JP6845233B2 - 組み合せ抗細菌組成物および短期抗細菌レジメン - Google Patents
組み合せ抗細菌組成物および短期抗細菌レジメン Download PDFInfo
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- JP6845233B2 JP6845233B2 JP2018518950A JP2018518950A JP6845233B2 JP 6845233 B2 JP6845233 B2 JP 6845233B2 JP 2018518950 A JP2018518950 A JP 2018518950A JP 2018518950 A JP2018518950 A JP 2018518950A JP 6845233 B2 JP6845233 B2 JP 6845233B2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- JVAZJLFFSJARQM-YBXAARCKSA-N n-Hexyl-beta-D-glucopyranoside Natural products CCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-YBXAARCKSA-N 0.000 description 1
- WNRIDZUNMXATND-ZDUSSCGKSA-N n-[[(5s)-3-[3-fluoro-4-(1-oxo-1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCS(=O)CC1 WNRIDZUNMXATND-ZDUSSCGKSA-N 0.000 description 1
- UMWKZHPREXJQGR-XOSAIJSUSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]decanamide Chemical compound CCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO UMWKZHPREXJQGR-XOSAIJSUSA-N 0.000 description 1
- SBWGZAXBCCNRTM-CTHBEMJXSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]octanamide Chemical compound CCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SBWGZAXBCCNRTM-CTHBEMJXSA-N 0.000 description 1
- HEGSGKPQLMEBJL-UHFFFAOYSA-N n-octyl beta-D-glucopyranoside Natural products CCCCCCCCOC1OC(CO)C(O)C(O)C1O HEGSGKPQLMEBJL-UHFFFAOYSA-N 0.000 description 1
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- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 229920001987 poloxamine Polymers 0.000 description 1
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- 238000013105 post hoc analysis Methods 0.000 description 1
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- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- XEAOMHDITWFRFL-UHFFFAOYSA-N pyrazine-2-carboxamide Chemical compound NC(=O)C1=CN=CC=N1.NC(=O)C1=CN=CC=N1 XEAOMHDITWFRFL-UHFFFAOYSA-N 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000429 sodium aluminium silicate Substances 0.000 description 1
- 235000012217 sodium aluminium silicate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- FCZYGJBVLGLYQU-UHFFFAOYSA-M sodium;2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethanesulfonate Chemical compound [Na+].CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCS([O-])(=O)=O)C=C1 FCZYGJBVLGLYQU-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
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- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- FNDDDNOJWPQCBZ-ZDUSSCGKSA-N sutezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCSCC1 FNDDDNOJWPQCBZ-ZDUSSCGKSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
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- 229960001722 verapamil Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- 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
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- 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
- A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
-
- 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
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- 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
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は一般に、抗細菌活性を有する、より具体的には、抗結核特性を有する化合物の組み合わせに関する。特に、本発明は、結核の処置のための短期経口投与レジメンにおける、抗細菌剤であるリネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミドとの化学的に安定な組み合わせに関する。
Mycobacterium tuberculosisは、甚大な被害をもたらす感染性疾患である結核(「TB」)の原因因子である。全世界で、約200万人のTB患者が毎年死亡していると概算される。結核を適切に処置し損ねたことで、mycobacterium tuberculosisにおいて全世界的な薬物耐性が引き起こされたので、いくつかの薬物療法が無効になっている。
MDR−TB患者の不応性症例にとっての救済療法において効力が判明したが、その使用は、用量依存性および継続期間依存性の毒性によって縮小されてきた。3もしくはこれより多くの経口薬剤(そのうちの1つは、LZDであり、以前から存在する耐性がほとんどまたは全くない)に基づく新規なレジメンは、より単純で、より全般的に活性なレジメンを提供する。従って、薬剤感受性TBの現在の第1選択レジメンより有効であり、それによって、既存の薬物への耐性に関係なく、肺TBの処置を短期間にしかつ単純にする新規なレジメンが当該分野で必要である。
リネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを含む薬学的組成物が提供される。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
リネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを含む、薬学的組成物。
(項目2)
リネゾリドは、100mg/kgの投与量である、項目1に記載の薬学的組成物。
(項目3)
リネゾリドは、50mg/kgの投与量である、項目1に記載の薬学的組成物。
(項目4)
結核の処置のための方法であって、該方法は、必要性のある患者に、リネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを投与する工程を包含する方法。
(項目5)
リネゾリドは、3ヶ月間まで投与される、項目4に記載の方法。
(項目6)
リネゾリドは、2ヶ月間まで投与される、項目4に記載の方法。
(項目7)
リネゾリドは、1ヶ月間まで投与される、項目4に記載の方法。
(項目8)
リネゾリドは、100mg/kg/日で1〜2ヶ月間まで投与される、項目4に記載の方法。
(項目9)
リネゾリドは、50mg/kg/日で2ヶ月間まで投与される、項目4に記載の方法。
(項目10)
リネゾリドは、100mg/kg/日で1ヶ月間まで投与される、項目4に記載の方法。
(項目11)
リネゾリドは、最初の1〜2ヶ月間にわたって1日に1回、600mgの投与量で投与される、項目4に記載の方法。
(項目12)
リネゾリドは、1〜2週間の休薬日後に再投与される、項目4に記載の方法。
(項目13)
ベダキリンは、200〜400mg qdの投与量である、項目1に記載の薬学的組成物。
(項目14)
ベダキリンは、2週間にわたって400mg qd、続いて200mg tiwで投与される、項目4に記載の方法。
(項目15)
リネゾリドは、600mg bidまたは1200mg qdの投与量である、項目1に記載の薬学的組成物。
(項目16)
プレトマニドは、100〜200mg qdの投与量にある、項目1に記載の薬学的組成物。
本発明の説明は、明瞭さを目的として、代表的な薬学的組成物において見出される多くの他のエレメントを排除しながら、本発明の明瞭な理解のために直接関連のあるエレメントを例証するために単純化されていることが理解されるべきである。当業者は、他のエレメントおよび/または工程が、本発明を実施するにあたって望ましいおよび/または必要とされることを認識する。しかし、このようなエレメントおよび工程は、当該分野で周知であるので、そしてそれらは本発明のよりよい理解を促進しないので、このようなエレメントおよび工程の考察は、本明細書では提供されない。本明細書での開示は、当業者に公知のこのようなエレメントおよび方法に対する全てのそのようなバリエーションおよび改変に関連する。さらに、本明細書で同定され、例証される実施形態は、例示目的に過ぎず、それらの本発明の説明において排他的であることも限定されることも意味されない。
本発明は一般に、リネゾリド、ベダキリンおよびプレトマニド、必要に応じてピラジナミドとの経口投与量組み合わせに関する。
本明細書で商品名が使用される場合、出願人は、独立して、その商品名の製品およびその商品名の製品の活性な薬学的成分(単数または複数)を含むことを意図する。
マイコバクテリア株. M.tuberculosis H37Rvをマウスで継代し、アリコートに分けて凍結し、感染させる前に、10% オレイン酸−アルブミン−デキストロース−カタラーゼ(OADC)(Fisher, Pittsburgh, PA)および0.05% Tween 80を含むMiddlebrook 7H9ブロス中で継代した。
BDQ+PMDとの新規組み合わせへのLZDおよびSZDの寄与
実施例1を、市場に出ているオキサゾリジノンLZDが、効力を失うことなくこの組み合わせにおいてSZDに置き換わり得るか否かを評価するために、およびこの組み合わせの活性への各薬物成分の寄与を明らかにするために行った。
処置の間の肺CFU数。処置の開始時の平均CFU数(±S.D.)は、6.17±0.27であった。処置の1ヶ月、2ヶ月、および3ヶ月後の肺CFU数を表1に示す:
BDQ+PZA+PMDへのLZDの寄与
マウスにおけるBDQ+PZA+SZDの強力な滅菌活性およびPMDの相加的滅菌活性が以前に報告された(7, 9, 10, 12)。LZDが、実施例1においてBDQ+PMDとの組み合わせにおいてSZDに匹敵する滅菌活性を有したという観察の後に、LZDはまた、BDQ+PZA+PMD+SZD組み合わせにおいてSZDに置き換わることができた。処置開始時の平均CFU数は、7.92±0.26であった。肺CFU数および再発結果を、表2に示す:
BDQ+PMDとの新規組み合わせへのオキサゾリジノンの寄与
実施例3は、実施例1におけるBDQ+PMDに加えた場合に、SZDおよびLZDの相加的滅菌活性を確認するために、およびLZD用量を50%程度低減するかまたはLZDの継続期間を最初の1〜2ヶ月に制限することが、その寄与に有意に影響を及ぼすか否かを評価するために行った。
処置完了後の再発。再発結果を、表3に示す:
BALB/cマウスにおけるオキサゾリジノン薬物動態を、表4に示す:
1. リネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを含む、薬学的組成物。[臨床投与量を追加]
2. リネゾリドは、100mg/kgの投与量である、項1に記載の薬学的組成物。
3. リネゾリドは、50mg/kgの投与量である、項1に記載の薬学的組成物。
4. 結核の処置のための方法であって、該方法は、必要性のある患者に、リネゾリド、ベダキリンおよびプレトマニド、ならびに必要に応じてピラジナミド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを投与する工程を包含する方法。
5. リネゾリドは、3ヶ月間まで投与される、項4に記載の方法。
6. リネゾリドは、2ヶ月間まで投与される、項4に記載の方法。
7. リネゾリドは、1ヶ月間まで投与される、項4に記載の方法。
8. リネゾリドは、100mg/kg/日で1〜2ヶ月間まで投与される、項4に記載の方法。
9. リネゾリドは、50mg/kg/日で2ヶ月間まで投与される、項4に記載の方法。
10. リネゾリドは、100mg/kg/日で1ヶ月間まで投与される、項4に記載の方法。
11. リネゾリドは、最初の1〜2ヶ月間にわたって1日に1回、600mgの投与量で投与される、項4に記載の方法。
12. リネゾリドは、1〜2週間の休薬日後に再投与される、項4に記載の方法。
13. ベダキリンは、200〜400mg qdの投与量である、項1に記載の薬学的組成物。
14. ベダキリンは、2週間にわたって400mg qd、続いて200mg tiwで投与される、項4に記載の方法。
15. リネゾリドは、600mg bidまたは1200mg qdの投与量である、項1に記載の薬学的組成物。
16. プレトマニドは、100〜200mg qdの投与量にある、項1に記載の薬学的組成物。
Claims (23)
- リネゾリド、ベダキリンおよびプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の治療上有効な量、ならびに薬学的に受容可能なキャリアを含む、結核の処置のための薬学的組成物であって、前記リネゾリドが1〜2週間の休薬日後に再投与されることを特徴とする、薬学的組成物。
- ピラジナミドまたはその薬学的に受容可能な塩の治療上有効な量をさらに含む、請求項1に記載の薬学的組成物。
- リネゾリドは、100mg/kgの投与量である、請求項1または2に記載の薬学的組成物。
- リネゾリドは、50mg/kgの投与量である、請求項1または2に記載の薬学的組成物。
- 結核の処置のための組成物であって、該組成物は、リネゾリドまたはその薬学的に受容可能な塩を含み、ベダキリンおよびプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩、ならびに薬学的に受容可能なキャリアと組み合わせて投与されることを特徴とする、前記リネゾリドが1〜2週間の休薬日後に再投与されることを特徴とする、組成物。
- ピラジナミドまたはその薬学的に受容可能な塩と組み合わせて投与されることを特徴とする、請求項5に記載の組成物。
- 3ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 2ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 1ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 100mg/kg/日のリネゾリドで1〜2ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 50mg/kg/日のリネゾリドで2ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 100mg/kg/日のリネゾリドで1ヶ月間まで投与されることを特徴とする、請求項5または6に記載の組成物。
- 最初の1〜2ヶ月間にわたって1日に1回、600mgのリネゾリドの投与量で投与されることを特徴とする、請求項5または6に記載の組成物。
- ベダキリンは、200〜400mg qdの投与量である、請求項1または2に記載の薬学的組成物。
- ベダキリンは、2週間にわたって400mg qd、続いて200mg tiwで投与される、請求項5または6に記載の組成物。
- リネゾリドは、600mg bidまたは1200mg qdの投与量である、請求項1または2に記載の薬学的組成物。
- プレトマニドは、100〜200mg qdの投与量である、請求項1または2に記載の薬学的組成物。
- 結核の処置のための組合せ物であって、リネゾリド、ベダキリンおよびプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩、ならびに薬学的に受容可能なキャリアを含む、組合せ物であって、前記リネゾリドが1〜2週間の休薬日後に再投与されることを特徴とする、組合せ物。
- ピラジナミドまたはその薬学的に受容可能な塩をさらに含む、請求項18に記載の組合せ物。
- 前記薬学的組成物が、複数の単位投与量の形態であり、前記複数の単位投与量が、集合的に、リネゾリド、ベダキリンおよびプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の前記治療上有効な量を含む、請求項1または2に記載の薬学的組成物。
- 前記薬学的組成物が、複数の単位投与量の形態であり、前記複数の単位投与量が、集合的に、600mgまたは1200mgのリネゾリド、200〜400mgのベダキリン、100〜200mgのプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩を含む、請求項1または2に記載の薬学的組成物。
- 前記薬学的組成物が、単一の単位投与量の形態であり、前記単一の単位投与量が、リネゾリド、ベダキリンおよびプレトマニド、またはこれらのうちの各々の薬学的に受容可能な塩の各々の前記治療上有効な量を含む、請求項1または2に記載の薬学的組成物。
- 前記複数の単位投与量の各々が、錠剤またはカプセル剤の形態である、請求項20に記載の薬学的組成物。
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