils and dendritic cells, resulting in immunosuppression.
- cannabinoids down regulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses.
- the endocannabmoid system is also involved in immunoregulation.
- endocannabinoids For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endoeannabinoids, leads to immunosuppression and recovery from immune-mediated injury to organs such as the liver.
- Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo is a potent treatment modality against inflammatory disorders.
- Cannabinoids are hydrophobic oily substances and, as such, not water-soluble. They can, however, be formulated to be water-compatible and appear w3 ⁇ 4ter ⁇ soluble.
- CBD eannabidiol
- THC tetrahydrocannabinol
- w3 ⁇ 4ter-soluble CBD has lately been extensively used throughout the medical cannabis industry.
- Water-soluble means able to homogeneously incorporate into water by separating into molecules or ions (dissolve like sugar, alcohol or salt). Oily substances, however, are repelled by water, which forces them to stay separate from it.
- Hydrophobic cannabinoids can be made water compatible if they are formulated as micro- or nanoemulsions, which are stable and visually homogeneous oil/water mixtures. Both micro- and nanoemulsions can be prepared in concentrated forms that are fully miscible with water and, therefore, appear water-soluble. Both require the use of surfactants, which dilute the products, but are not otherwise a major concern, since several natural options are available with minimal negative effects. It is, of course, beneficial to use as little surfactants as possible. This is where nanoemulsions have a clear advantage: the amounts of surfactants used for their preparation are up to 10 times lower that those needed to make microemulsions.
- cannabis extract nanoemulsions provide exceptionally high bioavaiiability and therapeutic effect, and are absorbed by the body, e.g., subcutaneously, very rapidly and completely. This means higher potency and faster onset of action for lower doses. See e.g., the internet ati. blog.sonomechanics.com/blog/water-soluble ⁇ cbd.
- hydrophobic cannabinoids such as CBD THC
- CBD THC can be rendered water-soluble by derivatization.
- the alkyl side chain and/or the phenolic hydroxyl group of tetrahydrocannabinol can be derivatized.
- Water-soluble cannabinoids are useful for various treatments including treatment of inflammation, cancer, post-traumatic stress and related conditions, appetite loss, pain, multiple sclerosis, nausea and vomiting, and epilepsy.
- Preferred water-soluble eannabinoid compounds for tumescent delivery have high CB1 and CB2 receptor affinity' and high bioavailability.
- Structural alterations in tetrahydrocannabinol increase its water solubility and/or miscibility.
- structural alterations By making structural alterations m the alkyl side chains and at the phenolic hydroxyl group of tetrahydrocannabinol, a series of analogs can be made that are soluble and/or miscible in water, and which show high bioavailabihty, as summarized in U.S. Application Publication No. 2008/0064679, for example.
- the analogs exhibit high affinity for the CB1 and CB2 receptors, and are thus water-soluble eannabinoid agonists.
- the compounds are useful for treating diseases and disorders related to CB1 and CB2 receptor function, including inflammation, appetite loss, nausea and vomiting, pain, multiple sclerosis and epilepsy.
- Water-soluble cannabinoids may be provided as a salt (e.g. HCi, iodine, ammonia, sulfates, tartrates, succinates, quaternary salts, etc.).
- a salt e.g. HCi, iodine, ammonia, sulfates, tartrates, succinates, quaternary salts, etc.
- any salts of the compounds may be used, so long as the salt retains water solubility.
- Water-soluble cannabinoids may be synthesized based on two approaches to modification of tetrahydrocannabinol: structural alterations in: 1) the alkyl side chains; and 2) at the phenolic hydroxyl group.
- the resulting analogs are soluble and/or miscible in water, show high bioavailability, and exhibit high affinity for the CB1 and CB2 receptors (i.e., they are eannabinoid agonists.)
- water-soluble applies to compounds in which at least 0.2 mg, 0.3 mg, 0.4mg, 0.5 mg, 0.6 rng, 0.7 mg, 0.8 rng, 0 9 mg or 1 mg of material, when dissolved in 1 ml of water, gives a clear solution and is water miscible.
- the total dosage of a drug such as a eannabinoid may be in the range of 1 pg/kg to 2,000 pg/kg.
- the dosage of cannabinoid administered tumescently is in the range of 10- 1500 pg/kg, 10-1000 pg/kg, 10-700 pg/kg, 10-300 pg/kg or 100-300 pg/kg.
- “High affinity” compounds exhibit a Ki in the range of about 0 03 nM to about 80 nM, and preferably from about 0.03 nM to about 50 nM, for either the CBl or CB2 receptors, or both.
- the subcutaneous concentration of the anti-inflammatory drug achieved is simultaneously: (i) below r the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the anti-inflammatory drug.
- the subcutaneous concentration of the anti inflammatory drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 1 10%, 1 15%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the anti-inflammatory drug.
- Treating a localized cancer or reducing the growth of a tumor by localized delivery of a cancer medication can be achieved by using the tumescent technique.
- Using chemotherapy to treat cancer typically has unpleasant side effects.
- the toxic effects of the medication affect healthy cells, as well as those of the tumor itself. This leads to symptoms like nausea, hair loss or reduced effectiveness of the immune system.
- the tumescent technique allows higher doses of medication to be used, while the rest of the patient's body remains unaffected.
- Chemotherapy agents are selected based on the type of cancer, the stage of the cancer (how far it has spread), the patient’s age, the patient’s overall health, other serious health problems (such as heart, liver, or kidney diseases) and the types of cancer treatments given in the past.
- Chemotherapy regimens or treatment plans may use a single drug or a combination of drugs, which may be more effective than a single drug, because the cancer cells can be attacked in several different ways.
- Alkylating agents directly damage DNA (the genetic material in each cell) to keep the cell from reproducing.
- DNA the genetic material in each cell
- These drugs work in all phases of the cell cycle and are used to treat many different cancers, including leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary. Because these drugs damage DNA, they can cause long-term damage to the bone marrow. In rare cases, this can lead to acute leukemia.
- the risk of leukemia from alkylating agents is“dose-dependent,” meaning that the risk is small with lower doses, but goes up as the total amount of the drug used gets higher.
- the risk of leukemia after getting alkylating agents is highest about 5 to 10 years after treatment.
- Alkylating agents are divided into different classes, including: Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan; Nitrosoureas: such as streptozocin, carmustme (BCNU), and lomustine; Alkyl sulfonates: busulfan; Triazmes: dacarbazine (DTIC) and temozolomide (Temodar®); and Ethylenimines: thiotepa and altretamine (hexamethylmelamme).
- Nitrogen mustards such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan
- Nitrosoureas such as streptozocin, carmustme (BCNU), and lomustine
- the platinum drugs (such as cisplatin, carboplatin, and oxalaplatin) are sometimes grouped with alkylating agents because they kill cells in a similar way. These drugs are less likely than the alkydating agents to cause leukemia later.
- Antimetabolites interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase, when the cell’s chromosomes are being copied. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer.
- antimetabolites include: 5-fluorouracil (5-FU), 6- mercaptopunne (6-MP), Capecitabine (Xeloda®), Cytarabine (Ara-C®), Fioxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxyurea, Methotrexate and Pemetrexed (Alimta®).
- Anthracyc!ines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. Examples of anthracyclines include: Daunorubicin, Doxorubicin (Adriamycin®), Epirubicin and Idarubiein. A major concern when giving these drugs systemieal!y is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs. However, with the tumescent technique, this problem is avoided.
- Anti-tumor antibiotics that are not anthracyclines include: Actinomycin- D, Bleomycin, Mitomycin-C, and Mitoxantrone (also acts as a topoisomerase II inhibitor).
- Topoisomerase inhibitors are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Topoisomerase inhibitors are grouped according to which type of enzyme they affect.
- Topoisomerase I inhibitors include Topotecan and Irinotecan (CPT-1 1).
- Topoisomerase II inhibitors include Etoposide (VP- 16), Teniposide and Mitoxantrone (which also acts as an anti-tumor antibiotic).
- Topoisomerase II inhibitors can increase the risk of a second cancer - acute myelogenous leukemia (AML) - as early as 2 to 3 years after the drug is given.
- AML acute myelogenous leukemia
- Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They work by stopping mitosis in the M phase of the cell cycle but can damage cells in all phases by keeping enzymes from making proteins needed for cell reproduction.
- mitotic inhibitors include: Taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®); Epothilones: ixabepilone (Ixempra®); Vinca alkaloids: vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®); and Estramustine (Emeyt®). They are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs may cause nerve damage, which can limit the amount that can be given. Corticosteroids
- Corticosteroids often simply called steroids, are natural hormones and hormone-like drugs that are useful in the treatment of many types of cancer, as well as other illnesses. When these drugs are used as part of cancer treatment, they are considered chemotherapy drugs. Examples of corticosteroids include: Prednisone,
- Methylprednisoione Solumedroi ⁇
- Dexamethasone Dexamethasone
- Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories. Examples include drugs like L-asparaginase, which is an enzyme, and the proteosome inhibitor bortezomib (Velcade®).
- a localized cancer is usually found in the tissue or organ where it began, and has not spread to nearby lymph nodes or to other parts of the body, or the spread is limited in scope.
- Non-limiting examples of localized cancers include single-lesion skin cancers, solitary pulmonary nodules (single lung tumor), Adrenal Cancer, Anal Cancer, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain/CNS Tumors In Adults, Brain/CNS Tumors In Children, Breast Cancer, Breast Cancer In Men, Cancer in Adolescents, Cancer in Children, Cancer m Young Adults, Cancer of Unknown Primary, Cast] e an Disease, Cervical Cancer, Colon/Rectum Cancer, Endometrial Cancer, Esophagus Cancer, Ewing Family Of Tumors, Eye Cancer, Gallbladder Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumor (GIST), Gestational Trophoblastic Disease, Hodgkin Disease, Kaposi Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngea!
- localized cancers suitable for treatment by tumescent delivery of a chemotherapy drug include: Pancreatic cancer. Ovarian cancer, Lung cancer. Breast cancer. Liver cancer. Melanoma, Kidney cancer, Colon cancer, as well as discrete metastatic lesions.
- the subcutaneous concentration of the chemotherapy drug achieved is simultaneously: (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery' or oral delivery of the chemotherapy drug.
- the subcutaneous concentration of the chemotherapy drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the chemotherapy drug.
- Biologic drugs generally consist of large organic molecules derived from biological sources. Traditional anticancer chemotherapy drugs are akin to weapons of mass destruction that can damage any living cell. An anticancer chemotherapy drug is only therapeutic if it is more toxic to cancer cells than to healthy cells. In contrast biologic drugs are focused weapons that targets specific pathologic cells or pathologic cellular products. Examples of Biologic drugs include: cytokines, chemokines, growth factors, viral antigens,
- HH enzymes hormones, neurotrophms, antibodies, proteins that target specific genes, antibody to a specific antigen.
- CD Cluster of Differentiation or Classification Determinant
- Lymph node targeted drug delivery of anticancer medications using tumescent infiltration provides a unique mode of drug delivery. Lymphatic vessels specifically absorb large molecules from interstitial tissue spaces and return these large molecules to the systemic circulation via lymph nodes. Tumescent infiltration drug delivery can target metastatic cancer cells within lymph nodes. For example, a large volume of dilute solution of proteinaceous anti-melanoma drugs, if infiltrated into the subcutaneous tissue around the site of a primary melanoma tumor, will be absorbed into the lymph vessels that drain the primary tumor site and deliver the drugs directly to the lymph nodes which might have trapped metastatic melanoma cells, thus preventing further, more wide spread metastases.
- Snake antivenin delivery is another unique application of tumescent infiltration.
- Snake venom contains multiple large proteins, which have both local and systemic effects.
- Antivenin contains antibodies to the venomous proteins.
- Snakebite is painful. Tumescent infiltration of a snake antivenin can, 1) immediately relieve the pain (lidocame effect), dilute the venom decreasing tissue toxicity, neutralize much of the venom at the site of the bite before it is systemical!y absorbed.
- Venom is absorbed via lymphatic vessels. Large molecular antivenin antibodies are also specifically absorbed via lymphatic vessels. Following tumescent infiltration around the site of a snakebite, the antivenin is absorbed into the same lymphatic vessels as the venom. In this fashion, tumescent antivenin can neutralize the venom within lymphatic vessels before the venom reaches the systemic circulation.
- Sepsis is a body's overwhelming and life-threatening response to an infection, which can lead to tissue damage, organ failure, and even death. Patients are given a diagnosis of sepsis when they develop clinical signs of infections or systemic inflammation. Sepsis is not diagnosed based on the location of the infection or by the name of the causative microbe. Physicians draw from a list of signs and symptoms m order to make a diagnosis of sepsis, including abnormalities of body temperature, heart rate, respiratory rate, and white blood cell count. For example, sepsis may be diagnosed in a 72-year-old man with pneumonia, fever, and a high white blood cell count, and in a 3 -month-old with appendicitis, low body temperature, and a low white blood cell count.
- Sepsis is defined as severe when these findings occur in association with signs of organ dysfunction, such as hypoxemia, oliguria, lactic acidosis, elevated liver enzymes, and altered cerebral function. Nearly all victims of severe sepsis require treatment in an intensive care unit for several days or weeks. While most cases of sepsis are associated with disease or injury, many events follow routine, even elective surgery.
- Tumescent drug delivery can achieve a localized reservoir of a drug, which is present at a relatively high concentration in local interstitial tissues. While the high concentration of drug delivered by the tumescent technique is confined to localized tissues targeted, a lower systemic level of the drug can also be atained, originating from the localized reservoir established by tumescent delivery.
- antibiotic or anti-inflammatory agents delivered tumescent can provide ongoing systemic levels of the antibiotic or anti inflammatory agent, which can effectively prevent or treat sepsis in a subject.
- TLAnti can be used to provide anesthesia, hemostasis, and antibiotic prophylaxis during liposuction or other medical procedures.
- Liposuction is a well-known procedure that is disclosed in U.S. Patent Nos. 5,052,999 and 5,472,416, the disclosures of which are incorporated herein in their entirety by reference thereto.
- TLAnti is infiltrated into the subcutaneous fat compartment (“infiltration procedure”) using a small gauge injection cannula, typically beginning at the location that the practitioner expects to be the deepest portion of adipose tissue removal.
- This area is filled with a sufficient quantity of TLAnti so that it becomes saturated and swollen or“tumescent.”
- the operator can recognize whether sufficient TLAnti has been injected during the infiltration procedure if the area appears swollen, pale and relatively cool because of vasoconstriction.
- the removal of adipose tissue can begin through a cannula capable of suctioning fat out of the body and into a reservoir.
- An example of such a procedure albeit one involving standard tumescent anesthesia without the use of TLAnti is described in Jeffrey A. Klein, Tumescent Technique Blogs, DERMATOLOGIC SURGERY, vo!. 21, pp. 449-457, 1995.
- the cannula typically used in such procedures include a tubular needle portion with proximal and distal ends.
- the proximal end of the tubular needle is attached to a hub that is used by the anesthesiologist or surgeon to grasp and hold the cannula during the infiltration procedure.
- the hub is connected to the tubular needle at a first end and has a connector, such as a luer lock, at an opposing second end.
- the connector is, in turn, connected to a fluid source, such as tubing connected to a fluid reservoir containing the TLAnti such as an IV bag.
- the TLAnti enters via the connector.
- the distal end of the cannula is sealed and the TLAnti exits the cannula through a plurality of apertures located proximate of the distal end in a linear, helical, or spiral pattern distributed over the distal 33% to 100% of the tubular needle.
- TLAnti exits the cannula through a plurality of apertures located proximate of the distal end in a linear, helical, or spiral pattern distributed over the distal 33% to 100% of the tubular needle.
- the TLAnti can be withdrawn from the reservoir and injected into the patient manually using a syringe, hand pump or electrical pumping system.
- the TLAnti is injected from the reservoir using a peristaltic pump.
- a peristaltic pump can be found in United States Patent No. 5,236,414, the disclosure of which is incorporated herein m its entirety by reference thereto.
- Another embodiment of a peristaltic pump that can be used with the current disclosure is described m pending U.S. Patent Application Ser. No. 1 1/641,228. Persons skilled in the art will recognize that there are a number of possible mechanisms that can be used to transfer the TLAnti from the reservoir to the subcutaneous fat compartment.
- the same cannula that is used for the removal of adipose tissue can be used for the delivery' of TLAnti.
- the cannula can have two lumens, one for incoming adipose tissue and blood and a second lumen for outgoing TLAnti.
- such cannula can have a single lumen that can be used aiternatingly for the removal of adipose tissue and the injection of TLAnti.
- the practitioner can switch the cannula from a mode wherein incoming adipose tissue and blood is being drawn into the cannula lumen, to an alternative mode wherein TLAnti passes out of the cannula lumen into the subcutaneous fat compartment.
- a switching system can be found in United States Patent No. 4,696,669, the disclosure of which is incorporated herein in its entirety by reference thereto.
- Such embodiments can comprise separate pumping systems, for example, one for incoming tissue and fluid and another for the TLAnti.
- Other embodiments can utilize a single, reversible pumping system.
- An example of this technique, albeit one using standard tumescent anesthesia can be found in United States Patent No. 5,472,416 the disclosures of which are incorporated herein in their entirety by reference thereto.
- TLAnti can be used during mastectomy procedures.
- the surgical excision of breast cancer is associated with a beter prognosis than other therapeutic options such as chemotherapy, immunotherapy, endocrine therapy, or radiation therapy.
- surgery under general anesthesia is associated with significant systemic metabolic, neuroendocrine, and cytokine side-effects which may induce a transient perioperative inhibition of immune function including immune mediated anticancer surveillance thus enabling malignant cells to successfully spread to other parts of the body during the surgical procedure.
- Local anesthesia using the tumescent technique can reduce or prevent the immunosuppressive effects of general anesthesia.
- Lumpectomy and mastectomy are safer when performed by tumescent local anesthesia instead of general anesthesia.
- the tumescent technique also reduces or eliminates the need for postoperative narcotics which can inhibit immune function.
- TLAnti can also help to reduce the risk of metastases by preventing malignant cells from entering the bloodstream through a number of mechanisms.
- the tumescent technique induces profound vasoconstriction, thus providing a physical barrier to malignant cells entering the blood stream and thereby reducing the risk of metastasis to distant organs.
- the use of TLAnti can reduce platelet activation which prevents endothelial wall retraction and reduces the likelihood of cancer cells entering the body.
- the surface of an activated platelet contains newly synthesized bioactive molecules including thromboxane Ai and thrombin. Activated platelets may produce and release products which augment tumor cell survival and decrease the effectiveness of immune surveillance.
- High localized tissue concentrations of tumescent lidocaine inhibit platelet activation and thereby reduce the risk of surgery-precipitated metastasis.
- TLAnti is administered utilizing the Klein infiltration cannula (Klein cannula) described in pending United States Patent Application Ser. No. 11/800,355.
- Klein cannula are sealed on the distal end so that the TLAnti can exit the cannula from a senes of apertures on the side of the cannula.
- This enables the operator to insert the cannula into the target area without the need for the operator to repeatedly push the cannula in and out of the surgical area during the infiltration procedure.
- the procedure can be performed using cannula other than the Klein cannula.
- TLAnti can help to reduce the risk of surgical site infection.
- Some embodiments relate to the tumescent delivery of chemotherapeutic agents.
- Some embodiments relate to the prevention of chronic pain after mastectomy or other surgical procedures by administration of TLAnti to achieve preemptive analgesia and reduce post-surgical pain.
- Use of TLAnti along with a Klein cannula can reduce the risk of chronic pain after mastectomy.
- PMPS Post-mastectomy pain syndrome
- the prevalence rate of PMPS is estimated to be 43%.
- the most important factor associated with chronic pain and phantom pain after mastectomy is the intensity of acute post operative pain. This fact suggests that aggressive management of acute postoperative pain may reduce chronic post-mastectomy pain.
- Preemptive surgical analgesia such as can be achieved by tumescent delivery of local anesthetic
- Preincisional paravertebral block (a form of local anesthesia) reduces the prevalence of chronic pain after mastectomy.
- paravertebral blocks are relatively difficult achieve, require considerable clinical expertise, and are associated with a relatively high risk of systemic local anesthetic toxicity as a result of inadvertent IV injection.
- the tumescent technique is relatively easy to perform with virtually no risk of toxicity associated with tumescent infiltration using a Klein cannula.
- TLAnti can be used in a variety of surgical procedures. When so employed, TLAnti can also reduce the risk of deep vein thrombosis and post-operative thromboembolism. Thromboembolism, a leading cause of perioperative morbidity and mortality, is the direct result of platelet activation by surgical trauma. There is both clinical and experimental evidence that lidocaine can reduce surgical trauma-associated platelet activation and aggregation. For example, in vivo bleeding volume and bleeding time tests show prolonged bleeding after local subcutaneous infiltration of tumescent local anesthesia containing dilute lidocaine, indicating a decrease in platelet activity.
- Blood platelet activation is associated with a degranulation and release of vasoactive and thrombogenic chemical mediators including serotonin and thromboxane- A2, which play a role in acute coronary thrombosis and arrhythmias.
- the lidocaine present in the TLAnti solution can affect platelet function by means of several diverse mechanisms: For example, the release of the phospholipid messenger lysophosphatidate from activated platelets is inhibited by the extracellular application of lidocaine in concentrations injected into surgical wounds.
- iidoeaine may inhibit platelet aggregation by acting on adenosine diphosphate (ADP).
- ADP adenosine diphosphate
- the tumescent drug delivery system in conjunction with tumescent local anesthesia and tumescent antibiotic delivery-, is uniquely able to deliver long-lasting elevated lidocaine concentration to the site of surgical trauma and thereby prevent thromboembolism.
- the tumescent technique is capable of producing sufficient concentrations for lidocaine to achieve its antithrombic effects.
- safe systemic concentrations e.g. ⁇ 6 micrograms/ml
- lidocaine seems to have no effect on platelet aggregation.
- tissue concentrations achieved after infiltration of TLAnti there is a significant inhibition of in-vitro platelet aggregation.
- lidocaine concentrations equal to or greater than 0.5mg/ml.
- concentration of lidocaine in TLAnti typically ranges from 0.4 mg/ml to ! .2mg/ml.
- in-vitro testing of the effect of lidocaine on platelet aggregation has shown that the longer the incubation time with lidocaine, the more efficient the anti-aggregating effect.
- the local tissue vasoconstriction associated with TLAnti impairs systemic absorption of tumescent lidocaine and dramatically prolongs the local tissue concentrations of lidocaine. Tumescent local anesthesia infiltrated into the site of surgical incision produces very high and prolonged local tissue concentrations of lidocaine and can thereby significantly reduce platelet activation and the risk of perioperative thromboembolism.
- thromboembolism is a greater risk with surgery under general anesthesia compared to the same surgery under local anesthesia. For example, comparisons of orthopedic surgical procedures of the knee done under general anesthesia versus procedures done under epidural/spmal regional local anesthesia show that the incidence of pulmonary embolism and deep vein thrombosis associated with the procedure is reduced. Lidocame, a component of the regional local anesthesia used may have contributed to the reduction in thromboembolism observed. Circumstantial evidence also supports the potential role of TLAnti in preventing the occurrence of thromboembolism. When liposuction is performed under general anesthesia, pulmonary embolism is the leading cause of death. However, there have been no reported cases of pulmonary embolism associated with liposuction under tumescent local anesthesia.
- TLAnti may be delivered to the surgical site while the patient is under general anesthesia.
- the higher tissue concentration of lidocame achieved with TLAnti may inhibit platelet function far more effectively than either IV delivery or peripheral nerve block delivery'.
- the preoperative infiltration with of the surgical site with TLAnti enables the lidocaine concentration within surgically traumatized tissues to reach sufficiently high levels for the lidocame to achieve an antithrombic effect.
- TLAnti can reduce the risk of perioperative thromboembolic disease such as deep vein thrombosis (DVT) and pulmonary embolism (PE), while the systemic concentrations of lidocaine remain uniformly well below the toxic threshold.
- lidocaine provided in TLAnti may act synergistical!y with other antibiotics to decrease the risk of surgical site infection.
- Lidocaine is known to affect nerve conduction by inhibiting cell membrane sodium pumps. Not wishing to be bound to a particular theory, it is likely that lidocaine exerts its antibiotic affect through inhibition of trans-membrane ion transport or antibiotic efflux channels.
- lidocaine and other antibiotics such as cefazolin or metronidazole
- MIC minimum inhibitory concentration
- MMC minimum bactericidal concentration
- Time-Kill studies involving methaciilin- ⁇ resistant Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli
- lidocaine Several embodiments relate to methods and compositions for reducing the risk of thromboembolism by oral administration of lidocaine.
- the bioavailability of orally administered lidocame is limited by rapid degradation of lidocaine by cytochrome P450 enzymes.
- cytochrome P450 enzymes Several embodiments described herein relate to methods of reducing the risk of thromboembolism by oral administration of lidocaine in combination with an inhibitor of cytochrome P450 enzymes.
- cytochrome P450 inhibitors include free bases or pharmacologically acceptable salts of: alpha- naphthoflavone, beta-naphthoflavone, apigemn, daralem, beta-myrcene, catechm, 3-phenylpropyl acetate, formononetin, gallic acid, hesperetin, hesperidin, isoquereitrin, lauryl alcohol, luteolm, luteolin-7-glycoside, narigin, nordihydroguaiaretic acid, quercitrin, swertiamarin, terpineol, and trans-cinnamaldehyde.
- Lidocaine and one or more cytochrome P450 inhibitors may be administered simultaneously or sequentially.
- TLAnti can be delivered using a disposable, plastic cannula as described in U.S. Patent Application Ser. No. 1 1 /800,355, the disclosures of which are incorporated herein in their entirety by reference thereto.
- This device provides a method for relatively rapid fluid resuscitation and the administration of anesthesia and antibiotics in situations wherein establishing intravenous (IV) access is not feasible (e.g., in a remote area, an obese patient with poor venous access, burn/trauma victim, unavailable trained medical professional, etc.).
- IV intravenous
- a significant advantage of using the tumescent technique to deliver fluids and medications is that the infiltration procedure is relatively easy to perform.
- tumescent antibiotic solution can be modified by eliminating a vasoconstrictor such as epinephrine, and instead adding a vasodilator such as methyl nieotinate. The resulting systemic absorption and redistribution of TLAnti into the intracellular and intravascular compartments could be life-saving.
- the tumescent technique performed with disposable catheters and TLAnti provides a useful method of administering fluids and medications to patients when establishing an IV line is difficult or impossible. For example, it can be extremely difficult to obtain IV access among patients who are obese, elderly, have a history of IV drug abuse, or with severe dehydration. By contrast, the subcutaneous infiltration of medications using the tumescent technique can often be achieved relatively easily in many such cases. In such cases, the ability to administer IV fluids, anesthetic, and antibiotics through the alternative subcutaneous route can be invaluable and, at times, lifesaving.
- the use of tumescent drug delivery for emergency fluid resuscitation when IV access is not feasible has been previously described in U.S. Patent 7,572,613 the disclosure of which is incorporated herein m their entirety by reference thereto.
- the tumescent technique can also be useful in certain conditions where various aspects of the environment make IV insertion difficult or impractical . Such conditions could include the treatment of wounded soldiers in night-time combat conditions when establishing an IV access in total darkness is nearly impossible and the use of a flash light might attract enemy fire. It could also be useful in low gravity environments, such as on the International Space Station where a normal gravity-fed IV could not function, but injecting medications subcutaneously using the tumescent technique would not be affected. Cannula with pre-mixed dosages of TLAnti could be provided in emergency medical kits for use in such conditions if and when the need arises.
- TISF interstitial space fluid
- Several embodiments described herein relate to a novel method for conducting pharmakinetie measurements of ISF by sequential sampling of tumescent interstitial space fluid (TISF).
- TISF tumescent interstitial space fluid
- Several embodiments relate to a method of conducting pharmakinetie measurements of one or more drugs m ISF comprising obtaining from subcutaneous adipose tissue sequential samples of TISF by hand-held syringe liposuction for a period of time after tumescent delivery of the one or more drugs and measuring the amount of one or more drugs m each sample.
- sequential sampling of TISF is conducted hourly, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, or every ten hours for up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,
- the methods described herein may be used to investigate the absorption pharmacokinetics of antibiotics.
- TISF subcutaneous adipose tissue by hand-held syringe liposuction for a period of time after tumescent delivery of TLAnti solution and measuring the amount of the one or more antibiotics in each sample.
- a sample of TISF is obtained every 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 minutes after TAD.
- a sample of TISF is obtained hourly after TAD.
- a sample of TISF is obtained every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after TAD.
- sequential samples of TISF are obtained for a period of 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, or 68 hours after TAD.
- One embodiment relates to a method of conducting pharmakinetic measurements of one or more antibiotics in ISF comprising obtaining a sample of TiSF hourly for a period of 10 hours after TAD and measuring the amount of one or more antibiotics m each sample.
- the methods described herein may be utilized to measure important pharmacokinetic (PK) metrics for bioavailability of drugs, such as antibiotics, within subcutaneous adipose tissue, such PK metrics including: area under the curve of concentration as a function of time (AUC) and the maximum concentration (Cmax) of the drug.
- PK metrics including: area under the curve of concentration as a function of time (AUC) and the maximum concentration (Cmax) of the drug.
- AUC area under the curve of concentration as a function of time
- Cmax maximum concentration
- the magnitude of the cumulative tissue exposure a tissue over time to a given drug can be measured by determining the AUC of drug concentration within the interstitial fluid (ISF) as a function of time.
- ISF interstitial fluid
- the methods described herein may further be utilized to measure the duration of time that the antibiotic concentration exceeds the minimal inhibitory concentration (MIC) for a specific bacteria (T>MIC).
- the methods described herein may be utilized to evaluate the effectiveness of tumescent drug delivery compared to other modes of delivery.
- the methods described herein may be utilized to evaluate the effectiveness of tumescent antibiotic delivery (TAD) and intravenous antibiotic delivery (IV AD) for preventing surgical site infection (SSI).
- TAD tumescent antibiotic delivery
- IV AD intravenous antibiotic delivery
- TAD is superior to IV AD for preventing SSIs where free[ISF]IVAD ⁇ free[TISF]TAD.
- TAD is superior to IV AD for preventing SSIs where experimental data demonstrates total[Serum]IVAD ⁇ total[TISF]TAD.
- Adit a small round hole in the skin (typically 1 mm, 1.5 mm or 2 mm diameter) made by a skin-biopsy punch, and intended to be an access port for percutaneous entry into the subcutaneous fat by a tumescent infiltration cannula and/or a liposuction cannula.
- Infiltration an injection that causes a fluid to permeate or percolate through pores and/or interstices.
- an infiltration refers to an injection directly into tissue.
- Infusion an injection that pours a fluid into a place or into the lumen of a blood vessel.
- an infusion refers to an intravascular injection
- Injection The action of forcing a fluid, etc. into tissue or cavity, as by means of a syringe, or by some impulsive force.
- Tumescent Technique is a method of subcutaneous drug delivery of large volumes of very dilute solution of a medication together with either a dilute vasoconstrictor such as epinephrine or a dilute vasodilator such a methyl mcotmate in an isotonic solution of crystalloid (e.g.
- physiologic saline, lactated Ringer’s solution, Hartman’s solution infiltrated directly into subcutaneous fat or muscle or along the exterior of a length of vein or other tissue to produce either a vasoconstrictor-induced ver slow' systemic absorption or a vasodilator-induced rapid systemic absorption, as well as direct hydrostatic effect on capillaries, veins, and arterioles.
- the tumescent technique can be used to deliver large volumes of very dilute medication together with dilute epinephrine in isotonic solution of crystalloid (e.g., physiologic saline, lactated Ringer’s solution, Hartman’s solution, etc). Inclusion of a vasoconstrictor in the tumescent solution produces very slow systemic absorption as a result of intense subcutaneous vasoconstriction, as well as direct hydrostatic compression of capillaries and veins.
- Minimum Bactericidal Concentration is the lowest concentration of antibiotic required to kill a particular bacterial isolate in vitro. Antimicrobials are usually regarded as bactericidal if the MBC is no more than four times the MIC.
- Minimum Inhibitory Concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a particular bacterial isolate. Measurements of MIC are used to confirm resistance of microorganisms to an antimicrobial agent and also to monitor the activity of new' antimicrobial agents. Clinically, the minimum inhibitory concentrations may be used not only to determine the amount of antibiotic that the patient will receive but also the type of antibiotic used, which prevents the development of microbial resistance to antimicrobial agents.
- Tumescent drug delivery and synonyms refer to the tumescent technique for delivering a drug into the subcutaneous space.
- tumescent delivery is a process of infiltration of very large volumes of very dilute solutions of therapeutic substances dissolved in a crystalloid solution with either a vasoconstrictor such as epinephrine or a vasodilator such as methyl mcotmate into subcutaneous tissue to the point of producing tumescence of the targeted tissue.
- TLA Tumescent Local Anesthesia
- Tumescent Local Anesthetic Solution is the local anesthetic solution used to produce TLA.
- TLA Solution consists of a 10 to 20 fold dilution of commercially available concentration of lidocaine and epinephrine.
- TLA Solution comprises very dilute lidocaine ⁇ 1 gram/liter) and epinephrine ( ⁇ 1 milligram/liter) with sodium bicarbonate (10 milliequivendings/iiter) in a crystalloid solution such as physiologic saline or lactated Ringer’s solution.
- the volume of TLA Solution infiltrated into the target tissue is so large that the skin and subcutaneous tissue becomes tumescent, in other words swollen and firm.
- the terms“tumescent local antibiotic solution,”“TLAnti solution,” “tumescent antibiotic delivery solution,” or “TAD solution,” may be used interchangeably to refer to a solution comprising an antibiotic component, an anesthetic component, a vasoconstrictor component and a solvent/pharmaceutically acceptable carrier.
- Tumescent, tumescence swollen and firm.
- Tumescent liposuction liposuction performed by local anesthesia using tumescent local anesthesia.
- Tumescent fluid tumescent solution
- dilute solutions of therapeutic substances dissolved in an aqueous solvent, such as crystalloid solution intended for tumescent delivery into subcutaneous tissue.
- Tumescent “drug” the “drug” in the context as an ingredient in a tumescent solution and its pharmacokinetic behavior as a result of the pharmacokinetics of a tumescent solution; for example tumescent lidocaine, tumescent epinephrine, tumescent antibiotic.
- Tumescent Pharmacokinetics The absorption pharmacokinetics (the pharmacologic and physiologic factors associated with the systemic absorption of a drug) after tumescent infiltration of a drug is either dramatically slower with a vasoconstrictor such as epinephrine or dramatically faster with a vasodilator such as methyl nicotinate than the rate of systemic absorption of routine injection of the drug.
- a vasoconstrictor such as epinephrine
- a vasodilator such as methyl nicotinate
- the intense vasoconstriction induced by epinephrine slows the rate of drug absorption into the central circulation and prolongs the local effects of the drug.
- the duration of routine local anesthesia with lidocaine is typically 2 hours; in contrast the duration of tumescent local anesthesia may be 12 to 18 hours or more.
- a similar prolonged effect of tumescent antibiotic infiltration significantly improves the prophylactic effect of preoperative antibiotic therapy in the prevention of surgical site infections.
- the term“[FLUIDjMODE” refers to the concentration of a drug (e.g., an antibiotic) in a specified FLUID, for example, interstitial fluid, blood serum, whole blood, ammotie fluid, aqueous humour, breast milk, cerebrospinal fluid, lymph, peritoneal fluid, pleural fluid, saliva, sweat, mucus, etc., after a specified MODE of drug delivery.
- a drug e.g., an antibiotic
- MODES of drug delivery include, but are not limited to ingestion, topical administration, transmuscosal administration, inhalation, injection, intravenous administration, intrartal administration, intramuscular administration, intraosseous administration, intrathecal administration, intraperitoneal administration, intravesical administration, intravitreal administration, intradermal administration, and tumescent administration.
- ISFJIVAD and [SerurnjIVAD represent the antibiotic concentration in interstitial fluid (ISF) and serum, respectively, after IV AD.
- TISFJTAD and [Serum] TAD refer to the antibiotic concentrations in TISF and serum after TAD.
- bound[FLUID]MODE refers to the concentration of protein bound drug (e.g., antibiotic) in the specified FLUID after delivery by a specified MODE.
- free[FLUID]MODE refers to the concentration of free drug (e.g., antibiotic) (not bound to protein) in the specified FLUID after delivery by a specified MODE.
- pharmacodynamic quantity refers to a quantitative measure of drug effect in terms of drug concentration as a function of time.
- area under the curve (AUC)” and “time to Cmax” refer to pharmacokinetic quantities.
- the term“Cmax” refers to the peak drug (e.g., antibiotic) concentration in a tissue after drug delivery.
- the term“Cmax[FLUID]MQDE” refers to the peak drug (e.g., antibiotic) concentration in a specified FLUID after delivery by a specified MODE.
- T(Cmax) refers to the time from initiation of drug (e.g., antibiotic) delivery to the time when Cmax is achieved.
- T>MIC refers to the length of time during which the drug concentration exceeds the Minimum Inhibitory Concentration (MIC) for a given pathogen.
- T[TISF]TAD>MIC refers to the length of time the antibiotic concentration exceeds the MIC for a given bacteria in Tumescent Interstitial Space Fluid (TISF) after TAD.
- ISF interstitial space fluid
- the term“Tumescent Interstitial Space Fluid (TISF)” refers to a mixture of a small volume of ISF and a larger volume of tumescently-delivered solution, for example, TLA Solution, TLAnti Solution, TAD solution, etc., said mixture resulting from tumescent infiltration. Immediately after tumescent infiltration, TISF is chemically equivalent to the TAD solution.
- the term“Minimum Inhibitory Concentration (MIC)” refers to the lowest concentration of a drug (e.g., an antimicrobial) that wall inhibit the visible growth of a pathogen (e.g., a microorganism) after overnight incubation. MIC is a function of both the pathogen and the drug under consideration.
- the term“area under the curve (AUC)” is a pharmacokinetic term that refers to drug concentration as a function of time following drug delivery. AUC is calculated from the area under the plot of body fluid concentration of drug (not logarithm of the concentration) against time after drug administration. The AUC is of particular use in estimating hioavaiiabihty of drugs, and in estimating total clearance of drugs. Area under the curve (AUC) of drug concentration within blood or tissue as a function of time is a pharmacokinetic metric for measuring the magnitude of the cumulative tissue exposure over time to a given drug. Whenever drug concentration is measured continuously then AUC is
- AUC can be estimated using the trapezoid rule:
- the term“AUC[FLUID]MODE” refers to the AUC of the drug in a specified body FLUID by a specified MODE.
- AUC[ISF]TAD refers to the AUC in interstitial space fluid of the drug administered by tumescent deliver ⁇ '
- AUC [Serum] TAD refers to the AUC in serum of the drug administered by tumescent delivery
- AUC[ISF]IVAD refers to the AUC in interstitial space fluid of the drug administered by IV delivery
- AUC [Serum] TAD refers to the AUC in serum of the drug administered by IV delivery.
- each antibiotic has a characteristic fraction of its total concentration which is bound to proteins. Only free antibiotic molecules interact with bacteria or diffuse across capillary walls between serum and ISF.
- the term“freeAUC[TISF]TAD” refers to the AUC of free (unbound) antibiotic in ISF after TAD.
- the term “totalAUC[Serum]XVAD” refers to the ALIC of total (bound and unbound) antibiotic in Serum after IV AD.
- a fraction of an antibiotic in ISF is protein bound.
- the term“patient” refers to the recipient of a therapeutic treatment and includes all organisms within kingdom animaha. In preferred embodiments, the animal is within the family of mammals, such as humans, bovine, ovine, porcine, feline, buffalo, canine, goat, equine, donkey, deer and primates. The most preferred animal is human.
- the terms “treat” “treating” and “treatment” include “prevent”“preventing” and“prevention” respectively.
- the use of the singular includes the plural unless specifically stated otherwise.
- the use of “or” means“and/or” unless stated otherwise.
- the use of the term“including”, as well as other forms, such as“includes” and“included”, is not limiting.
- terms such as “element” or“component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.
- the use of the term“portion” can include part of a moiety or the entire moiety.
- the term“effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to prevent thromboembolism or infection.
- An effective amount of TLAnti or other tumescent solution may vary according to factors such as the disease state, age, and weight of the subject, and the ability' of TLAnti or other tumescent solution to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of TLAnti or other tumescent solution are outweighed by the therapeutically beneficial effects.
- the language“a prophylactically effective amount” of TLAnti refers to an amount of TLAnti which is effective, upon single or multiple dose administration to the subject, in preventing or treating infection or thromboembolism.
- the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
- the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved.
- an“increase” or“decrease” m a measurement is typically in comparison to a baseline value.
- an increase in time to hospitalization for subjects undergoing treatment may be in comparison to a baseline value of time to hospitalization for subjects that are not undergoing such treatment.
- an increase or decrease in a measurement can be evaluated based on the context m which the term is used.
- TAD was achieved using blunt-tipped Monty infiltration cannula and peristaltic tumescent infiltration pump.
- Treated areas included: abdomen (Patient 1 & Patient 4); female breasts (Patient 2); and hips-outer thighs (Patient 3).
- Patient 4 received Cefazolin and Metronidazole.
- Patient 1 was studied on 3 separate occasions with treatments occurring at least one week apart.
- Patient 1 was treated with: TAD lOOOmg Cefazolin/Tl 1 1ml; TAD 500mg Cefazolin/1061ml; or IVAD l OOOmg Cefazolin.
- the 10 hour Cefazolin AUC and Cmax for TAD (abdomen) and IV AD treatments for Patient 1 are shown in Table 1. Other patients studied gave similar results (not shown).
- subcutaneous tissue fluid AUC for TAD 1000 mg Cefazoiin and TAD 500mg Cefazoiin yielded 15.2 and 7.2 times AUC, respectively, compared to IV AD 1000 mg Cefazoiin (assuming Cefazoiin concentration in subcutaneous tissue after IV AD is less than or equal to the concomitant Cefazoiin concentration in serum).
- TAD yields reduced AUC & Cmax, while prolonging duration of serum Cefazoiin compared to IV AD.
- antibiotic surgical site infection prophylaxis by TAD may be better and have fewer risks compared to the current standard of care, IV AD.
- bactericidal properties of three antimicrobial compounds were evaluated by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration for Staphyloccus aureus (MRS A) ATCC 33592.
- a standardized suspension of Staphyloccus aureus (MRS A) ATCC 33592 was prepared by culturing on tryptic soy agar for 3-5 days at 35° C. The agar slant was washed with sterile phosphate buffer solution and the organism concentration was adjusted. Innoculum levels of Staphyloccus aureus (MRS A) ATCC 33592 w3 ⁇ 4re between 4.4 x ! 0 5 to 4 7 x 1 O' CFlJ/ml.
- Table 8 shows the results of the analysis of the Minimum Bactericidal Concentration (MBC) of Lidoeaine, Cefazolin, and Lidocaine + Cefazolin. Determinations of MBC followed the method described in “Report on the Working Party on Antibiotic Sensitivity Testing of the British Society of Antimicrobial Chemotherapy: A Guide to Sensitivity Testing.”
- MBC Minimum Bactericidal Concentration
- Endpoints were achieved for ail 3 test products, Lidocaine, Cefazoiin, and Lidocaine + Cefazoiin, evaluated in the MIC and MBC study.
- the MIC endpoints are shown in Table 9 and the MBC endpoints are shown in Table 10.
- the results of this evaluation indicate that the MIC for Cefazoiin is between 125 and 250 mg/L, Lidocaine was around 5,000 mg/L and the combination of both Cefazoiin and Lidocaine had an MIC of 100 mg/L.
- a patient presenting with a localized infection characterized by a central abscess and inflammation is treated by tumescent antibiotic delivery to the affected area.
- a solution of 250 mg of cetazoiin (150 mi from a solution consisting of 500 mg of cefazolin), 300 mg iidoeaine. 0.3 mg epinephrine, 3 meq sodium bicarbonate is dissolved in saline to a total volume of 280 ml. The solution is then infiltrated in the area of inflammation. The patient is examined approximately 12-24 hours after infiltration for visible evidence of inflammation and/or redness.
- TLAnti is administered to the subcutaneous compartment of a surgical site in a 70 kg adult patient under general anesthesia. The patient is subsequently monitored for perioperative and postoperative thromboembolism.
- TLAnti is administered to the subcutaneous compartment of a surgical site or site of other injury in a 70 kg adult patient without general anesthesia. The patient is subsequently monitored for perioperative and postoperative thromboembolism.
- TLAnti is administered to the subcutaneous compartment at a site of infection in a 70 kg adult patient without general anesthesia.
- concentrations of the antibiotic component and anesthetic component used in TLAnti for the treatment of infection exceed concentrations considered safe for systemic use.
- the progress of the infection is subsequently monitored in the treated patient.
- a catheter is inserted into the surgical site and the area infiltrated with a tumescent solution.
- the tumescent solution comprising .9% normal saline, 500mg of cefazolin, 500mg Hdocaine 2%, Img epinephrine, and lOmEq bicarbonate. Once sufficient anesthesia is achieved, the surgeon removes cancerous tissue with sufficient margins to ensure complete removal of the tumor. The site can subsequently be closed and dressed.
- TAD Tumescent Antibiotic Delivery
- IV AD IV Antibiotic Delivery
- mice Eighty rats are anesthetized and their backs shaved and cleansed. Groups of 20 rats each are given a 250 mg/kg dose of cefazolin either by subcutaneous tumescent administration (TAD), intraperitoneal injection (IVAD), or a combination of TAD and IVAD 15 to 35 minutes prior to making a 4 cm sterile vertical incision through the skin of the back into the subcutaneous tissue. The incisions are then immediately inoculated with Staphylococcus aureus at concentrations of I Q 2 , I Ok ! 0 4 or ! 0 5 organisms per ml and closed.
- TAD subcutaneous tumescent administration
- IVAD intraperitoneal injection
- Staphylococcus aureus 15 to 35 minutes prior to making a 4 cm sterile vertical incision through the skin of the back into the subcutaneous tissue. The incisions are then immediately inoculated with Staphylococcus aureus at concentrations of I Q 2 , I Ok ! 0 4 or
- one group of 10 rats is untreated prior to undergoing incision and inoculation as described above and one group of 10 rats is given a 250 mg/kg dose of cefazolin by a combination of TAD and IVAD prior to incision, but the incision is closed without inoculation.
- the rats are euthanized and samples of 1 cnr of tissue from the lateral side of the incisions is collected for microbiological assessment.
- the collected tissue is weighed and placed in individual sterile tubes containing 1ml of sterile tryptic soybean broth (TBS).
- TBS sterile tryptic soybean broth
- the tissue is homogenized and four 1 : 10 serial dilutions of each homogenate with 0.5-ml aliquots and diluted with 4.5 ml of sterile TSB: 10 to lO 4 are made.
- Blood agar plates are inoculated with 0.1 mi of each dilution and the plates are incubated at 35 °C for 18 to 24 hours.
- the Duke method of determining bleeding time is used to assess effect of tumescent administration of TLAnti comprising 0.5 mg/ml lidocaine on hemostatic function (platelet response to injury and functional capacity of vasoconstriction).
- TLAnti comprising 0.9% normal saline, 500mg of cefazolin, 500mg lidocame 2%, I mg epinephrine, l OrnEq bicarbonate is infiltrated into the subcutaneous tissue of the left thigh until the skin becomes swollen and taught— tumescent.
- Simultaneous 4 mm deep puncture wounds are made to the same area of the left and right thighs with disposable lancets.
- the puncture sites are blotted with filter paper every 30 seconds, until bleeding stops and the bleeding time for each thigh is recorded.
- the bleeding times of the left and right thigh are compared to determine if administration of TLAnti increases bleeding time. Normal bleeding time measured by the Duke method is 1 to 3 minutes.
- the Center for Disease Control has defined 3 classes of surgical site infection (SSI): 1) Superficial Incisional SSI, an infection involving skin or subcutaneous tissue within 30 days of surgery; 2) Deep Incisional SSI, an infection involving fascia and muscle layers within 30 days after surger without an implant or 1 year if an implant is left in place and the infection appears to be related to the surgery and the incision; and 3) Organ/Space SSI, an infection involving any organ or spaces opened and manipulated during the surgery occurring within 30 days of surgery' without an implant or 1 year if an implant is left m place and the infection appears to be related to the surgery and the infection.
- SSI surgical site infection
- antibiotic concentration profile of the antibiotic depends upon the concentration profile of the antibiotic (magnitude and duration) within the interstitial space fluid (XSF) at the site of potential bacterial contamination.
- antibiotic concentration m ISF depends upon the mode of antibiotic delivery and the total dose of antibiotic.
- the area under the curve of concentration as a function of time (AUC), the maximum concentration (Crnax) and the duration of time that the antibiotic concentration exceeds the AUC for specific bacteria (T > MIC) are important pharmacokinetic (PK) metrics for bioavailability of antibiotics within subcutaneous adipose tissue.
- the mode of antibiotic delivery with the greatest AUC, Cmax and T>MIC in subcutaneous tissue is expected to be the most effective at preventing surgical incision site infections.
- IV AD intravenous antibiotic delivery
- P penetration ratio
- ISF freeAUC[ISF]IVAD/freeAUC[SERUM]IVAD.
- Penetration ratios can be used to compare different drugs or different formulations of the same drug after IV AD.
- Antibiotic penetration ratio varies widely between different patients and between different tissues and is decreased by surgery, diabetes and obesity. For example, the penetration of an antibiotic is quantitatively different after IV AD among obese patients compared to normal patients.
- Peri -incisional or intra-incisionai injection of antibiotics has been found to reduce the risk of SSI compared to IV AD.
- Such techniques for local delivery of antibiotics involve the infiltration of small volumes of antibiotic solution, resulting in a minimal reservoir effect and minimal dispersion into adjacent tissue.
- Antibiotic solutions introduced by peri- incisionaf or intra-incisionai injection which do not contain a vasoconstrictor drug like epinephrine, are rapidly absorbed with rapid decline of antibiotic concentrations within the targeted tissue.
- tumescent antibiotic delivery involves the infiltration of a relatively large volume of an antibiotic- containing solution into the subcutaneous compartment, such that the surrounding tissue becomes swOllen and firm, i.e., tumescent
- a TAD solution comprises one or more antibiotics dissolved in tumescent local anesthesia (TLA), which comprises relatively large volumes of dilute lidocaine ( ⁇ 1 grams/L), epinephrine ( ⁇ 1 milligrams/L), sodium bicarbonate (10 milliequivalents/L) m physiologic saline or lactated Ringer’s solution.
- TLA tumescent local anesthesia
- TAD solution The physical and physiologic effects of infiltrating a TAD solution are identical to the effects of a solution of TLA and include prolonged and profound local anesthesia, extensive local epinephrine- induced capillary and venous constriction for surgical hemostasis, hydrostatic pressure- induced capillary and venous compression, inhibition of incisional-trauma-induced platelet activation and delayed systemic absorption of solution components, for example, lidocaine and antibiotics
- the spread of tumescent fluid within subcutaneous tissue occurs by means of rapid bulk flow through the interstitial gel substance. Efficient infiltration of up to five liters of solution or more into subcutaneous fat may be facilitated by use of specialized infiltration cannulas, peristaltic infiltration pumps and tubing. Equilibration of ISF pressures results in a uniform distribution of tumescent fluid throughout the infiltrated tissues A process of detumescence occurs during 1 to 2 hours following infiltration. The rate of systemic absorption of antibiotics from tumescent subcutaneous tissue is slow as a result of wide spread tumescent vasoconstriction. TAD produces a prolonged large-volume subcutaneous reservoir of an antibiotic solution within a mass of vasoconsticted local tissues.
- Tumescent techniques were developed for local delivery of to enable liposuction to be done totally by local anesthesia.
- Tumescent local anesthesia produces profound surgical local anesthesia persisting for more than 6 to 8 hours with peak serum lidocaine concentrations occurring between 10 to 16 hours after completion of the subcutaneous infiltration.
- 1% or 2% commercial concentrations of lidocaine with epinephrine reliably provide local anesthesia for 2 to 3 hours or less.
- TLA tumescent local anesthesia
- Intravenous antibiotic delivery' may not reliably achieve adequate subcutaneous antibiotic concentrations for prevention of surgical site infections (SSIs).
- Tumescent antimicrobial delivery TAD
- TLA dilute tumescent lidocaine anesthesia
- the primary' aim of this research was to measure eefazolm and metronidazole concentrations as a function of time in subcutaneous interstitial fluid after TAD, in serum after TAD and m serum after IV AD.
- TAD provides uniformly higher subcutaneous antibiotic concentrations compared to IV AD and that the area under the curve (AUC ⁇ ) of the concentration-time profile and the peak concentrations (Cmax) of concomitant TAD+IVAD are superior to IV AD alone for SSI prevention.
- TAD of Igm of cefazolin resulted m AUG» and Cmax in subcutaneous interstitial fluid 16.5 and 5.6 times greater, respectively, than in serum after Igm by TV AD.
- TAD of 500mg of metronidazole resulted in AUC ⁇ and Cmax in TISF that was 8.1 and 24.7 times greater, respectively, than in serum after 500mg by IV AD.
- subcutaneous Cmax is approximately equal to the antibiotic concentration in the TAD solution.
- Slow systemic absorption after subcutaneous infiltration by TAD resulted in serum antibiotic concentration-time profiles that resemble a slow IV infusion. There were no adverse events or evidence of tissue toxicity associated with TAD.
- TAD+IVAD provides superior antibiotic bioavailability in both local subcutaneous tumescent interstitial fluid and serum, suggesting TAD+IVAD might improve SSI prevention.
- tumescent antibiotic deliver alone may be superior to IV drug delivery alone.
- tumescent interstitial fluid ISF
- TISF tumescent interstitial fluid
- TAD is the direct subcutaneous infiltration of antimicrobial drug(s) dissolved in a large volume of a TLA solution.
- a TLA solution consists of lidocaine ( ⁇ I gm), epinephrine ( ⁇ lmg), and sodium bicarbonate (10 mEq) per liter bag of physiologic saline or lactated Ringer’s solution.
- Sodium bicarbonate neutralizes the acidic pH of commercial local anesthetics thereby reducing the stinging-pain associated with subcutaneous infiltration of commercial solutions of lidocaine with epinephrine (McKay W, Morris R, Mushlin P.
- a TLA solution consists of at least a 10-fold dilution of commercial 1% lidocaine with epinephrine 1 : 100,000.
- Cefazoim and metronidazole were selected because they are water soluble and generally safe, effective and economical for prevention of SSIs (Meyer NL, Hosier KV, Scott K, Lipscomb GH.
- 201 1 update endorsed by the Infectious Diseases Society of America and the Surgical Infection Society. J Trauma. 201 1 ;71 (2 Suppl 2): S210-34; Cho MJ, Kurtz RR, Lewis C, Machkovech SM, Houser DJ. Metronidazole phosphate— a water-soluble prodrug for parenteral solutions of metronidazole. J Pharm Sci. 1982;71 :410-4).
- Cefazoim and metronidazole when mixed together in a saline solution for IV delivery, are both chemically stable for at least 72 hours at 8°C (Rivers TE, McBride HA, Trang JM. Stability of cefazolin sodium and metronidazole at 8 degrees C for use as an i.v. admixture. J Parenter Sci Technol. 1993;47: 135-7).
- Diminishing surgical site infections after colorectal surgery with surgical care improvement project is it time to move on? Dis Colon Rectum. 201 1 ; 54:394-400; Serra-Aracil X, Garcia-Dommgo MI, Pares D, Espin-Basany E, Biondo S, Guirao X, Orrego C, Sitges-Serra A. Surgical site infection in elective operations for colorectal cancer after the application of preventive measures. Arch Surg. 2011 ; 146:606- 12; Owens PL, Barrett ML,Raetzman S, Maggard-Gihhons M, Steiner CA. Surgical site infections following ambulatory surgical procedures. JAMA 2014; 31 1 :709-716).
- Anesthesiologists are most frequently responsible for administering perioperative antimicrobial prophylaxis (Sinha B, van Assen S, Friedrich AW. Important issues for perioperative systemic antimicrobial prophylaxis in surgery. Curr Opm Anaesthesiol. 2014;27:377-81 ; Roth JV. More reasons why anesthesiologists should administer preoperative antibiotics. Anesthesiology 2004; 101 :258-259).
- SSI subcutaneous surgical site infections
- IV AD antibiotic penetration from serum into subcutaneous interstitial fluid at a surgical incision site varies widely between different patients and between different tissues and is decreased by diabetes and obesity.
- Surgical incision reduces local subcutaneous antibiotic bioavailability following IVAD as the result of capillary hypotension, vasoconstriction, capillary' thrombosis, tissue edema and tissue desiccation (Kennedy MJ, Van Riji A. Effects of surgery on the pharmacokinetic parameters of drugs.
- TAD is a novel form of drug delivery'.
- TAD has unexpected local and systemic effects. Wide spread subcutaneous vasoconstriction resulting from a large volume of dilute tumescent epinephrine produces in slow' steady systemic absorption of drugs dissolved in the TLA solution, persistent high local tissue concentrations of the drugs, prolonged local anesthesia and reduced surgical blood loss (Klein JA. Tumescent technique for local anesthesia improves safety in large volume liposuction. Plast Reconstr Surg 1993; 92: 1085- 1098).
- the mean inhibitory' concentration (MIC) is an ex-vivo predictor of the susceptibility of a specific strain of bacteria to a specific antibiotic. In-vivo predictors of susceptibility of a specific bacterium to a specified antibiotic within a specified tissue depend on both the MIC as well as antibiotic access to the site of infection. Antibiotic access to the site of infection is measured by the area under the curve (AUC ⁇ ) of a drug’s concentration time profile, the drug’s peak concentration (Cmax) and the length of time that the MIC is exceeded by antibiotic concentration (T>MIC) AUC ⁇ , Cmax and T>MIC depend upon the antibiotic’s pharmacokinetic properties, formulation and mode of delivery. In this research AUCoo is used as the metric for bioavaiiability.
- a second research aim was to determine the correlation between the antibiotic concentration (pg/ml) in a TAD solution and the resulting antibiotic concentration (mg/L) in TISF immediately after TAD. We hypothesized that the respective concentrations are highly correlated and nearly equal.
- a third research aim was 1) to observe the concentration vs time profiles of cefazolin and metronidazole in serum after rapid IV AD and in TISF after TAD, at equal mg doses and equal mg/L concentrations in the TAD solution.
- concentration time profiles of these two drugs are different in serum after IV AD and identical in TISF after TAD.
- a fourth research aim was to document evidence of adverse effects of subcutaneous deliver ⁇ of large volumes of dilute cefazolin, metronidazole, !idocaine and epinephrine. We hypothesize that there would be no evidence of either systemic or local tissue toxicity associated with subcutaneous delivery of these drugs and therefore TAD represents a non-significant risk of harm to patients.
- a fifth research aim was to observe the serum concentration-time profile of the antibiotics after TAD and subsequent systemic absorption. We hypothesize that, following TAD, the slow systemic absorption of the antibiotics from the subcutaneous TISF would produce a serum concentration-time profile of the antibiotics similar to that of a continuous slow IV infusion.
- a sixth aim was to apply the present research results to generate new hypotheses that can be tested in future randomized clinical trials comparing tumescent antimicrobial delivery versus IV antimicrobial deliver ⁇ for surgical site infection prophylaxis or for other clinical applications.
- Eligibility requirements were: good health (ASA I) and good candidate for liposuction, age at least 18, not pregnant, no history of allergy to lidocaine, cefazolin or metronidazole, and good venous access. Exclusion criteria were: current significant health problems, history' or evidence of HIV or Hepatitis C infection and no current use of drugs that block cytochrome P450 3A4 or 1A2 or impair hemostasis.
- IV AD IV antibiotic delivery
- TLA tumescent lidocaine anesthesia
- TAD solution of cefazolin was prepared by withdrawing 10ml of TLA solution and injecting this 10ml into a vial containing lOOOmg of cefazolin powder. The solubilized cefazolin was then re-injected into the TLA solution. Metronidazole for IV delivery is available as 5QQmg in 100ml.
- TAD with metronidazole was prepared by adding 500mg in 100ml to 1 1 10ml of a TLA solution.
- a bag of TAD solution with lOOOmg of cefazolin and 500mg of metronidazole contained 1210ml. In other words the TAD solution contained 826mg/L of cefazolin (1000mg/1210ml), 423mg/L of metronidazole
- TISF aqueous infranate tumescent interstitial fluid
- the research cohort consisted of non-obese healthy adult females, age range 37-64 years. There were 5 separate studies. Each study consisted of 2 to 3 pharmacokinetic procedures involving an individual subject There were a total of 14 pharmacokinetic procedures.
- cefazolin concentrations in the TAD solutions ranged from 225mg/L to 900mg/L.
- metronidazole concentrations in the TAD solutions ranged from 345mg/L or 413mg/L.
- TAD provides prolonged local subcutaneous antibiotic concentrations, prolonged systemic therapeutic concentrations of antibiotics and lidocaine, prolonged local anesthesia for intraoperative and postoperative analgesia, prolonged local vasoconstriction for surgical hemostasis and local tissue hydration to prevent incision site desiccation.
- TAD+IVAD provides a pharmacokinetiea!ly superior AUC ⁇ and Cmax compared to TAD alone or IV AD alone with respect to preventing surgical site infections (SSI).
- TAD alone is pharmacokinetically superior to IV AD alone or TAD+IVAD for preventing SSI while minimizing exposure of the gut microbiota to antibiotics.
- TAD The antibiotic concentration in TISF immediately after TAD is virtually identical to the antibiotic concentration in the TAD solution. TAD can provides a predictable high initial subcutaneous antibiotic concentration at the site of a proposed surgical incision.
- TISF tumescent interstitial fluid
- other drugs for example lidocaine, antiviral, antifungal, or anti-tumor drugs may also demonstrate prolonged high subcutaneous concentrations in TISF after tumescent delivery.
- TAD may provide safe prolonged extraordinary high concentrations of drugs in subcutaneous TISF where similar concentrations in serum following IVAD would result in significant systemic toxicity. In other words, TAD may be able to achieve localized therapeutic results that would be impossible with IVAD.
- Inequality 1 Concentrations of cefazolin and metronidazole in ISF after IV AD are always less than, or equal to, their concentrations in serum after IVAD (Muller M, dela Pena A, Derendorf H Minireview: issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue. Antimicrob Agents Chemother, 2004; 48: 1441— 1453; van Kralingen S, Taks M, Diepstraten J, van de Garde EM, van Dongen EP, Wiezer MJ, van Ramshorst B, Vlaminckx B, Deneer VH, Knibbe CA. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients.
- Inequality 2 Our data show that the concentrations of cefazolin and metronidazole in serum after IVAD are always less than their concentrations in subcutaneous TISF after TAD (within the range of antibiotic concentrations in TAD solution utilized in the present study).
- Inequality 3 Concentrations of cefazolin and metronidazole in ISF after IVAD are always less than the antibiotic concentrations in TISF after TAD.
- Dilute lidocame, epinephrine and sodium bicarbonate are essential components of the TAD solution.
- Dilute epinephrine m a local tumescent antibiotic solution produces delayed systemic absorption of antibiotics, prolonged localized high concentrations of antibiotics, long-lasting local capillary vasoconstriction and incision-site hemostasis.
- Dilute lidocaine eliminates the pain of subcutaneous antibiotic injection.
- lidocaine Systemic administration of lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol-remifentanil-based anaesthesia. Eur J Anaesthesiol. 2010; 27: 41-46). Lidocaine is has bactericidal effects (Sakuragi T, ishino H, Dan K. Bactericidal activity of clinically used local anesthetics on Staphylococcus aureus. Reg Anesth. 21 : 239-42, 1996; Parr AM, Zoutman DE, Davidson JS. Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection. Ann Plast Surg.
- IV AD provides approximately 160 (10 x 16) times less subcutaneous bioavailability (of cefoxitin or cefazoim) than does TAD for a significant proportion of patients. Note that TAD produces such an extreme dilution of subcutaneous interstitial fluid that essentially all antibiotic in TISF can be regarded as unbound protein-free.
- TAD tumescent antibiotic delivery
- Table 16A Cefazolin, Abdomen Table 16B. Metronidazole, Abdomen
- Table 17 Dose, concentration and volumes of cefazo!in, lidocaine in the TAD solutions.
- Table 18 Dose, concentration and volumes of cefazoiin, metronidazole, lidocaine in the tumescent antimicrobial delivery (TAD) solutions and by intravenous antimicrobial delivery' (IVAD).
- Subcutaneous TI of Acyclovir (lgm acyclovir in 1130ml of tumescent lidocaine solution) resulted in: 1) no stinging upon injection, 2) no ecchymosis and 3) no local tenderness upon palpation in 6 of 6 subjects.
- Subcutaneous TI of Gentamicin (80mg in 1110ml of tumescent lidocaine solution) resulted in: 1) no stinging upon in j ection but with 9 to 12 hours of transient erythema and edema, 2) no ecchymosis and 3) no local tenderness upon palpation in 6 of 6 subjects.
- Bacteriostatic saline 1% benzyl alcohol
- Bacteriostatic saline is commonly used as a vehicle for intradermal and subcutaneous drug injections. It is known that 1% benzoyl alcohol is bacteriostatic and provides brief (30 seconds) of local anesthesia. It is not well recognized that 1% benzoyl causes relatively intense subcutaneous inflammation, ecchymosis and prolonged tenderness.
- NP chronic neuropathic pain
- TLA Tumescent lidocaine anesthesia
- Precipitating factors for NP typically involve intense pain, or traumatic and inflammatory damage to peripheral nerves. (Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain; risk factors and prevention. Lancet. 2006; 367: 1618-25).
- TLA provides local (peripheral nervous system) anesthetic effects by eliminating painful sensor ⁇ neural stimuli and acting as a potent local anti-inflammatory.
- TLA concomitantly provides distant (central nervous system) effects as a result of slow steady systemic lidocaine absorption from tumescent subcutaneous tissues.
- TLA provides preoperative intraoperative and prolonged postoperative local anesthesia all of which are important to treating postoperative pain.
- TLA provides potent anti-inflammatory effects on immune cells and molecules involved in the pathophysiology of peripheral neuropathic pain.
- TLA can attenuate the severity of neuropathic pain (traumatic wounds) and traumatic neural damage (spinal cord injury) by simultaneously treating the local (direct) inflammatory damage to peripheral sensory nerves and treating distant (central) neural inflammation.
- Macrophages comprise the most important cellular component in inflammation-mediated neuropathic pain. (Thacker MA, Clark AK, Marchand F, McMahon SB. Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg. 2007; 105: 838-47).
- Lidocaine inhibits macrophage function and inhibits macrophage mediated inflammation.
- Inhibition of toll-like receptor-4, nuclear factor-kappaB and mitogen-activated protein kinase by iignocaine may involve voltage-sensitive sodium channels.
- IV lidocaine for palliative care of opioid-refractory cancer pain with a neuropathic component is an effective therapeutic option. Tumescent infiltration of lidocaine is uniquely effective in providing both local anesthesia and systemic analgesia.
- Tumescent Lidocaine Anesthesia produces both long lasting local anesthesia and prolonged slow systemic lidocaine absorption with serum lidocaine concentrations ranging from 1 to 4pg/ml.
- serum lidocaine concentrations ranging from 1 to 4pg/ml.
- systemic lidocaine absorption following TLA is clinically equivalent to a slow continuous IV infusion.
- IV lidocaine infusion produces effective perioperative analgesia.
- IV lidocaine provides effective postoperative analgesia after laparoscopic cholecystectomy.
- Ram D Sistla SC, Karthikeyan VS, Ali SM, Badhe AS, Mahalakshmy T. Comparison of intravenous and intraperitoneal Iignocaine for pain relief following laparoscopic cholecystectomy: a double-blind, randomized, clinical trial. Surg Endosc. 2014; 28: 1291-7).
- IV lidocaine significantly improves postoperative pain after complex spine surgery ' .
- Drag E Ghobrial M, Sessler DI, Dalton JE, Liu I, Lee JH, Zaky S, Benzel E, Bingaman W, Kurz A. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery'. Anesthesiology. 2013; 119: 932-40).
- lidocaine improves preoperative and intraoperative analgesia and reduces surgery-induced immune alterations.
- Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H The effect of perioperative intravenous lidocaine on postoperative pain and immune function Anesth Analg. 2009; 109: 1464-9)
- Serum lidocaine concentrations of 2 to 5 micrograms/ml are effective following subcutaneous infiltration of lidocaine for treatment of cancer neuropathic pain.
- IV Lidocaine provided complete analgesia for neuropathic pain at a mean serum lidocaine concentration of 3.79 ⁇ 1.00 pg/ml. (Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. The analgesic response to intravenous lidocaine in the treatment of neuropathic pam. Anesth Analg. 1996; 82: 91-7).
- Tumescent Infiltration prevents systemic inflammation and sepsis.
- Tumescent infiltration of lidocaine combined with tumescent antibiotics has potent any inflammatory effects.
- Lidocaine has long been known to have significant anti-inflammatory properties.
- Tumescent infiltration (TI) antibiotic delivery has the potential to significantly reduce the risk of sepsis and inappropriate systemic inflammatory response including organ failure and adult respiratory distress syndrome (ARDS).
- ARDS adult respiratory distress syndrome
- TLA delivers interstitial lidocaine concentrations (1000pg/ml) that are nearly 200 times greater than clinically safe serum lidocaine concentrations ( ⁇ 5 pg/ml).
- TLA provides very high concentrations of subcutaneous lidocaine throughout a large volume of tissue at the site of a surgical incision and thus profoundly inhibits local platelet activation, neutrophil priming, platelet-leukocyte aggregation (PLA) and endothelial-platelet and endothelial-leukocyte inflammatory interactions.
- TLA prevents the contents of cells that have been ruptured by infection, surgeiy, or trauma, including bum or combat injury, from flooding the systemic circulation and precipitating an excessive inflammatory response.
- Lidocaine can reduce a systemic inflammatory response.
- Tumescent antibiotic delivery provides local interstitial antibiotic bioavailability that can be 10 to 100 times grater than that provided by IV antibiotic delivery'. Tims TAD is more effective than IV delivery for preventing of surgical site infections and treating localized life-threatening cutaneous infections (e.g. cellulitis in a diabetic or necrotizing soft tissue infections in a traumatic combat injury), both of which are commonly associated with sepsis.
- ⁇ antibiotic delivery produces a concentration-time profile that resembles that of a prolonged slow constant IV antibiotic infusion.
- Seram antibiotic concentrations persist far longer following II antibiotic delivery than after a single rapid IV infusion of antibiotics.
- T! antibiotic delivery by itself or II + IV antibiotic delivery' can achieve more effective systemic effects and better reduce the risk of sepsis than IV delivery alone.
- Lidocaine reduces platelet activation, platelet aggregation and platelet- leukocyte aggregation in a concentration-dependent fashion. Recent evidence suggests there is a critical connection between infection, ceil damage, inflammation and coagulation.
- Intracellular contents which are known to be potent triggers of systemic inflammation and thrombosis include mitochondria cell free DMA, chromatin DNA-histone complexes, extracellular RNA, neutrophil extracellular traps (NETs), polyphosphates secreted from platelet dense granules, and leukocyte contents.
- mitochondria cell free DMA mitochondria cell free DMA
- chromatin DNA-histone complexes extracellular RNA
- neutrophil extracellular traps (NETs) polyphosphates secreted from platelet dense granules
- leukocyte contents include mitochondria cell free DMA, chromatin DNA-histone complexes, extracellular RNA, neutrophil extracellular traps (NETs), polyphosphates secreted from platelet dense granules, and leukocyte contents.
- NETs neutrophil extracellular traps
- lidocaine Slow' constant IV infusion of lidocaine may decrease the inappropriate leukocyte activation, transmigration across capillary endothelium, interstitial positioning, and recruitment during sepsis.
- Lidocaine inhibits platelet activation, platelet activation of neutrophils and neutrophil mediated inflammation. Inappropriate activation of neutrophils contributes to tissue damage during inflammatory diseases.
- tumescence delays the systemic absorption of lidocaine and antibiotics
- the physical isolation produced by tumescent infiltration can delay the systemic absorption of intracellular contents and prevent an excessively rapid systemic exposure to these inflammatory and thrombogenic molecules.
- Lidocaine priming reduces ADP-induced P-seleetin expression and platelet-leukocyte aggregation. Acta Anaesthesiol Taiwan. 47:56-61,2009; Futosi Kl, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways hit Immunopharmacol. 2013;17:638-50; Berger C, Rossaint J, Van Aken H, Westphal M, Hahnenkamp K, Zarbock A.
- Lidocaine reduces neutrophil recruitment by abolishing chemokine-induced arrest and transendothelial migration in septic patients.
- Lidocaine Reduces Neutrophil Recruitment by Abolishing Chemokine-induced Arrest and Transendothelial Migration in Septic Patients. J Immunology , 2014;192:367-376; Kawasaki C, Kawasaki T, Ogata M, Sata T, Chaudry ⁇ H.
- Lidocaine enhances apoptosis and suppresses mitochondrial functions of human neutrophils in vitro. J Trauma.
- lidocaine on in vitro neutrophil and endothelial adhesion molecule expression induced by plasma obtained during tourniquet- induced ischaemia and reperfusion.
- Lidocaine attenuates cytokine-induced cell injury in endothelial and vascular smooth muscle cells.
- NETs Neutrophil extracellular traps
- Platelet TLK4 activates NETs to ensnare bacteria in septic blood (Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen- Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P.
- Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463-9; Sun H, Wang X, Degen JL, Ginsburg D.
- IL-10 Interleukin- 10
- Lidoeaine increases the anti-inflammatory cytokine IL-10 following mechanical ventilation in healthy mice. Acta Anaesthesiol Seand. 2015; 59: 47-55).
- lidoeaine 100-fold higher than safe serum lidoeaine concentrations ( ⁇ 5pg/mi) effectively reduced reactive oxygen species (ROS) production by human neutrophils.
- Therapeutic serum lidoeaine concentrations have no effect on ROS.
- Concentration of lidoeaine in TLA solution and peak lidoeaine concentrations in tumescent subcutaneous interstitial fluid is between SOOpg/mi and 1000pg/ml (Mikawa K, Akamatsu H, Nishina K, Shiga M, Maekawa N, Obara H, Niwa Y. Inhibitory effect of local anaesthetics on reactive oxygen species production by human neutrophils. Acta Anaesthesiol Scand. 1997; 41: 524-8).
- Pretreatment with intravenous lidoeaine attenuates the inflammatory lung injury induced by the pancreatic enzymes or hydrochloric acid (Kiyonari Y, Nishina K, Mikawa K, Maekawa N, Obara H. Lidoeaine attenuates acute lung injury induced by a combination of phospholipase A2 and trypsin. Crit Care Med. 2000; 28: 484-489; Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, Obara H. Intravenous lidoeaine attenuates acute lung injury induced by hydrochloric acid aspiration in rabbits. Anesthesiology. 1998; 88: 1300-9).
- phrases“at least one of’ is intended to require at least one item from the subsequent listing, not one type of each item from each item in the subsequent listing.
- “at least one of A, B, and C” can include A, B, C, A and B, A and C, B and C, or A, B, and C.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/264,440 US11241412B2 (en) | 2015-10-12 | 2019-01-31 | Tumescent infiltration drug delivery of cannabinoids |
PCT/US2020/015963 WO2020160328A1 (en) | 2019-01-31 | 2020-01-30 | Tumescent infiltration drug delivery of cannabinoids |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3917507A1 true EP3917507A1 (en) | 2021-12-08 |
EP3917507A4 EP3917507A4 (en) | 2022-11-09 |
Family
ID=71840463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20747957.7A Pending EP3917507A4 (en) | 2019-01-31 | 2020-01-30 | Tumescent infiltration drug delivery of cannabinoids |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP3917507A4 (en) |
WO (1) | WO2020160328A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11696890B2 (en) | 2015-10-12 | 2023-07-11 | Hk Pharma | Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3090743A1 (en) * | 2008-01-09 | 2016-11-09 | Charleston Laboratories, Inc. | Pharmaceutical compositions for treating headache and eliminating nausea |
BRPI1007812B1 (en) * | 2009-03-02 | 2017-09-26 | Doris Maria Hexsel | MEDICAL COSMETIC LIPOATROPHY |
US8957060B2 (en) * | 2009-11-30 | 2015-02-17 | Jeffrey Alan KLEIN | Tumescent antibiotic solution |
WO2013009928A1 (en) * | 2011-07-11 | 2013-01-17 | Organic Medical Research | Cannabinoid formulations |
US10493024B2 (en) * | 2015-10-12 | 2019-12-03 | Hk Tumescent Pharma Corporation | Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity |
US11389396B2 (en) * | 2016-10-28 | 2022-07-19 | The Regents Of The University Of California | Tumescent antibiotic injection for treatment of chronic skin and soft tissue infections |
-
2020
- 2020-01-30 WO PCT/US2020/015963 patent/WO2020160328A1/en unknown
- 2020-01-30 EP EP20747957.7A patent/EP3917507A4/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11696890B2 (en) | 2015-10-12 | 2023-07-11 | Hk Pharma | Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity |
US11723859B2 (en) | 2015-10-12 | 2023-08-15 | Hk Pharma | Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity |
Also Published As
Publication number | Publication date |
---|---|
WO2020160328A1 (en) | 2020-08-06 |
EP3917507A4 (en) | 2022-11-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11723859B2 (en) | Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity | |
US10322083B2 (en) | Tumescent drug delivery | |
US20220160677A1 (en) | Tumescent infiltration drug delivery of cannabinoids | |
Ware et al. | Disseminated sporotrichosis with extensive cutaneous involvement in a patient with AIDS | |
RU2667974C2 (en) | Pharmaceutical combined composition for local and external use on basis of dioxidine | |
CN109152780B (en) | CXCR-2 inhibitors for the treatment of crystalline joint disorders | |
US10660865B2 (en) | Cannabidiol for the prevention and treatment of graft-versus-host disease | |
RU2655808C2 (en) | Pharmaceutical combined composition for local and external use on basis of bacteriolytic and proteolytic complex of enzymes | |
EP3917507A1 (en) | Tumescent infiltration drug delivery of cannabinoids | |
US11213481B2 (en) | Tumescent drug delivery | |
WO2014205159A1 (en) | Poloxamer based inhalation composition | |
RU2682171C2 (en) | Pharmaceutical combined composition for the treatment of purulent wounds on the basis of fluoroquinolons (options) | |
CN109562098A (en) | Treatment causes PLA2 the and HMG-COA inhibitor of the pathological state of haemolysis, the cerebrovascular and acute kidney injury | |
US20240148776A1 (en) | Tumescent solution with b vitamins | |
Park et al. | Atraumatic compartment syndrome: a manifestation of toxic shock and infectious pyomyositis in a child: a case report | |
CN111356453A (en) | Methods of intravenously administering meloxicam preoperatively and in combination with other drugs | |
Kartal et al. | Nicolau syndrome: a rare complication of injection that should be kept in mind | |
WO2012091629A1 (en) | Use of a lysate of actinomycetins for the preparation of external treatment agents for acne and method for treating acne | |
US20240082294A1 (en) | Cancer treatment regimen using anti-parasitic compounds and gut microbiome modulating agents | |
WO2024178350A1 (en) | Methods of treating sepsis using poly(lactic acid) nanoparticles | |
Stewart | Clostridial myositis and collapse in a standardbred filly | |
Khattak et al. | Efficacy of Post Operative Intra-peritoneal instillation of Rupivicaine as an Analgesic in Patients with Laproscopic Cholecystectomy. | |
Tremblay | Ciprofloxacin/meropenem | |
Buchbinder et al. | Arthrographic distension with saline and steroid reduced pain and disability and improved range of motion in the short term in patients with painful stiff shoulder | |
Bohanon | Septic arthritis in foals. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20210826 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40066815 Country of ref document: HK |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20221010 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 23/02 20060101ALI20221004BHEP Ipc: A61K 31/522 20060101ALI20221004BHEP Ipc: A61K 31/352 20060101ALI20221004BHEP Ipc: A61K 31/137 20060101AFI20221004BHEP |
|
RAP3 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: HK TUMESCENT PHARMA |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20240731 |