CN108126201A - Enterobacteriaceae antibiotic is preparing the application in preventing Chemotherapy Complications drug - Google Patents
Enterobacteriaceae antibiotic is preparing the application in preventing Chemotherapy Complications drug Download PDFInfo
- Publication number
- CN108126201A CN108126201A CN201810082878.2A CN201810082878A CN108126201A CN 108126201 A CN108126201 A CN 108126201A CN 201810082878 A CN201810082878 A CN 201810082878A CN 108126201 A CN108126201 A CN 108126201A
- Authority
- CN
- China
- Prior art keywords
- antibiotic
- enterobacteriaceae
- chemotherapeutics
- drug
- damage
- 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.)
- Granted
Links
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 50
- 241000588921 Enterobacteriaceae Species 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title claims abstract description 32
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 29
- 229940079593 drug Drugs 0.000 title claims abstract description 23
- 241000894006 Bacteria Species 0.000 claims abstract description 20
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 15
- 230000009885 systemic effect Effects 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 229960001699 ofloxacin Drugs 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 6
- 229960002949 fluorouracil Drugs 0.000 claims description 6
- 229960000575 trastuzumab Drugs 0.000 claims description 5
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- -1 Trastuzumab Substances 0.000 claims description 4
- 229960001433 erlotinib Drugs 0.000 claims description 4
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229960004821 amikacin Drugs 0.000 claims 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 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 239000002285 corn oil Substances 0.000 claims description 3
- 235000005687 corn oil Nutrition 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 229960000723 ampicillin Drugs 0.000 claims 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 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 230000006378 damage Effects 0.000 abstract description 16
- 239000002158 endotoxin Substances 0.000 abstract description 13
- 206010061218 Inflammation Diseases 0.000 abstract description 9
- 230000004054 inflammatory process Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 210000004347 intestinal mucosa Anatomy 0.000 abstract description 6
- 210000001519 tissue Anatomy 0.000 abstract description 4
- 230000008485 antagonism Effects 0.000 abstract description 3
- 244000052616 bacterial pathogen Species 0.000 abstract description 3
- 230000017531 blood circulation Effects 0.000 abstract description 3
- 230000008520 organization Effects 0.000 abstract description 3
- 230000000451 tissue damage Effects 0.000 abstract description 3
- 231100000827 tissue damage Toxicity 0.000 abstract description 3
- 230000000968 intestinal effect Effects 0.000 abstract description 2
- 230000000813 microbial effect Effects 0.000 abstract description 2
- 239000003053 toxin Substances 0.000 abstract description 2
- 231100000765 toxin Toxicity 0.000 abstract description 2
- 239000000304 virulence factor Substances 0.000 abstract description 2
- 230000007923 virulence factor Effects 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract 1
- 229940126586 small molecule drug Drugs 0.000 abstract 1
- 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 22
- 229930182566 Gentamicin Natural products 0.000 description 22
- 229960002518 gentamicin Drugs 0.000 description 22
- 230000006872 improvement Effects 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 13
- 210000002966 serum Anatomy 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000020670 canker sore Diseases 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588724 Escherichia coli 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
- 241000282326 Felis catus Species 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-butylamine Natural products CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 210000004953 colonic tissue Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 231100000284 endotoxic Toxicity 0.000 description 1
- 230000002346 endotoxic effect Effects 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940095970 imodium Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class 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
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 229910021647 smectite Inorganic materials 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- 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 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses enterobacteriaceae antibiotic and is preparing the application in preventing Chemotherapy Complications drug, enteron aisle Gram-negative bacteria antibiotic can remove the flora of main gram negative bacilli in enteron aisle, after chemotherapeutics causes intestinal mucosa to damage, it is grown because no enterobacteriaceae enters blood circulation, proliferation, so as to reduce the release of a large amount of toxin and inflammatory factor, the nonspecific inflammatory reaction of antagonism, inhibit and block virulence factor to the damage in loop organization cell, eliminate local inflammation reaction, so as to the side effect of reduce inflammation reaction and chemotherapeutics, this has unexpected prevention effect to slowing down damage.The present invention inhibits microbial bacteria to discharge endotoxin and inflammatory factor in the intestinal tissue of damage, activates systemic tissue damage by giving the preparation containing antibiotic；Meanwhile antibiotic used in the present invention is small-molecule drug, is easily obtained, cheap, property is stablized, convenient for storage and transport.
Description
Technical field
The present invention relates to a kind of enterobacteriaceae antibiotic to prepare the application in preventing Chemotherapy Complications drug, specifically
A kind of enteron aisle Gram-negative bacteria antibiotic is prepared in the Systemic inflammatory syndrome drug that prevention chemotherapeutics causes
Using belonging to biomedicine technical field.
Background technology
Malignant tumour is one of common disease of serious threat human health.At present, about the research of tumour obtained compared with
Big progress, with the continuous application released with various combined chemotherapies of antitumor drug, the life cycle of malignant tumor patient obtains
To extend, but there are limitations for various drugs and therapy, are extremely difficult to ideal effect, and drug resistance and secondary work easily occur
With.Wherein most commonly seen with bone marrow suppression and gastrointestinal reaction, it is early stage impaired tissue that this, which is primarily due to alimentary canal mucous membrane,
One of, therefore Function of intestinal mucosa, structural integrity is maintained also to become the research hotspot for preventing side effects of chemotherapy.
One important and common complication of antineoplaston, almost all of chemotherapeutic have the potential that cause is spat, and change
It treats drug and easily causes stomatitis, canker sore, esophagitis.The drug for most often causing mucositis is methopterin, antibiotics
And fluorouracil, it treats based on suiting the medicine to the illness, as canker sore pain can be relieved the pain with part.Chemotherapeutics also often causes diarrhea,
Apparent diarrhea can give the intestinal mucosas protective agent such as imodium, dioctahedral smectite；Temporary fasting when necessary and application antibiotic prevent intestines
Road infects, so that intestinal mucosa restores normal.
Most of enterobacteriaceaes belong to Gram-negative bacteria, they can generate endotoxin, cause a disease by endotoxin.Common leather is blue
Family name's negative bacterium have shigella dysenteriae, typhoid bacillus, Escherichia coli, proteus, Pseudomonas aeruginosa, Bordetella pertussis, comma bacillus and
Diplococcus meningitidis etc..The antibiotic of main anti-Gram-negative bacteria includes aminoglycoside, rifomycins and polymyxin
Deng mechanism of action also differs, for example, aminoglycoside antibiotics can be combined with the ribosomes of bacterium, so as to interfere bacterium egg
White matter building-up process has powerful antibacterial activity to gram negative bacilli.
Current clinically common enteron aisle Gram-negative bacteria antibiosis is known as streptomysin, gentamicin, kanamycins, butylamine
Kanamycins, tobramycin etc..Systemic inflammatory syndrome (SIRS) is mainly passed through by bacterium infection in blood circulation
Endotoxin is discharged, activates systemic inflammatory reaction caused by inflammatory factor.
Invention content
In view of the above existing problems in the prior art, the present invention provides a kind of enterobacteriaceae antibiotic to prepare prevention chemotherapy simultaneously
The application in disease drug is sent out, can effectively prevent Systemic inflammatory syndrome caused by chemotherapy.
To achieve these goals, the enterobacteriaceae antibiotic that the present invention uses is in prevention Chemotherapy Complications drug is prepared
Using.
As an improvement, the enterobacteriaceae antibiotic is specially enteron aisle Gram-negative bacteria antibiotic.
As an improvement, the enteron aisle Gram-negative bacteria antibiotic using gentamicin, lavo-ofloxacin, ampicillin,
Any one of Amikacin or several mixing.
As an improvement, the Chemotherapy Complications are specially the Systemic inflammatory syndrome that chemotherapeutics causes.
As an improvement, the chemotherapeutics is cis-platinum, 5-Fluorouracil, camptothecine, taxol, Trastuzumab, sieve in distress replace
Any one of Buddhist nun, IL-12, CART, PD-1 or several mixing.
As an improvement, the prevention Chemotherapy Complications drug is using enterobacteriaceae antibiotic as active constituent, in addition water-soluble
The medicament that property organic carrier is prepared.
As an improvement, the water-soluble organic carrier is using any one of dextrin, corn oil or dimethyl sulfoxide (DMSO).
As an improvement, the medicament is oral preparation or ejection preparation.
As an improvement, the dosage of the enterobacteriaceae antibiotic is 0.05g/kg-10g/kg, it is administered daily.
As a further improvement, the dosage of the enterobacteriaceae antibiotic is 0.5g/kg-10g/kg, is administered daily.
The principle of the present invention is：Enteron aisle Gram-negative bacteria antibiotic can remove main gram negative bacilli in enteron aisle
Flora, when chemotherapeutics cause intestinal mucosa damage after, grown, be proliferated because no enterobacteriaceae enters blood circulation, from
And reduce the release of a large amount of toxin and inflammatory factor, the nonspecific inflammatory reaction of antagonism, inhibit and block virulence factor to
Local inflammation reaction is eliminated in the damage of loop organization cell, and so as to the side effect of reduce inflammation reaction and chemotherapeutics, this is right
Slowing down damage has unexpected prevention effect.
Compared with prior art, the present invention inhibits microbial bacteria in the intestines of damage by giving the preparation containing antibiotic
Endotoxin and inflammatory factor are discharged in tissue, activates systemic tissue damage；Meanwhile antibiotic used in the present invention is small point
Sub- drug, is easily obtained, cheap, and property is stablized, and convenient for storage and transport, is preventing and treating group caused by chemotherapeutics
Knitting has very important clinical value in damage.
Description of the drawings
The content that Fig. 1 is TNF-a in chemotherapy animal blood serum in the embodiment of the present invention；
Fig. 2 is chemotherapy animal intestinal tract mucosa injury schematic diagram in the embodiment of the present invention.
Specific embodiment
Understand to make the object, technical solutions and advantages of the present invention clearer, it is right below by attached drawing and embodiment
The present invention is further elaborated.However, it should be understood that specific embodiment described herein is only used to explain this hair
Range that is bright, being not intended to restrict the invention.
Unless otherwise defined, all technical terms and scientific terms used herein are led with belonging to the technology of the present invention
The normally understood meaning of technical staff in domain is identical, and used term is intended merely to retouch in the description of the invention herein
State the purpose of specific embodiment, it is not intended that in the limitation present invention.
Enterobacteriaceae antibiotic provided by the invention is preparing the application in preventing Chemotherapy Complications drug.
As an improvement, the enterobacteriaceae antibiotic is specially enteron aisle Gram-negative bacteria antibiotic.
As a further improvement, the enteron aisle Gram-negative bacteria antibiotic is using gentamicin, lavo-ofloxacin, ammonia
Any one of benzyl XiLin, Amikacin or several mixing.It is micro- by the way that after the pretreatments such as gentamicin enteron aisle can be removed
Biology, slow down as the release of endotoxin and inflammatory mediator that chemotherapeutics causes and caused by extensive tissue damage, therefore, can be with
This kind of antibiotic is prepared into tolerance dose, the systemic inflammatory damage caused applied to prevention chemotherapeutics.
As an improvement, the Chemotherapy Complications are specially the Systemic inflammatory syndrome that chemotherapeutics causes.
As an improvement, the chemotherapeutics is cis-platinum (25mg/kg), and 5-Fluorouracil (10mg/kg), camptothecine (10mg/
Kg), taxol (20mg/kg), Trastuzumab (15mg/kg), Erlotinib (150mg/kg), IL-12 (100 μ l, 0.5 μ g/ of injection
Ml), (it is 6 × 10 that left dorsal subcutaneous is inoculated with 100 μ l sums to CART6CART cells), PD-1 (15mg/kg).Chemotherapeutics draws
The malignant tumour for playing damage includes liver cancer, oophoroma, cancer of the esophagus, lymph cancer, malignant mela noma, cancer of pancreas and breast cancer etc..
As an improvement, the prevention Chemotherapy Complications drug is using enterobacteriaceae antibiotic as active constituent, in addition water-soluble
The medicament that property organic carrier is prepared.
As an improvement, the water-soluble organic carrier is using any one of dextrin, corn oil or dimethyl sulfoxide (DMSO).
As an improvement, the medicament is oral preparation or ejection preparation.Antibiotic medicine in the present invention can pass through mouth
The mode of chamber, vein, abdominal cavity or other any active materials that can convey effective dose is administered.
As an improvement, the enterobacteriaceae antibiotic is administered daily dosage as 0.05g/kg-10g/kg.As further
It improves, the enterobacteriaceae antibiotic is administered daily dosage as 0.5g/kg-10g/kg.Suitable dosage refers to obtain required
The dosage for the final quantity wanted.And different dosage may also be needed by treating different diseases.The effective quantity of antibiotic in the present invention
It is the amount that can make chemotherapeutics that the degree of damage be caused to be substantially reduced.Researcher with routine techniques will determine this item
The most effective dosage of drug in invention and time consider administering mode, and drug metabolism and some other medicine generation are dynamic
Mechanics parameter such as drug distribution, clearance rate etc..
The present invention is by observing enterobacteriaceae antibiotic to toxicity such as function of organization's damages caused by large dosage of antitumor drug
The antagonism of reaction carries out illustration.Antitumor drug is divided into three classes by mechanism of action employed in the present invention：(i) Cytotoxic drugs
Object：Cis-platinum, 5-Fluorouracil, camptothecine, taxol；(ii) molecular targeted agents：Trastuzumab, Erlotinib；(iii) it is immunized and controls
Treat drug：IL-12, CART, PD-1.
ICR experiment mices of the present invention, for simulating main disease of the mankind to the confrontation research of chemotherapeutics toxicity
Reason process.Animal herein includes but not limited to mouse, rat, and performing animal includes but not limited to cat, dog and some other
Animal is such as, but not limited to ox, sheep, pig, horse, and primate is such as, but not limited to monkey and people.
Following example is not to be construed as the function model to this invention to explain the detail of this invention
The restriction enclosed.
Embodiment 1
Enterobacteriaceae antibiotic of the present invention is preparing the application in preventing Chemotherapy Complications drug, specific preparation process
It is as follows：
1) water soluble antibiotics are formulated as certain density storing solution with PBS, -20 DEG C preserve, wherein, in the present embodiment
The water soluble antibiotics of use are respectively gentamicin, lavo-ofloxacin；
2) storing solution is diluted in drinking water, by the antibiotic drinking water that 1.25g/kg compound concentrations are 5g/L.
Embodiment 2
Application of the oral intestinal canal bacterium antibiotic in the Systemic inflammatory syndrome for preparing prevention chemotherapeutics initiation.
1. experimental animal
Male ICR mouse, weight 18-22g are purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.'s (SPF grades),
Nanjing University's Experimental Animal Center raising.
2. grouping and processing
2.1 experiment packet
Mouse is randomly divided into normal group, chemotherapeutics group, gentamicin group, lavo-ofloxacin group and gentamicin+
Chemotherapeutics group, lavo-ofloxacin+chemotherapeutics group, totally six groups.
2.2 experiment process
A) gentamicin group, lavo-ofloxacin group and gentamicin+chemotherapeutics group, lavo-ofloxacin+chemotherapeutics
Group gives the drinking water containing antibiotic respectively, and normal group gives the drinking water of corresponding amount with chemotherapeutics group；
B) after two weeks, chemotherapeutics group and gentamicin+chemotherapeutics group, lavo-ofloxacin+chemotherapeutics group respectively into
Row intraperitoneal injection contains chemotherapeutic drugs Cisplatin (25mg/kg), 5-Fluorouracil (10mg/kg), camptothecine (10mg/kg), Japanese yew
Alcohol (20mg/kg), Trastuzumab (15mg/kg), Erlotinib (150mg/kg), IL-12 (100 μ l, 0.5 μ g/ml of injection), CART
(it is 6 × 10 that left dorsal subcutaneous, which is inoculated with 100 μ l sums,6CART cells), the normal saline solution of PD-1 (15mg/kg), daily
It is administered once, successive administration 3 days；
C) sample is received within the 2nd day after being discontinued, fasting plucks eyeball and takes blood after 12 hours, detect containing for endotoxin and TNF-α in serum
Amount；The state of animal observation liver,spleen,kidney, each histoorgan of colon is put to death, colonic tissue is fixed, is embedded, carries out HE dyeing.
Specific processing see the table below 1.
The processing procedure of 1 each experimental group of table
2.3 enterobacteriaceae antibiotic influence the performance of Systemic inflammatory syndrome
A) the influence of gentamicin, lavo-ofloxacin to chemotherapy the weight of animals
Gentamicin, lavo-ofloxacin are classified as in table 2 on influencing to become through chemotherapeutics treated each group mouse weight
Change.
The influence (g) that 2 enterobacteriaceae antibiotic of table changes chemotherapeutics mouse weight
Data are shown that significant difference is determined by ANOVA inspections in the form of average value.* represent P≤
0.05。
As can be seen that two groups of (C, E) weight gain trend of advance antibiotic treatment keep one with normal group (A) in table 2
It causes；Giving the mouse weight of the chemotherapeutics group (B) of chemotherapeutics significantly reduces；With individually giving chemotherapeutics group (B) ratio, celebrating
Big mycin+chemotherapeutics group (D), the weight of test mice of lavo-ofloxacin+chemotherapeutics group (F) increased, mouse
Weight loss amplitude is small, and there are significant differences.It is found that gentamicin, lavo-ofloxacin are to chemotherapy mouse table from aforementioned result
Reveal certain chemotherapeutic protection effect.
B) the influence of gentamicin, lavo-ofloxacin to chemotherapy animal overall survival
Further whether investigation gentamicin, lavo-ofloxacin can influence the overall survival after animal chemotherapy, to change
It is node that it is all dead, which to treat drug taxol group mouse,.It the results are shown in Table 3.
Influence of the 3 enterobacteriaceae antibiotic of table to chemotherapeutics mouse overall survival
Data are shown that significant difference is subject to really by ANOVA inspections in the form of mean+SD
It is fixed.* P≤0.05 is represented.
As can be known from Table 3, gentamicin, levofloxacin on treating group (D, F) can extend the Average Survival of chemotherapy mouse
Number of days, survival rate are significantly higher than chemotherapeutics group (B).Prompting, the totality that enterobacteriaceae antibiotic is remarkably improved chemotherapy animal are raw
Deposit rate.
C) gentamicin, lavo-ofloxacin are on endotoxic influence in chemotherapy animal blood serum
The main component endotoxin for forming gram-negative bacteria outer membrane has extremely strong inducing systemic inflammatory response syndrome
The ability of generation.Each group mouse took eyeball blood at the 2nd, 4 day, after isolating serum, measures serum endotoxin with ELISA method and contains
Amount.As a result 4 be see the table below.
Influence (EU/ml) of the 4 enterobacteriaceae antibiotic of table to chemotherapeutics Mouse endotoxin content
Data are shown that significant difference is subject to really by ANOVA inspections in the form of mean+SD
It is fixed.* P≤0.05. is represented
The level of endotoxin for testing the 2nd day chemotherapeutics group and antibiotic treatment group is significantly raised, and more normal group has statistics
Learn difference；The level of endotoxin for testing the 4th day enterobacteriaceae treatment group declines compared with chemotherapeutics group, has significant difference, explanation
Gentamicin, lavo-ofloxacin can mitigate the damage of intestinal mucosa
D) the influence of gentamicin, lavo-ofloxacin to TNF-α in DOX chemotherapy animal blood serums
Each group mouse drug-treated takes eyeball blood on the 4th day, after isolating serum, measures serum endotoxin with ELISA method and contains
Amount.As shown in Figure 1, result shows inflammatory factor TNF-α in the mice serum that enterobacteriaceae treatment group causes chemotherapeutics to handle
Content is decreased obviously, and has significant difference, illustrates that gentamicin, lavo-ofloxacin can mitigate systemic inflammatory reaction synthesis
Sign.
E) the influence of gentamicin, lavo-ofloxacin to chemotherapy animal intestinal tract mucous membrane
It takes out colon within the 4th day after each group mouse drug-treated, visually observes the degree of impairment of rear H＆E pathological examinations colon.
As a result as Fig. 2 shows that compared with Normal group, chemotherapeutics group shows more serious faulted condition, and inflammatory cell is big
Amount infiltration, and the mucosa injury state of enterobacteriaceae treatment group and inflammatory reaction significantly slow down, and prompt gentamicin, lavo-ofloxacin
There is mitigation systemic inflammatory response syndrome, protective tissue is from the function of damage.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
Any modification, equivalent replacement or improvement made within refreshing and principle etc., should all be included in the protection scope of the present invention.
Claims (10)
1. enterobacteriaceae antibiotic is preparing the application in preventing Chemotherapy Complications drug.
2. application according to claim 1, which is characterized in that the enterobacteriaceae antibiotic is specially enteron aisle gram-negative
Property bacterium antibiotic.
3. application according to claim 2, which is characterized in that the enteron aisle Gram-negative bacteria antibiotic is big mould using celebrating
Any one of element, lavo-ofloxacin, ampicillin, Amikacin or several mixing.
4. application according to claim 1, which is characterized in that the Chemotherapy Complications are specially what chemotherapeutics caused
Systemic inflammatory syndrome.
5. application according to claim 4, which is characterized in that the chemotherapeutics is cis-platinum, 5-Fluorouracil, camplotheca acuminata
Any one of alkali, taxol, Trastuzumab, Erlotinib, IL-12, CART, PD-1 or several mixing.
6. application according to claim 1, which is characterized in that the prevention Chemotherapy Complications drug is resisted with enterobacteriaceae
Raw element is active constituent, in addition the medicament that water-soluble organic carrier is prepared.
7. application according to claim 6, which is characterized in that the water-soluble organic carrier is using dextrin, corn oil
Or any one of dimethyl sulfoxide (DMSO).
8. the application described according to claim 6 or 7, which is characterized in that the medicament is oral preparation or ejection preparation.
9. application according to claim 1, which is characterized in that the dosage of the enterobacteriaceae antibiotic is 0.05g/
Kg-10g/kg is administered daily.
10. application according to claim 9, which is characterized in that the dosage of the enterobacteriaceae antibiotic is 0.5g/
Kg-10g/kg is administered daily.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810082878.2A CN108126201B (en) | 2018-01-29 | 2018-01-29 | Application of intestinal bacteria antibiotic in preparing medicine for preventing and treating chemotherapy complications |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810082878.2A CN108126201B (en) | 2018-01-29 | 2018-01-29 | Application of intestinal bacteria antibiotic in preparing medicine for preventing and treating chemotherapy complications |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108126201A true CN108126201A (en) | 2018-06-08 |
| CN108126201B CN108126201B (en) | 2020-09-01 |
Family
ID=62400934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810082878.2A Active CN108126201B (en) | 2018-01-29 | 2018-01-29 | Application of intestinal bacteria antibiotic in preparing medicine for preventing and treating chemotherapy complications |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108126201B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114028573A (en) * | 2021-12-09 | 2022-02-11 | 北京大学第一医院 | Application of bacteroid intestinal bacteria and metabolism related substances thereof in preparation of drugs for reversing drug resistance of fluorouracil drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1843508A (en) * | 2005-04-07 | 2006-10-11 | 安成制药科技股份有限公司 | A composition for treating gastrointestinal distress |
-
2018
- 2018-01-29 CN CN201810082878.2A patent/CN108126201B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1843508A (en) * | 2005-04-07 | 2006-10-11 | 安成制药科技股份有限公司 | A composition for treating gastrointestinal distress |
Non-Patent Citations (1)
| Title |
|---|
| 姚树坤等: "氧氟沙星治疗原发性腹膜炎和肝癌化疗后感染的临床研究", 《奥复星 临床应用论文集》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114028573A (en) * | 2021-12-09 | 2022-02-11 | 北京大学第一医院 | Application of bacteroid intestinal bacteria and metabolism related substances thereof in preparation of drugs for reversing drug resistance of fluorouracil drugs |
| CN114028573B (en) * | 2021-12-09 | 2023-02-24 | 北京大学第一医院 | Application of bacteroid intestinal bacteria and metabolism related substances thereof in preparation of drugs for reversing drug resistance of fluorouracil drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108126201B (en) | 2020-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114306616B (en) | New application of bacteroides fragilis and immune checkpoint inhibitor | |
| JP2015051970A (en) | Composition for producing adjuvant for cancer patients receiving chemotherapy | |
| CN104758300A (en) | Antibacterial applications of vitamin D and vitamin D composition | |
| US20220054561A1 (en) | Lachnospiraceae mitigates against radiation-induced hematopoietic/gastrointestinal injury and death, and promotes cancer control by radiation | |
| CN108126201A (en) | Enterobacteriaceae antibiotic is preparing the application in preventing Chemotherapy Complications drug | |
| Xu et al. | Effects of dietary galactooligosaccharide on growth, antioxidants, immunity, intestinal morphology and disease resistance against Aeromons hydrophila in juvenile hybrid sturgeon (Acipenser baerii♀× A. schrenckii♂) | |
| CN114392356A (en) | Application of bacteroides fragilis and immune checkpoint inhibitor in combination in treatment of digestive system tumor | |
| CN117045687A (en) | Application of bacillus coagulans in preparation of medicine for preventing and treating intestinal injury caused by ionizing radiation | |
| CN111450124B (en) | Application of Achimbe or prevotella in medicine for increasing tumor microenvironment gamma delta T cell accumulation and enhancing anti-tumor immune function | |
| Brook et al. | Quinolone therapy of Klebsiella pneumoniae sepsis following irradiation: comparison of pefloxacin, ciprofloxacin, and ofloxacin | |
| CN116172997B (en) | Application of phenyllactic acid in inhibiting helicobacter pylori infection | |
| Chauhan et al. | Isolation and evaluation of putative probiotic strains from different teleost to prevent Pseudomonas aeruginosa infection in Cyprinus carpio | |
| CN110664833A (en) | Preparation method and application of astragalus polysaccharide chitosan nanoparticles | |
| Riswold et al. | Cutaneous nocardiosis in an immunocompromised patient | |
| CN115813973A (en) | Application of Longyou in preparation of medicine for preventing and treating radiation enteritis | |
| JP2000336035A (en) | Prophylactic and therapeutic agent for infection of fish and shellfish | |
| Rahamat-Langendoen et al. | Disseminated Rhodococcus equi infection in a kidney transplant patient without initial pulmonary involvement | |
| CN111655252B (en) | Application of composition containing ferrous amino acid particles in preparing medicine for relieving ascites caused by pancreatic cancer and treating pancreatitis | |
| CN113398275A (en) | Bacterial vector for photodynamic therapy and preparation method and application thereof | |
| TWI773166B (en) | Probiotic composition for enhancing anti-pancreatic cancer effect in combination with chemotherapy drug gemcitabine and use thereof | |
| CN116549418B (en) | Nanoparticle for resisting postoperative infection and recurrence of gastric cancer as well as preparation method and application thereof | |
| CN116855397A (en) | Ackermansia muciniphila and application thereof in preparing antitumor drugs | |
| US20220249666A1 (en) | Cancer cell-targeted drug delivery carrier and composition for promoting photo-thermal treatment effects, both of which contain m1 macrophages as active ingredient | |
| Waterworth et al. | Single-dose minocycline in the treatment of gonococcal urethritis. Clinical efficacy in relation to bacterial resistance and its effects on associated Chlamydia trachomatis infections. | |
| JP3040699B2 (en) | Toxic reducer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |