JP2004513147A - Methods of using fluoroquinolones against pathogenic Helicobacter bacteria - Google Patents
Methods of using fluoroquinolones against pathogenic Helicobacter bacteria Download PDFInfo
- Publication number
- JP2004513147A JP2004513147A JP2002540739A JP2002540739A JP2004513147A JP 2004513147 A JP2004513147 A JP 2004513147A JP 2002540739 A JP2002540739 A JP 2002540739A JP 2002540739 A JP2002540739 A JP 2002540739A JP 2004513147 A JP2004513147 A JP 2004513147A
- Authority
- JP
- Japan
- Prior art keywords
- helicobacter
- bacterium
- pathogenic
- gemifloxacin
- species
- 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
- 241000589989 Helicobacter Species 0.000 title claims description 49
- 238000000034 method Methods 0.000 title claims description 44
- 230000001717 pathogenic effect Effects 0.000 title claims description 19
- 229940124307 fluoroquinolone Drugs 0.000 title description 9
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical class C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 claims abstract description 18
- 229960003170 gemifloxacin Drugs 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 26
- -1 gemifloxacin compound Chemical class 0.000 claims description 24
- 241000590002 Helicobacter pylori Species 0.000 claims description 20
- 229940037467 helicobacter pylori Drugs 0.000 claims description 20
- 241000894006 Bacteria Species 0.000 claims description 17
- 244000052769 pathogen Species 0.000 claims description 11
- 230000000844 anti-bacterial effect Effects 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 229960001151 gemifloxacin mesylate Drugs 0.000 claims description 7
- JIYMVSQRGZEYAX-CWUUNJJBSA-N gemifloxacin mesylate Chemical compound CS(O)(=O)=O.C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 JIYMVSQRGZEYAX-CWUUNJJBSA-N 0.000 claims description 7
- 208000035143 Bacterial infection Diseases 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 230000004060 metabolic process Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims 1
- 230000018406 regulation of metabolic process Effects 0.000 claims 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 244000052616 bacterial pathogen Species 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 9
- 238000011282 treatment Methods 0.000 description 7
- 150000007660 quinolones Chemical class 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229960003022 amoxicillin Drugs 0.000 description 3
- 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 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229960000282 metronidazole Drugs 0.000 description 3
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229960002180 tetracycline Drugs 0.000 description 3
- 229930101283 tetracycline Natural products 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 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 2
- 206010019375 Helicobacter infections Diseases 0.000 description 2
- 241001473949 Helicobacter pylori NCTC 11637 = CCUG 17874 = ATCC 43504 Species 0.000 description 2
- 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 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 101150114014 cagA gene Proteins 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 229960003923 gatifloxacin Drugs 0.000 description 2
- 229960003376 levofloxacin Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 229960003702 moxifloxacin Drugs 0.000 description 2
- 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 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 241000590008 Helicobacter sp. Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000037358 bacterial metabolism Effects 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000023652 chronic gastritis Diseases 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
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 244000000075 gastric pathogen Species 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本発明は、部分的には、キノロン抗生物質、特に、ゲミフロキサシン化合物の特定の病原性細菌に対する新規に同定された使用方法に関する。The present invention relates, in part, to newly identified uses of quinolone antibiotics, particularly gemifloxacin compounds, against certain pathogenic bacteria.
Description
【０００１】
本発明は、部分的には、新規に同定されたキノロン抗生物質の使用方法、特に、ヘリコバクター種（Ｈｅｌｉｃｏｂａｃｔｅｒ ｓｐ．）、ヘリコバクター・ピロリ（Ｈ． ｐｙｌｏｒｉ）などのヘリコバクター（Ｈｅｌｉｃｏｂａｃｔｅｒ）細菌、およびヘリコバクター属の病原性種に対するゲミフロキサシン（ｇｅｍｉｆｌｏｘａｃｉｎ）化合物の使用方法に関する。
【０００２】
（発明の背景）
キノロン類は多くの細菌病原体に対して様々な程度で有効であることが示されてきた。しかし、これら病原体によって引き起こされる疾患が増えつつあるため、既存のキノロン類の群よりも強力な抗菌化合物が必要とされている。
【０００３】
ゲミフロキサシンメシレートは強力な抗菌剤として有用な新規なフルオロキノロンである。ゲミフロキサシン化合物は、ＷＯ９８／４２７０５号として公表された特許出願ＰＣＴ／ＫＲ９８／０００５１号に詳細に記載されている。欧州特許出願ＥＰ６８８７７２号には、下記式Ｉの無水（Ｒ，Ｓ）−７−（３−アミノメチル−４−メトキシイミノピロリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−１，８−ナフチリジン−３−カルボン酸を含む新規なキノリン（ナフチリジン）カルボン酸誘導体が開示されている。
【０００４】
【化１】
【０００５】
ＰＣＴ／ＫＲ９８／０００５１号には、（Ｒ，Ｓ）−７−（３−アミノメチル−４−ｓｙｎ−メトキシイミノ−ピロリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−１，８−ナフチリジン−３−カルボン酸メタンスルホナートおよびセスキ水和物を含むその水和物が開示されている。本明細書において、ヘリコバクターに対してゲミフロキサシン化合物を用いてなされた有意な知見を提供し、これは本明細書においてより詳細に記載するように、多くの他のキノロン類より、ここで用いられるゲミフロキサシン化合物の活性の方が優れていることを示す。ゲミフロキサシン化合物は、通常の経口治療に耐性のものを含む、数多くのヘリコバクター病原体によって起こる細菌性感染の治療に有用な化合物であり、したがっていまだ満たされていない医療上の要求を満たすものである。
【０００６】
（発明の概要）
本発明の目的は、病原性ヘリコバクター細菌と抗菌的に有効な量のキノロン、特にゲミフロキサシン化合物またはその抗菌的に有効な誘導体を含む組成物とを接触させる工程を含む、病原性ヘリコバクター細菌の代謝を調節する方法である。
【０００７】
本発明のさらなる目的は、該病原性ヘリコバクター細菌が、ヘリコバクター属のメンバー、ヘリコバクター種、 ヘリコバクター・ピロリ、およびヘリコバクターの病原性種からなる群から選択される方法である。本発明により、病原性ヘリコバクター細菌による細菌感染症の治療または予防方法も提供され、該方法は、抗菌的に有効な量の、キノロン、特にゲミフロキサシン化合物を含む組成物を、病原性ヘリコバクター細菌による感染症の疑いまたは危険のある哺乳類に投与する工程を含む。
【０００８】
好適な方法において、該代謝の調節は該細菌の増殖阻害または該細菌の殺傷である。
【０００９】
さらに好適な方法において、該細菌の該接触は、該組成物を哺乳類、特にヒトに導入する工程をさらに含む。
【００１０】
本発明により提供されるさらに好適な方法において、該細菌はヘリコバクター属のメンバー、ヘリコバクター種、 ヘリコバクター・ピロリおよびヘリコバクターの病原性種からなる群から選択される。
【００１１】
投与するための本発明の好適な組成物には、特に、該組成物がゲミフロキサシンまたは医薬上許容されるその誘導体を含む方法が含まれる。本発明はまた、ゲミフロキサシン化合物がゲミフロキサシンまたは医薬上許容されるその塩、またはゲミフロキサシンメシレートまたはその水和物などのゲミフロキサシン化合物、および／またはゲミフロキサシン化合物がゲミフロキサシンメシレートセスキ水和物である方法を提供する。
【００１２】
以下の記載および本開示の他の部分を読むことにより、開示された本発明の精神および枠内で様々な変更および改変が可能であることが当業者にとって明白であろう。
【００１３】
（発明の記載）
本発明は特に、キノロン特にゲミフロキサシン化合物を含む組成物を一定の範囲の病原性細菌に対して使用する方法を提供する。
【００１４】
本明細書において用いる「ゲミフロキサシン化合物（類）」という語は、ＷＯ９８／４２７０５号として公表された特許出願ＰＣＴ／ＫＲ９８／０００５１号、または欧州特許出願ＥＰ６８８７７２号において記載された抗菌活性を有する化合物を意味する。
【００１５】
本発明は部分的には、ヒトの消化管に普通に見られるヘリコバクター種の低継代臨床分離株および基準株を用いてゲミフロキサシン化合物およびその他の新規なキノロン類のインビトロの活性を評価する分析に基づいている。分析に用いた生物には、ヘリコバクター属のメンバー、ヘリコバクター種，、ヘリコバクター・ピロリおよびヘリコバクターの病原性種が含まれる。一般的な胃の病原菌、ヘリコバクター・ピロリ（Ｈｅｌｉｃｏｂａｃｔｅｒ ｐｙｌｏｒｉ）は、慢性胃炎、十二指腸潰瘍、胃潰瘍および胃粘膜結合リンパ組織（ＭＡＬＴ）リンパ腫の進行に関係し、ヘリコバクター・ピロリ感染と胃癌の間の関係が確かめられている。症候性ヘリコバクター・ピロリ−陽性患者、特に十二指腸潰瘍または胃潰瘍を伴う患者には、感染の根絶が推奨されることが多い。しかし、通常のヘリコバクター・ピロリに対する三剤併用治療の効果は、抗生物質耐性分離株の頻度が上昇することから疑問視されている。アモキシシリンおよびテトラサイクリンに対する耐性はまれであるが、メトロニダゾールおよびクラリスロマイシンに対する耐性はかなり頻度が増しており、治療の失敗の重要な原因である（Ａｌａｒｃｏｎ， Ｔ．， Ｄｏｍｉｎｇｏ， Ｄ．， ＆ Ｌｏｐｅｚ−Ｂｒｅａ， Ｍ． １９９９． Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｊｏｕｒｎａｌ ｏｆ Ａｎｔｉｍｉｃｒｏｂｉａｌ Ａｇｅｎｔｓ １２， １９−２６）。したがってヘリコバクター・ピロリに対するより効果的な代替療法の同定に多大な関心が払われている。
【００１６】
フルオロキノロン類は消化管、呼吸器および尿路感染症の治療に広く用いられている。フルオロキノロン類はヘリコバクター・ピロリ感染の治療には通常用いられていないが、インビトロでヘリコバクター・ピロリに対して活性である。最近、ヒト胃生検試料から採取した５７株のヘリコバクター・ピロリの、４つのフルオロキノロン類を含む１１の抗菌剤に対する感受性が調べられた（Ｓａｎｃｈｅｚ， Ｊ． Ｅ．， Ｓａｅｎｚ， Ｎ． Ｇ．， Ｒｉｎｃｏｎ， Ｍ． Ｒ．， Ｍａｒｔｉｎ， Ｉ． Ｔ．， Ｓａｎｃｈｅｚ， Ｅ． Ｇ．， ＆ Ｍａｒｔｉｎｅｚ， Ｍ． Ｊ． ２０００． Ｊｏｕｒｎａｌ ｏｆ Ａｎｔｉｍｉｃｒｏｂｉａｌ Ｃｈｅｍｏｔｈｅｒａｐｙ ４６， ２８３−５）。
【００１７】
本発明の目的はヘリコバクター・ピロリの、新規なフルオロキノロン、ゲミフロキサシン（ＳＢ−２６５８０５）に対する感受性を評価することである。２１のヘリコバクター・ピロリの株を得た。これには１６の臨床分離株、ＣＣＵＧ ３９２９７、 ＣＣＵＧ ３０９８８ （Ｌｅｌｗａｌａ−Ｇｕｒｕｇｅ， Ｊ．， Ｌｊｕｎｇｈ， Ａ．， ＆ Ｗａｄｓｔｒｏｍ， Ｔ． １９９２． ＡＰＭＩＳ １００， ９０８−１３）、 ＣＣＵＧ １７８７５ （Ｌｅｌｗａｌａ−Ｇｕｒｕｇｅ， Ｊ．， Ｌｊｕｎｇｈ， Ａ．， ＆ Ｗａｄｓｔｒｏｍ， Ｔ． １９９２． ＡＰＭＩＳ １００， ９０８−１３； Ｉｌｖｅｒ， Ｄ．， Ａｒｎｑｖｉｓｔ， Ａ．， Ｏｇｒｅｎ， Ｊ．， Ｆｒｉｃｋ， Ｉ． Ｍ．， Ｋｅｒｓｕｌｙｔｅ， Ｄ．， Ｉｎｃｅｃｉｋ， Ｅ． Ｔ． ｅｔ ａｌ． １９９８． Ｓｃｉｅｎｃｅ ２７９， ３７３−７）、 ＣＣＵＧ ３８７７１、 ＣＣＵＧ １５８１８、 ＣＣＵＧ １７８７４ （Ｌｅｌｗａｌａ−Ｇｕｒｕｇｅ， Ｊ．， Ｌｊｕｎｇｈ， Ａ．， ＆ Ｗａｄｓｔｒｏｍ， Ｔ． １９９２． ＡＰＭＩＳ １００， ９０８−１３； Ｏ’Ｔｏｏｌｅ， Ｐ． Ｗ．， Ｌｏｇａｎ， Ｓ． Ｍ．， Ｋｏｓｔｒｚｙｎｓｋａ， Ｍ．， Ｗａｄｓｔｒｏｍ， Ｔ．， ＆ Ｔｒｕｓｔ， Ｔ． Ｊ． １９９１． Ｊｏｕｒｎａｌ ｏｆ Ｂａｃｔｅｒｉｏｌｏｇｙ １７３， ５０５−５１３）、 ＣＣＵＧ １９０８７、 ＣＣＵＧ ３０９８７ （Ｌｅｌｗａｌａ−Ｇｕｒｕｇｅ， Ｊ．， Ｌｊｕｎｇｈ， Ａ．， ＆ Ｗａｄｓｔｒｏｍ， Ｔ． １９９２． ＡＰＭＩＳ １００， ９０８−１３）、 ＣＣＵＧ ３８７７２、 ＣＣＵＧ １８９４３、 ＣＣＵＧ １８２９５、 ＣＣＵＧ ３６７１８、 ＣＣＵＧ ３６７１９、 ＣＣＵＧ ３５８９９、 ＣＣＵＧ ３６７２０、 ＣＣＵＧ ３９９２４、および研究室株Ｎｏｔ１８、 Ｎｏｔ３４、 ＡＴＣＣ ４３５０４、 ＳＳ１、および ＡＴＣＣ ７００３９２／２６６９５が含まれる。これらの株には、米国、スウェーデン、フランス、ベルギー、英国、南アフリカ共和国、およびオーストラリアからの胃生検試料分離株が含まれる。該臨床分離株の２つはｃａｇＡ ＋ 遺伝子型（株 ＣＣＵＧ １７８７４ および ＣＣＵＧ １７８７５） であり、３つはｃａｇＡ − （株 ＣＣＵＧ ３６７２０、 ＣＣＵＧ ３６７１９および ＣＣＵＧ ３０９８８）であると報告されているが、残りの株のｃａｇ遺伝子型は不明である。ＮＣＣＬＳ推奨寒天希釈法 （Ｎａｔｉｏｎａｌ Ｃｏｍｍｉｔｔｅｅ ｆｏｒ Ｃｌｉｎｉｃａｌ Ｌａｂｏｒａｔｏｒｙ Ｓｔａｎｄａｒｄｓ． ２０００． Ａｐｐｒｏｖｅｄ Ｓｔａｎｄａｒｄ − Ｆｉｆｔｈ ｅｄｉｔｉｏｎ． Ｍ７−Ａ５ ａｎｄ ＭＩＣ Ｔｅｓｔｉｎｇ Ｓｕｐｐｌｅｍｅｎｔａｌ Ｔａｂｌｅｓ Ｍ１００−Ｓ１０ （Ｍ７） Ｖｏｌ． ２０（２）． ＮＣＣＬＳ， Ｖｉｌｌａｎｏｖａ， ＰＡ） を用いてゲミフロキサシンおよび本発明の方法に有用な比較剤の活性を測定した。ゲミフロキサシンと比較されるこれら比較剤は、レボフロキサシン、シプロフロキサシン、モキシフロキサシンおよびガチフロキサシンを含む。アモキシシリン、テトラサイクリンおよびメトロニダゾールのヘリコバクター・ピロリ ＡＴＣＣ ４３５０４に対する活性も対照として試験した。寒天プレートにＳｔｅｅｒｓレプリケーターを用いて播種し、７２時間後に読みを取った。
【００１８】
対照抗生物質、アモキシシリン、テトラサイクリンおよびメトロニダゾールはヘリコバクター・ピロリ ＡＴＣＣ ４３５０４に対してそれぞれ０．０６、１．０および２５６ｍｇ／ＬのＭＩＣを示し、これらはＮＣＣＬＳ精度管理限界値の範囲内である。試験したフルオロキノロン類の中でゲミフロキサシンが最も活性であり、続いてガチフロキサシン、シプロフロキサシン、レボフロキサシンおよびモキシフロキサシンの順であった。またゲミフロキサシンは試験したすべてのヘリコバクター・ピロリ株に対して高度に活性であり、ＭＩＣ９０ は ０．１３ ｍｇ／Ｌであった（表１）。
【００１９】
【表１】
表１
ヘリコバクター・ピロリ の２１の分離菌のフルオロキノロン類に対するＭＩＣ（ｍｇ／Ｌ）
ＭＩＣとｃａｇ状態または地理的位置との間に明確な相関はなかった。一般に処方されていたフルオロキノロン類と比べて、ゲミフロキサシンは、様々な世界中の場所からの胃組織診分離株を含むヘリコバクター・ピロリ株に対してより強い活性を示すことが見出されたと結論される。
【００２１】
本発明は病原性ヘリコバクター細菌の代謝を調節する方法を提供する。当業者であれば簡単に、病原性ヘリコバクター細菌またはこれら生物に感染したかまたは感染した疑いのある患者を選択して本発明の方法を実施することができよう。また、本発明の方法に有用な細菌は本明細書において記載するものであってよい。
【００２２】
本発明の方法における接触工程は当業者に明らかな多くの方法によって行うことが出来る。しかし、接触工程は、ゲミフロキサシン化合物を含む組成物を、そのような組成物を必要とするヒト患者に提供するか、または培地または緩衝液中の細菌に直接提供するのが好ましい。
【００２３】
例えば、ヒト患者に接触させる場合、またはヒト患者内またはインビトロで該細菌に接触させる場合、キノロン、特にゲミフロキサシン化合物を含む、好ましくは医薬組成物である組成物は、あらゆる有効で簡便な方法で投与すればよく、例えば特に、局所、経口、肛門、膣、静脈内、腹腔内、筋肉内、皮下、鼻腔内、皮内経路による投与が含まれる。
【００２４】
これら組成物は非無菌または無菌の、細胞、組織または生物用の１または複数の担体、例えば、対象への投与に好適な医薬担体と組み合わせて用いるのが好適である。そのような組成物には例えば、培地添加剤または治療上有効な量の本発明の化合物、キノロン、好ましくはゲミフロキサシン化合物、および医薬上許容される担体または賦形剤を含むものが挙げられる。そのような担体には、食塩水、緩衝食塩水、デキストロース、水、グリセロール、エタノールおよびそれらの組み合わせが含まれるがそれらに限定されるものではない。製剤形態は投与様式に適合するようにすればよい。
【００２５】
キノロン化合物、特にゲミフロキサシン化合物および本発明の方法の組成物は単独で用いてもその他の化合物と組み合わせて用いてもよく、その他の化合物としては、細菌流出ポンプ阻害化合物または抗菌化合物、特に非−キノロン化合物、例えばベータ−ラクタム抗菌化合物が挙げられる。
【００２６】
治療において、または予防薬として、本発明の方法の活性薬剤は好ましくは注射可能な組成物として、例えば好ましくは等張性の無菌水性分散液として個体に投与される。
【００２７】
また、本発明の方法におけるゲミフロキサシン化合物または組成物は、例えば軟膏、クリーム、ローション剤、眼軟膏、点眼薬、点耳薬、洗口剤、浸透性包帯剤および縫合剤および噴霧剤などの形態の局所投与用に製剤してもよく、適当な一般的な添加剤を含んでいてもよい。添加剤には、例えば、保存剤、薬物の浸透を補助する溶媒、および軟膏およびクリームにおける緩和剤が含まれる。そのような局所用製剤は、例えばクリームまたは軟膏基剤、ローション剤用エタノールまたはオレイルアルコールなどの適合性の通常の担体を含んでいてもよい。そのような担体は製剤の約１重量％から約９８重量％を構成するものであってよいが、通常は製剤の約８０重量％までを構成するものであろう。
【００２８】
哺乳類、特にヒトへの投与用に、抗菌的に有効な量は、０．００１ｍｇ／ｋｇから１０ｍｇ／ｋｇ、典型的には、約０．１ｍｇ／ｋｇから１ｍｇ／ｋｇ、好ましくは約１ｍｇ／ｋｇの活性薬剤の１日用量レベルであると考えられる。少なくとも医師であれば、個々にとって最も好適な正確な用量を決定することが出来るであろうし、この用量は特定の個体の年齢、体重および応答によって変動するであろう。上記の用量は平均的な場合の例示に過ぎない。もちろん、より高用量または低用量範囲が好適な個体例もあるであろうし、そのような場合も本発明の枠内に含まれる。用量は細菌の増殖を阻害または停止するか細菌を殺傷するように、細菌の代謝を調節するように選択するのが好ましい。当業者であれば、本明細書において記載したようにして、および当該技術分野で公知のその他の方法、例えば、ＭＩＣ試験を適用することによってこの量を決定することが出来るであろう。
【００２９】
本発明のさらなる態様は、本方法の接触工程にさらに、患者において内在（ｉｎ−ｄｗｅｌｌｉｎｇ）装置を接触させる工程を提供する。内在装置には、外科的インプラント、補綴装置およびカテーテル、即ち個体の体に導入されて長期間その位置に残る装置が含まれるが、それらに限定されるものではない。そのような装置には、例えば、人工関節、心臓弁、ペースメーカー、血管移植片、血管カテーテル、脳脊髄液シャント、尿カテーテル、および連続携帯式腹膜透析（ＣＡＰＤ）カテーテルが含まれる。
【００３０】
キノロン、特に本発明のゲミフロキサシン化合物または組成物は、内在装置の導入の直前に、関連する細菌、好ましくは病原性ヘリコバクター細菌に対する全身効果を達成するために注射によって投与される。治療は手術後も、装置が体内にある時間中継続できる。さらに組成物は、病原性ヘリコバクター細菌に関連あるいは起因する細菌創傷感染を防ぐためのあらゆる手術技術のために、手術前後の保護を強化するためにも使用できる。
【００３１】
上記の治療に加えて、本発明の方法において用いられるゲミフロキサシン化合物または組成物は、一般に創傷組織にさらされた細菌、特に病原性ヘリコバクター細菌がマトリックスタンパク質に接着するのを防ぐための創傷治療薬としても、また、歯科治療において抗菌予防法の替わりにまたはそれと組み合わせて予防用にも、使用することができる。
【００３２】
また、キノロン、特に本発明のゲミフロキサシン化合物または組成物は、導入の直前に内在装置を浸すために用いてもよい。活性薬剤は、創傷または内在装置を浸すために１μｇ／ｍｌから１０ｍｇ／ｍｌの濃度で存在するのが好ましい。
【００３３】
本発明によってまた、抗菌的に有効な量のキノロン、特にゲミフロキサシン化合物を含む組成物を、哺乳類、好ましくは病原性ヘリコバクター細菌による感染の疑いまたは危険があるヒトに投与する工程を含む、病原性ヘリコバクター細菌による細菌感染症の治療または予防方法が提供される。
【００３４】
本発明の好適な目的は、該病原性ヘリコバクター細菌が、ヘリコバクター種．、 ヘリコバクター・ピロリおよびヘリコバクターの病原性種からなる群から選択される方法を提供する。その他の病原性ヘリコバクター細菌も本方法に含まれる。当業者であれば本明細書において記載されたようにして、また、その他の当該技術分野で公知の方法、例えばＭＩＣ試験を用いてこれらの生物を同定できるであろう。
【００３５】
投与用に好適な本発明の組成物は、特に、該組成物がゲミフロキサシンまたはその医薬上許容される誘導体を含む方法を含む。本方法はまた、ゲミフロキサシン化合物が、ゲミフロキサシンまたはその医薬以上許容される塩、またはゲミフロキサシンメシレートまたはその水和物などのゲミフロキサシン化合物および／またはゲミフロキサシン化合物がゲミフロキサシンメシレートセスキ水和物である方法を提供する。
【００３６】
本明細書において引用した参考文献はすべて引用によりその全体が本明細書に含まれる。さらに本出願が優先権を主張する各特許出願は引用によりその全体が本明細書に含まれる。[0001]
The present invention is based, in part, the use of quinolone antibiotics to newly identified, in particular, Helicobacter species (Helicobacter sp.), Helicobacter, such as Helicobacter pylori (H. pylori) (Helicobacter) bacteria, and Helicobacter Of gemifloxacin compounds against pathogenic species of E. coli.
[0002]
(Background of the Invention)
Quinolones have been shown to be effective to varying degrees against many bacterial pathogens. However, with the increasing disease caused by these pathogens, there is a need for more potent antimicrobial compounds than the existing group of quinolones.
[0003]
Gemifloxacin mesylate is a novel fluoroquinolone useful as a potent antimicrobial agent. Gemifloxacin compounds are described in detail in patent application PCT / KR98 / 00051, published as WO 98/42705. European Patent Application EP688872 discloses anhydrous (R, S) -7- (3-aminomethyl-4-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo of the following formula I: Novel quinoline (naphthyridine) carboxylic acid derivatives containing -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid are disclosed.
[0004]
Embedded image
[0005]
PCT / KR98 / 00051 discloses (R, S) -7- (3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo- 1,4-Dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including sesquihydrate are disclosed. Provided herein are significant findings made with the gemifloxacin compound on Helicobacter, which, as described in more detail herein, are more useful than the gemifloxacin used herein, compared to many other quinolones. It shows that the activity of the compound is superior. Gemifloxacin compounds are useful compounds for the treatment of bacterial infections caused by a number of Helicobacter pathogens, including those that are resistant to conventional oral treatments, and thus fulfill unmet medical needs.
[0006]
(Summary of the Invention)
It is an object of the present invention to comprise the step of contacting a pathogenic Helicobacter bacterium with an antibacterial effective amount of a quinolone, in particular a composition comprising a gemifloxacin compound or an antibacterial effective derivative thereof, comprising the steps of: How to adjust.
[0007]
A further object of the present invention is a method wherein said pathogenic Helicobacter bacterium is selected from the group consisting of members of the genus Helicobacter, Helicobacter species, Helicobacter pylori, and pathogenic species of Helicobacter. The present invention also provides a method of treating or preventing a bacterial infection by a pathogenic Helicobacter bacterium, comprising the step of infecting a composition comprising an antibacterial effective amount of a quinolone, particularly a gemifloxacin compound, with a pathogenic Helicobacter bacterium. Administering to a mammal suspected of being at risk or at risk.
[0008]
In a preferred method, the modulation of metabolism is inhibition of growth of the bacterium or killing of the bacterium.
[0009]
In a further preferred method, said contacting said bacterium further comprises the step of introducing said composition into a mammal, especially a human.
[0010]
In a further preferred method provided by the present invention, the bacterium is selected from the group consisting of members of the genus Helicobacter, Helicobacter species, Helicobacter pylori and pathogenic species of Helicobacter.
[0011]
Preferred compositions of the present invention for administration include, inter alia, methods wherein the composition comprises gemifloxacin or a pharmaceutically acceptable derivative thereof. The invention also provides that the gemifloxacin compound is gemifloxacin or a pharmaceutically acceptable salt thereof, or a gemifloxacin compound such as gemifloxacin mesylate or a hydrate thereof, and / or that the gemifloxacin compound is gemifloxacin mesylate sesquihydrate Provide a method that is a thing.
[0012]
After reading the following description and other parts of the present disclosure, it will be apparent to one skilled in the art that various changes and modifications can be made within the spirit and scope of the disclosed invention.
[0013]
(Description of the invention)
The invention particularly provides a method of using a composition comprising a quinolone, particularly a gemifloxacin compound, against a range of pathogenic bacteria.
[0014]
As used herein, the term "gemifloxacin compound (s)" refers to compounds having antimicrobial activity described in patent application PCT / KR98 / 00051, published as WO 98/42705, or in European patent application EP 688772. I do.
[0015]
The present invention is directed, in part, to an assay to assess the in vitro activity of gemifloxacin compounds and other novel quinolones using low passage clinical isolates and reference strains of Helicobacter species commonly found in the human gastrointestinal tract. Based on. Organisms used in the analysis include members of the genus Helicobacter, Helicobacter species, Helicobacter pylori and pathogenic species of Helicobacter. A common gastric pathogen, Helicobacter pylori, is involved in the development of chronic gastritis, duodenal ulcer, gastric ulcer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and the relationship between Helicobacter pylori infection and gastric cancer. Has been verified. Eradication of infection is often recommended for symptomatic Helicobacter pylori-positive patients, especially those with duodenal or gastric ulcers. However, the effect of triple therapy on normal Helicobacter pylori has been questioned due to the increased frequency of antibiotic resistant isolates. Resistance to amoxicillin and tetracycline is rare, but resistance to metronidazole and clarithromycin is quite frequent and is an important cause of treatment failure (Alarcon, T., Domingo, D., & Lopez-Brea). , M. 1999. International Journal of Antimicrobial Agents 12, 19-26). There is therefore a great deal of interest in identifying more effective alternative therapies for Helicobacter pylori.
[0016]
Fluoroquinolones are widely used in the treatment of gastrointestinal, respiratory and urinary tract infections. Fluoroquinolones are not commonly used in the treatment of Helicobacter pylori infection, but are active against Helicobacter pylori in vitro. Recently, the susceptibility of 57 strains of Helicobacter pylori taken from human stomach biopsy samples to 11 antimicrobial agents, including four fluoroquinolones, was examined (Sanchez, JE, Saenz, NG, Rincon, MR, Martin, IT, Sanchez, EG, & Martinez, MJ 2000. Journal of Antimicrobial Chemotherapy 46, 283-5).
[0017]
An object of the present invention is to evaluate the sensitivity of Helicobacter pylori to a novel fluoroquinolone, gemifloxacin (SB-265805). 21 Helicobacter pylori strains were obtained. This includes 16 clinical isolates, CCUG 39297, CCUG 30988 (Lelwalla-Guruge, J., Ljungh, A., & Wadstrom, T. 1992. APMIS 100, 908-13), CCUG 17875 (Lelwal-urgal-urwal-G). , Ljungh, A., & Wadstrom, T. 1992. APMIS 100, 908-13; Ilver, D., Arnqvist, A., Ogren, J., Frick, IM, Kersulite, cerkite, c. E. T. et al. 1998. Science 279, 373-7), CCUG 38771, CCUG 15818, CCUG 17874 (Lelwalla-Guruge, J., Ljungh). A., & Wadstrom, T. 1992. APMIS 100, 908-13; O'Toole, P.W., Logan, S.M., Kostrzynska, M., Wadstrom, T., & Trust, T.T. 1991. Journal of Bacteriology 173, 505-513), CCUG 19087, CCUG 30987 (Lelwalla-Guruge, J., Ljungh, A., & Wadstrom, T. 1978. CCUG 18295, CCUG 36718, CCUG 36719, CCUG 35899, CCUG 36720, CCUG 39924, and laboratory strain Not18, N t34, include ATCC 43504, SS1, and ATCC 700392/26695. These strains include gastric biopsy isolates from the United States, Sweden, France, Belgium, United Kingdom, South Africa, and Australia. Two of the clinical isolates are reported to be cagA + genotypes (strains CCUG 17874 and CCUG 17875) and three are reported to be cagA − (strains CCUG 36720, CCUG 36719 and CCUG 30988), while the remaining The cag genotype of the strain is unknown. NCCLS Recommended Agar Dilution Method (National Committee for Clinical Laboratories Standards. 2000. Applied Standard-Fifth edition. M7-A5 and N.V.Mal.Supplement. The activity of gemifloxacin and comparators useful in the method of the invention was determined. These comparators compared to gemifloxacin include levofloxacin, ciprofloxacin, moxifloxacin and gatifloxacin. The activity of amoxicillin, tetracycline and metronidazole against Helicobacter pylori ATCC 43504 was also tested as a control. The agar plates were seeded using a Steers replicator and read 72 hours later.
[0018]
The control antibiotics, amoxicillin, tetracycline and metronidazole show MICs of 0.06, 1.0 and 256 mg / L against Helicobacter pylori ATCC 43504, respectively, which are within the NCCLS quality control limits. Gemifloxacin was the most active of the fluoroquinolones tested, followed by gatifloxacin, ciprofloxacin, levofloxacin and moxifloxacin. Gemifloxacin was also highly active against all Helicobacter pylori strains tested, with an MIC 90 of 0.13 mg / L (Table 1).
[0019]
[Table 1]
Table 1
MIC (mg / L) of 21 isolates of Helicobacter pylori against fluoroquinolones
There was no clear correlation between MIC and cag status or geographic location. It is concluded that, compared to commonly prescribed fluoroquinolones, gemifloxacin was found to be more active against Helicobacter pylori strains, including gastric biopsy isolates from various locations around the world. You.
[0021]
The present invention provides a method for regulating the metabolism of pathogenic Helicobacter bacteria. One of ordinary skill in the art would readily be able to select the pathogenic Helicobacter bacteria or patients infected or suspected of being infected with these organisms and practice the methods of the invention. Also, bacteria useful in the methods of the invention may be those described herein.
[0022]
The contacting step in the method of the present invention can be performed by many methods apparent to those skilled in the art. However, it is preferred that the contacting step provides a composition comprising the gemifloxacin compound to a human patient in need of such a composition, or directly to bacteria in a medium or buffer.
[0023]
For example, when contacting a human patient or contacting the bacterium in a human patient or in vitro, a composition comprising a quinolone, especially a gemifloxacin compound, preferably a pharmaceutical composition, can be administered in any effective and convenient manner. It includes, for example, administration by topical, oral, anal, vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, intradermal routes, among others.
[0024]
These compositions are preferably used in combination with one or more non-sterile or sterile carriers for cells, tissues or organisms, for example, a pharmaceutical carrier suitable for administration to a subject. Such compositions include, for example, those comprising a media additive or a therapeutically effective amount of a compound of the invention, a quinolone, preferably a gemifloxacin compound, and a pharmaceutically acceptable carrier or excipient. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol and combinations thereof. The formulation may be adapted to the mode of administration.
[0025]
The quinolone compound, especially the gemifloxacin compound and the composition of the method of the present invention, may be used alone or in combination with other compounds, such as bacterial efflux pump inhibiting compounds or antibacterial compounds, especially non-quinolone Compounds, such as beta-lactam antimicrobial compounds.
[0026]
In therapy or as a prophylactic, the active agent of the method of the invention is preferably administered to an individual as an injectable composition, for example, preferably as an isotonic sterile aqueous dispersion.
[0027]
Further, the gemifloxacin compound or composition in the method of the present invention may be in the form of, for example, ointments, creams, lotions, eye ointments, eye drops, ear drops, mouth washes, osmotic dressings and sutures and sprays. It may be formulated for topical administration and may contain suitable common additives. Additives include, for example, preservatives, solvents to aid penetration of the drug, and emollients in ointments and creams. Such topical formulations may contain compatible conventional carriers, for example cream or ointment bases, ethanol or oleyl alcohol for lotions. Such carriers may comprise from about 1% to about 98% by weight of the formulation, but will usually comprise up to about 80% by weight of the formulation.
[0028]
For administration to mammals, especially humans, an antibacterial effective amount is 0.001 mg / kg to 10 mg / kg, typically about 0.1 mg / kg to 1 mg / kg, preferably about 1 mg / kg. Daily dose level of the active agent. At least the physician will be able to determine the most appropriate precise dose for the individual and this dose will vary with the age, weight and response of the particular individual. The above doses are exemplary of the average case only. Of course, there may be instances in which higher or lower dose ranges are preferred, and such are within the scope of the invention. The dose is preferably selected to modulate bacterial metabolism, such as to inhibit or stop bacterial growth or kill bacteria. One of skill in the art would be able to determine this amount as described herein and by applying other methods known in the art, for example, the MIC test.
[0029]
A further aspect of the invention provides the contacting step of the method further comprising contacting an in-dwelling device in the patient. Indwelling devices include, but are not limited to, surgical implants, prosthetic devices, and catheters, ie, devices that are introduced into an individual's body and remain in place for an extended period of time. Such devices include, for example, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urine catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
[0030]
The quinolone, in particular the gemifloxacin compound or composition of the invention, is administered by injection to achieve a systemic effect against the relevant bacterium, preferably the pathogenic Helicobacter bacterium, shortly before the introduction of the indwelling device. Treatment can continue after surgery for as long as the device is in the body. In addition, the compositions can be used to enhance perioperative protection, for any surgical technique to prevent bacterial wound infections associated with or caused by pathogenic Helicobacter bacteria.
[0031]
In addition to the above treatments, the gemifloxacin compounds or compositions used in the methods of the present invention may be used as wound healing agents to prevent bacteria exposed to wound tissue, particularly pathogenic Helicobacter bacteria, from adhering to matrix proteins. Can also be used for prophylaxis instead of or in combination with antimicrobial prophylaxis in dental treatment.
[0032]
Also, quinolones, particularly the gemifloxacin compounds or compositions of the present invention, may be used to bathe an indwelling device immediately prior to introduction. The active agent is preferably present at a concentration of 1 μg / ml to 10 mg / ml for soaking the wound or indwelling device.
[0033]
The present invention also provides a method of administering a composition comprising an antibacterial effective amount of a quinolone, particularly a gemifloxacin compound, to a mammal, preferably a human at risk of infection or risk of infection by a pathogenic Helicobacter bacterium. Methods for treating or preventing bacterial infection by bacteria are provided.
[0034]
A preferred object of the present invention is that the pathogenic Helicobacter bacterium is a Helicobacter spp. A method selected from the group consisting of Helicobacter pylori and pathogenic species of Helicobacter. Other pathogenic Helicobacter bacteria are also included in the method. Those skilled in the art will be able to identify these organisms as described herein and using other methods known in the art, for example, the MIC test.
[0035]
Compositions of the invention suitable for administration include, in particular, methods wherein the composition comprises gemifloxacin or a pharmaceutically acceptable derivative thereof. The method may also comprise gemfloxacin or a pharmaceutically acceptable salt thereof, or a gemifloxacin compound such as gemifloxacin mesylate or a hydrate thereof and / or gemifloxacin mesylate sesquihydrate. Provide a method that is a thing.
[0036]
All references cited herein are hereby incorporated by reference in their entirety. Further, each patent application for which this application claims priority is hereby incorporated by reference in its entirety.
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24709300P | 2000-11-10 | 2000-11-10 | |
| PCT/US2001/047460 WO2002038156A2 (en) | 2000-11-10 | 2001-11-08 | Methods of use of fluoroquinolone compounds against pathogenic helicobacter bacteria |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2004513147A true JP2004513147A (en) | 2004-04-30 |
Family
ID=22933518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002540739A Pending JP2004513147A (en) | 2000-11-10 | 2001-11-08 | Methods of using fluoroquinolones against pathogenic Helicobacter bacteria |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1337252A4 (en) |
| JP (1) | JP2004513147A (en) |
| KR (1) | KR20030060928A (en) |
| AU (1) | AU2002233995A1 (en) |
| WO (1) | WO2002038156A2 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11209286A (en) * | 1998-01-21 | 1999-08-03 | Kyorin Pharmaceut Co Ltd | An anti-H. pylori agent |
| US6262071B1 (en) * | 1999-06-29 | 2001-07-17 | Smithkline Beecham Corporation | Methods of use of antimicrobial compounds against pathogenic amycoplasma bacteria |
| US6331550B1 (en) * | 1999-06-29 | 2001-12-18 | Smithkline Beecham Corporation | Methods of use of quinolone compounds against anaerobic pathogenic bacteria |
| CA2282066C (en) * | 1999-06-29 | 2010-09-07 | Smithkline Beecham Corporation | Methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria |
-
2001
- 2001-11-08 KR KR10-2003-7006239A patent/KR20030060928A/en not_active Ceased
- 2001-11-08 EP EP01985001A patent/EP1337252A4/en not_active Withdrawn
- 2001-11-08 JP JP2002540739A patent/JP2004513147A/en active Pending
- 2001-11-08 AU AU2002233995A patent/AU2002233995A1/en not_active Abandoned
- 2001-11-08 WO PCT/US2001/047460 patent/WO2002038156A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| EP1337252A2 (en) | 2003-08-27 |
| WO2002038156A3 (en) | 2002-07-11 |
| KR20030060928A (en) | 2003-07-16 |
| AU2002233995A1 (en) | 2002-05-21 |
| EP1337252A4 (en) | 2005-06-22 |
| WO2002038156A2 (en) | 2002-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6340689B1 (en) | Methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria | |
| US6262071B1 (en) | Methods of use of antimicrobial compounds against pathogenic amycoplasma bacteria | |
| ES2299430T3 (en) | USE OF GEMIFLOXACINE COMPOUNDS AGAINST BACTERIA. | |
| Boerema et al. | Efficacy and safety of ciprofloxacin (Bay 0 9867) in the treatment of patients with complicated urinary tract infections | |
| US7595328B2 (en) | Methods of use of quinolone compounds against pneumococcal and Haemophilus bacteria | |
| US20040023983A1 (en) | Methods of use of fluoroquinolone compounds against pathogenic helicobacter bacteria | |
| JP2004513147A (en) | Methods of using fluoroquinolones against pathogenic Helicobacter bacteria | |
| CA2281817C (en) | Methods of use of fluoroquinolone compounds against maxillary sinus pathogenic bacteria | |
| US6455540B1 (en) | Methods of use of quinolone compounds against anaerobic pathogenic bacteria | |
| EP1458390B1 (en) | A method of treating bacterial infections using gemifloxacin or a salt thereof and a carbapenem antibacterial agent | |
| US20040147527A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant Streptococcus pneumoniae bacteria | |
| US20030073695A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant Streptococcus pneumoniae bacteria | |
| JP2001097891A (en) | Method for using fluoroquinolone compound against respiratory pathogenic bacterium | |
| US20020086868A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant Streptococcus pneumoniae bacteria | |
| US20030078272A1 (en) | Methods of use of fluoroquinolone compounds against ciprofloxacin-resistant and ciprofloxacin-sensitive pathogenic bacteria | |
| JP2001097864A (en) | Use of fluoroquinolone compound against respiratory tract and urinary tract pathogenic bacteria | |
| US20050032813A1 (en) | Methods of use of fluoroquinolone compounds against maxillary sinus pathogenic bacteria | |
| Inoshita et al. | A randomized prospective study of oral levofloxacin vs intravenous flomoxef prophylaxis in postoperative infection after endoscopic sinus surgery | |
| JP2001097863A (en) | Use of fluoroquinolone compound against anaerobic pathogenic bacteria | |
| EP1458391A4 (en) | A method of treating bacterial infections using gemifloxacin or a salt thereof and a beta-lactam antibiotic | |
| Figura et al. | Omeprazole versus ranitidine in the prevention of duodenal ulcer recurrence after eradication therapy | |
| DE19945885A1 (en) | Use of gemifloxacin compounds, which can be active against bacterial strains resistant to other antibiotics, in treatment of infections caused by respiratory tract pathogenic bacteria | |
| JP2004500337A (en) | Use of fluoroquinolone compounds against bacteria |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070925 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20071211 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20071218 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20080318 |