JP6069336B2 - 腎の脱神経を包含する治療効果を増強するための組織および細胞の局所的調節 - Google Patents
腎の脱神経を包含する治療効果を増強するための組織および細胞の局所的調節 Download PDFInfo
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- JP6069336B2 JP6069336B2 JP2014537336A JP2014537336A JP6069336B2 JP 6069336 B2 JP6069336 B2 JP 6069336B2 JP 2014537336 A JP2014537336 A JP 2014537336A JP 2014537336 A JP2014537336 A JP 2014537336A JP 6069336 B2 JP6069336 B2 JP 6069336B2
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- guanethidine
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- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 description 1
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- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
参考による組み込み
一つの実施形態において、本発明は、例えば、以下の項目を提供する。
(項目1)
8より高いpHを有するグアニジンを含む組成物。
(項目2)
前記グアニジンが、グアネチジンである、項目1に記載の組成物。
(項目3)
前記グアネチジンが、一硫酸塩を包含する、項目2に記載の組成物。
(項目4)
前記グアネチジンが、脱神経用に形成された溶液中のヘミ硫酸塩を包含する、項目2に記載の組成物。
(項目5)
前記グアネチジンが、脱神経に適した溶液中のヘミ硫酸塩を包含する、項目2に記載の組成物。
(項目6)
前記pHが9より高い、項目1に記載の組成物。
(項目7)
前記pHが10より高い、項目1に記載の組成物。
(項目8)
アルカリ性バッファーをさらに含む、項目1に記載の組成物。
(項目9)
前記アルカリ性バッファーが、NaOHを含む、項目1に記載の組成物。
(項目10)
前記アルカリ性バッファーが、NaOHを、前記グアニジンの濃度に対して50%またはそれよりも高いモル濃度比で含む、項目1に記載の組成物。
(項目11)
前記アルカリ性バッファーが、NaOHを、前記グアニジンと等モル濃度でまたはそれよりも高いモル濃度で含む、項目1に記載の組成物。
(項目12)
造影剤をさらに含む、項目1〜11のいずれか一項に記載の組成物。
(項目13)
塩化ナトリウムをさらに含む、項目1〜11のいずれか一項に記載の組成物。
(項目14)
前記塩化ナトリウムが、前記溶液の0.7%〜0.9%である、項目13に記載の組成物。
(項目15)
前記グアネチジン一硫酸塩が、0.1mg/mL〜50mg/mLの濃度で存在する、項目3に記載の組成物。
(項目16)
前記グアネチジン一硫酸塩が、1mg/mL〜20mg/mLの濃度で存在する、項目3に記載の組成物。
(項目17)
局所組織の生理機能を調節する方法であって、液体、ゲル、または半固体を含む調製物を該組織に送達する工程を含む、方法。
(項目18)
前記調製物が、前記局所組織のpHを高くするかまたは低くすることによって前記局所組織の生理機能を緩衝化する、項目17に記載の方法。
(項目19)
前記調製物が、該調製物の送達によって調節された生理条件で該調製物の指標効果を有するが、中性の生理条件では指標効果を有さない治療剤を含む、項目18に記載の方法。
(項目20)
前記調製物が、該調製物の送達によって調節された生理条件で追加の指標効果または強化された指標効果を有するが、中性の生理条件では該追加の指標効果や強化された指標効果を有さない治療剤をさらに包含する、項目18に記載の方法。
(項目21)
前記ゲルが、ヒドロゲルを含む、項目17に記載の方法。
(項目22)
前記ヒドロゲルが、前記組織で再吸収するときにプロトンを消費する、項目21に記載の方法。
(項目23)
前記ヒドロゲルが、アルカリ性である、項目21に記載の方法。
(項目24)
前記調製物が、グアネチジン一硫酸塩を包含する、項目17〜23のいずれか一項に記載の方法。
(項目25)
前記調製物が、8より高いpHを有する、項目24に記載の方法。
(項目26)
前記調製物が、造影剤を包含する、項目24に記載の方法。
(項目27)
十分に低いまたは高いpHを有する酸または塩基の限局性送達により、限局性神経損傷または破壊を生じさせる工程を含む、腎脱神経を生じさせる方法。
(項目28)
他の局所組織を温存しながらニューロンの破壊を生じさせる非等張または非等モル浸透圧溶液の限局性送達を含む、腎脱神経を生じさせる方法。
(項目29)
腎動脈外膜および血管周囲組織への、8より高いpHのグアネチジン一硫酸塩の調製物または8より高いpHのグアネチジンヘミサルフェートの調製物の送達を含む、高血圧を処置する方法。
(項目30)
血管内の側からの送達をさらに含む、項目29に記載の方法。
(項目31)
腎動脈外膜および血管周囲組織への、8より高いpHのグアネチジン一硫酸塩の調製物または8より高いpHのグアネチジンヘミサルフェートの調製物の送達を含む、心不全を処置する方法。
(項目32)
腎動脈外膜および血管周囲組織への、8より高いpHのグアネチジン一硫酸塩の調製物または8より高いpHのグアネチジンヘミサルフェートの調製物の送達を含む、インスリン抵抗性を処置する方法。
(項目33)
腎動脈外膜および血管周囲組織への、8より高いpHのグアネチジン一硫酸塩の調製物または8より高いpHのグアネチジンヘミサルフェートの調製物の送達を含む、全身性炎症を処置する方法。
(項目34)
腎動脈外膜および血管周囲組織への、8より高いpHのグアネチジン一硫酸塩の調製物または8より高いpHのグアネチジンヘミサルフェートの調製物の送達を含む、睡眠時無呼吸を処置する方法。
(項目35)
洗浄剤、溶媒、エタノール、強酸、強塩基、緩衝剤、アルカリ性緩衝剤、酸性緩衝剤、0.7%〜0.9%の間の塩化ナトリウム含量を有する組成物、約9.5のpHを有する組成物、アルカリ性緩衝剤で緩衝化することによって約9.5に調整されたpHを有する組成物、水酸化ナトリウムで緩衝化することによって約9.5に調整されたpHを有する組成物、または8〜11の間のpHを有する組成物から選択される薬剤の限局性送達を含む、腎脱神経を生じさせる方法。
(項目36)
前記緩衝剤が、水酸化ナトリウム、炭酸水素ナトリウム、水酸化マグネシウム、硫酸、塩酸、クエン酸、酢酸、クエン酸ナトリウム、酢酸ナトリウム、ホウ酸、リン酸二水素カリウム、ジエチルバルビツール酸、3−{[トリス(ヒドロキシメチル)メチル]アミノ}プロパンスルホン酸、N,N−ビス(2−ヒドロキシエチル)グリシン、トリス(ヒドロキシメチル)アミノメタン、N−トリス(ヒドロキシメチル)メチルグリシン、2−[ビス(2−ヒドロキシエチル)アミノ]−2−(ヒドロキシメチル)−1,3−プロパンジオール、3−[N−トリス(ヒドロキシメチル)メチルアミノ]−2−ヒドロキシプロパンスルホン酸、4−2−ヒドロキシエチル−1−ピペラジンエタンスルホン酸、2−{[トリス(ヒドロキシメチル)メチル]アミノ}エタンスルホン酸、3−(N−モルホリノ)プロパンスルホン酸、ピペラジン−N,N’−ビス(2−エタンスルホン酸)、ジメチルアルシン酸、サリンソジウムシトレート(saline sodium citrate)、2−(N−モルホリノ)エタンスルホン酸、およびグリシンのうち1つまたは複数を含む、項目35に記載の方法。
(項目37)
以下のもの:7より高いpHの1μg/mLから50mg/mLの範囲の濃度のグアネチジン、7より高いpHの1mg/mLから30mg/mLの範囲の濃度のグアネチジン、0.7%〜0.9%の間の塩化ナトリウム含量を有するグアネチジンを含む組成物、約9.5のpHを有するグアネチジンを含む組成物、アルカリ性緩衝剤で緩衝化することによって約9.5に調整されたpHを有するグアネチジンを含む組成物、水酸化ナトリウムで緩衝化することによって約9.5に調整されたpHを有するグアネチジンを含む組成物、または8〜11の間のpHを有するグアネチジンを含む組成物から選択される薬剤の限局性送達を含む、腎脱神経を生じさせる方法。
(項目38)
テトロドトキシンおよびバトラコトキシンのうち1つまたは複数を含む、ナトリウムチャネルを介して細胞に入る第一の毒素、
マウロトキシン、アジトキシン、カリブドトキシン、マルガトキシン、スロトキシン、シクラトキシン、およびヘフトキシンのうち1つまたは複数を含む、カリウムチャネルを介して細胞に入る第二の毒素、および/または
カルシセプチン、タイカトキシン、カルシクルジン、およびPhTx3のうち1つまたは複数を含む、カルシウムチャネルを介して細胞に入る第三の毒素
を局所的にの限局性送達を含む、腎脱神経を生じさせる方法。
(項目39)
アドレナリン遮断薬、アンドロゲン阻害剤、アドレナリン刺激剤、アルファ−/ベータ−アドレナリン遮断薬、アンギオテンシン変換酵素(ACE)阻害剤、ACE受容体アンタゴニスト、ベータ遮断薬、カルシウムチャネル遮断薬、I〜IV群の抗不整脈薬、抗不整脈薬、強心薬、アルファ−2−アゴニスト、グアニジン誘導体、イミダゾリン受容体アゴニスト、神経節遮断薬、ニコチンアンタゴニスト、神経節遮断薬、ニコチンアンタゴニスト、MAOI阻害剤、アドレナリン取り込み阻害薬、チロシンヒドロキシラーゼ阻害剤、アルファ−1遮断薬、非選択的アルファ遮断薬、セロトニンアンタゴニスト、エンドセリンアンタゴニスト、硬化薬、または脱感覚神経薬を含む薬剤の限局性送達を含む、腎脱神経を生じさせる方法。
(項目40)
ドキサゾシン、グアナドレル、グアネチジン、フェノキシベンザミン、プラゾシン+ポリチアジド、テラゾシン、メチルドパ、クロニジン、グアナベンズ、グアンファシン、ラベタロール、ベナゼプリル、カプトプリル、エナラプリル、エナラプリラート、フォシノプリル、リシノプリル、モエキシプリル、キナプリル、ラミプリル、およびカルシウムチャネル遮断薬と利尿薬との組合せ、ロサルタン、アセブトロール、アテノロール、ベタキソロール、ビソプロロール、カルテオロール、エスモロール、フィモロール、ピンドロール、プロプラノロール、ペンブトロール、メトプロロール、ナドロール、ソタロール、アミロリド、アムロジピン、ベプリジル、ジルチアゼム、イスラジピン、ニフェジピン、ベラパミル、フェロジピン、ニカルジビン、ニモジピン、ブレチリウム、ジソピラミド、エンカイニド、フレカイニド、リドカイン、メキシレチン、モリシジン、プロパフェノン、プロカインアミド、キニジン、トカイニド、エスモロール、プロプラノロール、アセブトロール、アミオダロン、ソタロール、ベラパミル、ジルチアゼム、ピンドロール、ブプラノロール塩酸塩、トリクロルメチアジド、フロセミド、プラゾシン塩酸塩、メトプロロール酒石酸塩、カルテオロール塩酸塩、オクスプレノロール塩酸塩、およびプロプラノロール塩酸塩、アデノシン、ジゴキシン;メチルジゴキシン、カフェイン、ドパミン塩酸塩、ドブタミン塩酸塩、オクトパミン塩酸塩、ジプロフィリン、ユビデカレノン、ジギタリス、カプサイシン、抗神経成長因子、抗ドパミンベータ−ヒドロキシラーゼ、抗アセチルコリンエステラーゼ、6−ヒドロキシルドパミン(6−OHDA)、トシル酸ブレチリウム、グアナクリン、およびN−(2−クロロエチル)−N−エチル−2−ブロモベンジルアミン(DSP4)、OX7−SAP、192−SAP、抗ドパミンベータ−ヒドロキシラーゼサポリン(DBH−SAP)、および抗ドパミンベータ−ヒドロキシラーゼ免疫毒素(DHIT)、フェノール、エタノール、クロニジン、グアンファシン、メチルドパ、ベタニジン、グアノキサン、デブリソキン、グアノクロル、グアナゾジン、グアノキサベンズ、モキソニジン、リルメニジン、メカミラミン、トリメタファン、パルギリン、レシンナミン、レセルピン、メチロシン、プラゾシン、インドラミン、トリマゾシン、ドキサゾシン、ウラピジル、フェントラミン、ケタンセリン、ボセンタン、アンブリセンタン、シタキセンタン、キナクリン、クロロキン、テトラデシル硫酸ナトリウム、オレイン酸エタノールアミン、モルイン酸ナトリウム、ポリドカノール、または高張液を含む薬剤の限局性送達を含む、腎脱神経を生じさせる方法。
(項目41)
前記薬剤それ自身または該薬剤を含む組成物が、少なくとも7のpH、最大で11のpH、少なくとも7および最大で11のpH、少なくとも8および最大で10のpH、該薬剤が送達される神経を脱神経させるのに効果的であるpH、または該薬剤が送達される神経を脱神経させるのに効果的であるレベルに調整されるpHを有する、項目39または項目40に記載の方法。
(項目42)
前記薬剤が送達される組織が、少なくとも7のpH、最大で11のpH、少なくとも7および最大で11のpH、少なくとも8および最大で10のpH、該薬剤が送達される神経を脱神経させるのに効果的であるpHに調節される、項目39または40に記載の方法。
(項目43)
前記薬剤の前記組織への送達の前に、その後に、またはその間に、該組織が調節される、項目42に記載の方法。
(項目44)
前記薬剤それ自身または該薬剤を含む組成物が、最大で7のpH、少なくとも3のpH、最大で7および少なくとも3のpH、最大で6および少なくとも4のpH、該薬剤が送達される神経を脱神経させるのに効果的である酸性pH、または該薬剤が送達される神経を脱神経させるのに効果的であるレベルに調整される酸性pHを有する、項目39または40に記載の方法。
(項目45)
前記薬剤が送達される組織が、最大で7のpH、少なくとも3のpH、最大で7および少なくとも3のpH、最大で6および少なくとも4のpH、該薬剤が送達される神経を脱神経させるのに効果的である酸性pHに調節される、項目39または40に記載の方法。
(項目46)
前記薬剤の前記組織への送達の前に、その後に、またはその間に、該組織が調節される、項目45に記載の方法。
(項目47)
組織への治療剤の取り込みを強化する方法であって、
中心と外縁とを有する該組織の帯を生じさせることにより該組織のpHを調節する工程
を含み、
ここで、該帯は、調節する前の該組織の調節前pHと比較して、または中性pHと比較して調節されたpHを含み、
帯は、該帯の該中心で最もよく調節され、かつ該帯の該外縁で該組織の該調節前pHまたは中性pHまで低下させるpHの勾配を含み、
該帯において、該調節前pHまたは中性pHで組織へと起こる取り込みと比較して治療剤の強化された取り込みが起こる、方法。
(項目48)
前記帯に前記治療剤を送達する工程を含む、項目47に記載の方法。
(項目49)
前記治療剤が全身に送達され、前記組織のpHの調節により、前記帯における該治療剤の集積が強化されるか、または該帯における治療指数が改善される、項目47に記載の方法。
(項目50)
前記強化された取り込みが、予め選択した量によって、前記調節前pHから調節された前記調節されたpHを有する前記帯の部分内で起こる、項目47に記載の方法。
(項目51)
前記強化された取り込みが、予め選択した量によって、中性pHから調節された前記調節されたpHを有する前記帯の部分内で起こる、項目47に記載の方法。
(項目52)
前記予め選択した量が、0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、−0.5、−1.0、−1.5、−2.0、−2.5、−3.0、−3.5、−4.0、−4.5、0.5から5.0、1.5から4.5、2.0から4.0、約0.5、−0.5から−5.0、−1.5から−4.5、−2.0から−4.0、約0.5、約1.0、約1.5、約2.0、約2.5、約3.0、約3.5、約4.0、約4.5、約−0.5、約−1.0、約−1.5、約−2.0、約−2.5、約−3.0、約−3.5、約−4.0、および約−4.5のうち1つまたは複数の、前記調節されたpHと前記調節前pHとの間のpHの差、または前記調節されたpHと前記中性pHとの間のpHの差である、項目48または49に記載の方法。
(項目53)
前記調節されたpHが、前記帯外側の前記組織よりも低いpH、該帯外側の該組織よりも高いpH、調節する前の該組織のpHよりも低いpH、または調節する前の該組織のpHよりも高いpHである、項目47に記載の方法。
(項目54)
前記調節されたpHが、前記帯外側の組織のpHよりも酸性であるか、または、該帯外側の組織のpHよりもアルカリ性である、項目47に記載の方法。該調節されたpHが、少なくとも7、最大で11、少なくとも7および最大で11、少なくとも8および最大で10、または前記治療剤が送達される神経を脱神経させるのに効果的である所定のpHである、項目47に記載の方法。
(項目55)
前記治療剤が、グアネチジンを含む、項目47に記載の方法。
(項目56)
前記グアネチジンが、一硫酸塩またはヘミ硫酸塩を包含する、項目55に記載の方法。
(項目57)
前記調節されたpHが、少なくとも7、最大で11、少なくとも7および最大で11、少なくとも8および最大で10、または前記治療剤が送達される神経を脱神経させるのに効果的である所定のpHである、項目47に記載。
in vitroでのpHおよびグアネチジン一硫酸塩濃度に対する神経および平滑筋細胞の応答
・ SH−SY5Y:プレート培養したが誘導しなかったヒト神経芽細胞腫系SH−SY5Y、
・ 誘導SH−SY5Y:レチノイン酸で誘導して軸索が成長している交感神経細胞に分化したSH−SY5Y、
・ rPC−12:プレート培養したが誘導しなかった接着性ラットPC−12細胞、
・ 誘導rPC−12:NGFで誘導して軸索が成長している交感神経細胞に分化したPC−12、
・ ラットSCG:初代ラット上頸神経節細胞、
・ hAoSMC:初代ヒト大動脈平滑筋細胞。
動物実験および追跡研究
Claims (14)
- 局所組織の生理機能を調節することに使用するための、液体、ゲル、または半固体を含む調製物であって、
該調製物が、該組織に送達され、
該調製物が、該局所組織のpHを高くすることによって該局所組織の生理機能を緩衝化するために8.5〜9.5の間のpHを有し、
該調製物が、該調製物の送達によって調節された生理条件で該調製物の指標効果を有するが、中性の生理条件では指標効果を有さない治療剤を含み、
該指標効果が、該局所組織の非ニューロン細胞型に対して実質的な細胞毒性を引き起こすことなく、該局所組織を脱神経することを含み、そして、
該治療剤が、アルカリ性に緩衝化した形態のグアネチジン一硫酸塩、またはグアネチジンヘミ硫酸塩を含む、調製物。 - 前記調製物が、該調製物の送達によって調節された生理条件で追加の指標効果または強化された指標効果を有するが、中性の生理条件では該追加の指標効果や強化された指標効果を有さない治療剤をさらに包含する、請求項1に記載の使用するための調製物。
- 前記ゲルが、ヒドロゲルを含む、請求項1に記載の使用するための調製物。
- 前記ヒドロゲルが、前記組織で再吸収するときにプロトンを消費する、請求項3に記載の使用するための調製物。
- 前記ヒドロゲルが、アルカリ性である、請求項3に記載の使用するための調製物。
- 前記調製物が、造影剤を包含する、請求項1〜5のいずれか一項に記載の使用するための調製物。
- 組織への取り込みを強化するための治療剤であって、
中心と外縁とを有する該組織の帯を生じさせることによって、該組織のpHが、調節され、
ここで、該帯は、調節する前の該組織の調節前pHと比較して、または中性pHと比較して調節されたpHを含み、該調節されたpHは8より高く、
該帯は、該帯の該中心で最もよく調節され、かつ該帯の該外縁で該組織の該調節前pHまたは中性pHまで低下させるpHの勾配を含み、
該帯において、該調節前pHまたは中性pHで組織へと起こる取り込みと比較して該治療剤の強化された取り込みが起こり、該強化された取り込みは、該組織の非ニューロン細胞型に対して実質的な細胞毒性を引き起こすことなく、該組織の脱神経を引き起こし、そして、
該治療剤が、アルカリ性に緩衝化した形態のグアネチジン一硫酸塩、またはグアネチジンヘミ硫酸塩を含む、治療剤。 - 前記治療剤が、前記帯に送達される、請求項7に記載の治療剤。
- 前記強化された取り込みが、予め選択した量によって、前記調節前pHから調節された前記調節されたpHを有する前記帯の部分内で起こる、請求項7に記載の治療剤。
- 前記強化された取り込みが、予め選択した量によって、中性pHから調節された前記調節されたpHを有する前記帯の部分内で起こる、請求項7に記載の治療剤。
- 前記予め選択した量が、0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、−0.5、−1.0、−1.5、−2.0、−2.5、−3.0、−3.5、−4.0、−4.5、0.5から5.0、1.5から4.5、2.0から4.0、約0.5、−0.5から−5.0、−1.5から−4.5、−2.0から−4.0、約0.5、約1.0、約1.5、約2.0、約2.5、約3.0、約3.5、約4.0、約4.5、約−0.5、約−1.0、約−1.5、約−2.0、約−2.5、約−3.0、約−3.5、約−4.0、および約−4.5のうち1つまたは複数の、前記調節されたpHと前記調節前pHとの間のpHの差、または前記調節されたpHと前記中性pHとの間のpHの差である、請求項9または10に記載の治療剤。
- 前記調節されたpHが、前記帯外側の前記組織よりも低いpH、該帯外側の該組織よりも高いpH、調節する前の該組織のpHよりも低いpH、または調節する前の該組織のpHよりも高いpHである、請求項7に記載の治療剤。
- 前記調節されたpHが、前記帯外側の組織のpHよりもアルカリ性である、請求項7に記載の治療剤。
- 前記調節されたpHが、最大で11、または少なくとも8および最大で10である、請求項7に記載の治療剤。
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EP3556749A1 (en) | 2019-10-23 |
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CN110200963A (zh) | 2019-09-06 |
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AU2012325801B2 (en) | 2016-05-12 |
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EP2768514A1 (en) | 2014-08-27 |
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WO2013059735A1 (en) | 2013-04-25 |
JP2016011311A (ja) | 2016-01-21 |
EP2768514B1 (en) | 2019-05-01 |
IL232155A0 (en) | 2014-05-28 |
US20130252932A1 (en) | 2013-09-26 |
CN103998047A (zh) | 2014-08-20 |
BR112014009634A2 (pt) | 2017-05-09 |
JP2014530876A (ja) | 2014-11-20 |
AU2016210704A1 (en) | 2016-08-18 |
AU2012325801A1 (en) | 2014-05-22 |
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