DE69727958D1 - Zusammenstellungen und verfahren zur änderung der bioverteilung von biologischen agentien - Google Patents
Zusammenstellungen und verfahren zur änderung der bioverteilung von biologischen agentienInfo
- Publication number
- DE69727958D1 DE69727958D1 DE69727958T DE69727958T DE69727958D1 DE 69727958 D1 DE69727958 D1 DE 69727958D1 DE 69727958 T DE69727958 T DE 69727958T DE 69727958 T DE69727958 T DE 69727958T DE 69727958 D1 DE69727958 D1 DE 69727958D1
- Authority
- DE
- Germany
- Prior art keywords
- biodistribution
- compilations
- changing
- biological agents
- improved
- 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.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title abstract 3
- 239000003124 biologic agent Substances 0.000 title 1
- 239000003814 drug Substances 0.000 abstract 3
- 229940124597 therapeutic agent Drugs 0.000 abstract 2
- 108091034117 Oligonucleotide Proteins 0.000 abstract 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 108091033319 polynucleotide Proteins 0.000 abstract 1
- 102000040430 polynucleotide Human genes 0.000 abstract 1
- 239000002157 polynucleotide Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Acoustics & Sound (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Nanotechnology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Materials For Medical Uses (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/670,999 US5849727A (en) | 1996-06-28 | 1996-06-28 | Compositions and methods for altering the biodistribution of biological agents |
US670999 | 1996-06-28 | ||
PCT/US1997/010766 WO1998000172A2 (en) | 1996-06-28 | 1997-06-20 | Compositions and methods for altering the biodistribution of biological agents |
Publications (2)
Publication Number | Publication Date |
---|---|
DE69727958D1 true DE69727958D1 (de) | 2004-04-08 |
DE69727958T2 DE69727958T2 (de) | 2005-04-07 |
Family
ID=24692746
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE69727958T Expired - Lifetime DE69727958T2 (de) | 1996-06-28 | 1997-06-20 | Zusammensetzungen und Verfahren zur Änderung der Bioverteilung von biologischen Agentien |
Country Status (7)
Country | Link |
---|---|
US (5) | US5849727A (de) |
EP (1) | EP0938341B1 (de) |
JP (2) | JP4201348B2 (de) |
AT (1) | ATE260677T1 (de) |
CA (1) | CA2258882C (de) |
DE (1) | DE69727958T2 (de) |
WO (1) | WO1998000172A2 (de) |
Families Citing this family (119)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
US6088613A (en) | 1989-12-22 | 2000-07-11 | Imarx Pharmaceutical Corp. | Method of magnetic resonance focused surgical and therapeutic ultrasound |
US5205290A (en) | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
US6743779B1 (en) | 1994-11-29 | 2004-06-01 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
US6176842B1 (en) * | 1995-03-08 | 2001-01-23 | Ekos Corporation | Ultrasound assembly for use with light activated drugs |
US6521211B1 (en) | 1995-06-07 | 2003-02-18 | Bristol-Myers Squibb Medical Imaging, Inc. | Methods of imaging and treatment with targeted compositions |
US5648098A (en) * | 1995-10-17 | 1997-07-15 | The Board Of Regents Of The University Of Nebraska | Thrombolytic agents and methods of treatment for thrombosis |
US6245747B1 (en) | 1996-03-12 | 2001-06-12 | The Board Of Regents Of The University Of Nebraska | Targeted site specific antisense oligodeoxynucleotide delivery method |
AU736301B2 (en) | 1996-05-01 | 2001-07-26 | Imarx Therapeutics, Inc. | Methods for delivering compounds into a cell |
US5849727A (en) * | 1996-06-28 | 1998-12-15 | Board Of Regents Of The University Of Nebraska | Compositions and methods for altering the biodistribution of biological agents |
CN1238700A (zh) * | 1996-10-28 | 1999-12-15 | 奈科姆成像有限公司 | 诊断和/或治疗剂的改进或与其相关的改进 |
CA2270120A1 (en) | 1996-10-28 | 1998-05-07 | Pal Rongved | Improvements in or relating to diagnostic/therapeutic agents |
US20070036722A1 (en) * | 1996-10-28 | 2007-02-15 | Pal Rongved | Separation processes |
EP0973552B1 (de) * | 1996-10-28 | 2006-03-01 | Amersham Health AS | Verbesserungen an oder in verbindung mit diagnotischen/therapeutischen verbindungen |
EP0963209A2 (de) * | 1996-10-28 | 1999-12-15 | Marsden, John Christopher | Verbesserungen in oder an diagnostischen/ therapeutischen mitteln |
US6331289B1 (en) * | 1996-10-28 | 2001-12-18 | Nycomed Imaging As | Targeted diagnostic/therapeutic agents having more than one different vectors |
WO1998018495A2 (en) * | 1996-10-28 | 1998-05-07 | Marsden, John, Christopher | Improvements in or relating to diagnostic/therapeutic agents |
US6261537B1 (en) | 1996-10-28 | 2001-07-17 | Nycomed Imaging As | Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
US6582392B1 (en) | 1998-05-01 | 2003-06-24 | Ekos Corporation | Ultrasound assembly for use with a catheter |
US6676626B1 (en) | 1998-05-01 | 2004-01-13 | Ekos Corporation | Ultrasound assembly with increased efficacy |
US6416740B1 (en) | 1997-05-13 | 2002-07-09 | Bristol-Myers Squibb Medical Imaging, Inc. | Acoustically active drug delivery systems |
US6548047B1 (en) | 1997-09-15 | 2003-04-15 | Bristol-Myers Squibb Medical Imaging, Inc. | Thermal preactivation of gaseous precursor filled compositions |
US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US20030078227A1 (en) * | 1998-07-02 | 2003-04-24 | Greenleaf James F. | Site-directed transfection with ultrasound and cavitation nuclei |
WO2000002588A1 (en) * | 1998-07-13 | 2000-01-20 | The Board Of Regents Of The University Of Nebraska | Targeted site specific drug delivery compositions and method of use |
KR100649035B1 (ko) * | 1998-07-13 | 2006-11-24 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 네브라스카 | 표적화된 부위특이적 약물 송달 조성물 및 사용방법 |
US6309355B1 (en) * | 1998-12-22 | 2001-10-30 | The Regents Of The University Of Michigan | Method and assembly for performing ultrasound surgery using cavitation |
US6822086B1 (en) | 1999-08-09 | 2004-11-23 | The General Hospital Corporation | Drug-carrier complexes and methods of use thereof |
US8106098B2 (en) | 1999-08-09 | 2012-01-31 | The General Hospital Corporation | Protein conjugates with a water-soluble biocompatible, biodegradable polymer |
DE60143085D1 (de) * | 2000-05-17 | 2010-10-28 | Univ Nebraska | Morpholino antisense oligomere als enzyminhibitoren zur verbesserung der pharmacokinetik eines wirkstoffs |
JP2002145784A (ja) * | 2000-11-10 | 2002-05-22 | Ryuichi Morishita | 生物学的活性薬剤導入組成物およびその使用方法 |
DE10119522A1 (de) * | 2001-04-20 | 2002-12-05 | Innovacell Biotechnologie Gmbh | Herstellung und Anwendung einer Suspensionszusammensetzung mit einem Ultraschall-Kontrastmittel |
EP1420643B1 (de) * | 2001-07-10 | 2008-04-23 | Sonogene, LLC | Verbesserung der transfektion von dna in die leber |
US7897382B2 (en) * | 2001-10-22 | 2011-03-01 | Alnylam Pharmaceuticals, Inc. | Transfection kinetics and structural promoters |
DE60214877T2 (de) * | 2001-10-22 | 2007-02-15 | Nucleonics, Inc. | Transfektionskinetik und strukturelle promotoren |
AU2002359576A1 (en) | 2001-12-03 | 2003-06-17 | Ekos Corporation | Catheter with multiple ultrasound radiating members |
WO2003080123A1 (fr) * | 2002-03-22 | 2003-10-02 | Anges Mg, Inc. | Compositions delivrant un medicament biologiquement actif, et procede d'utilisation |
US8226629B1 (en) | 2002-04-01 | 2012-07-24 | Ekos Corporation | Ultrasonic catheter power control |
US20040180438A1 (en) * | 2002-04-26 | 2004-09-16 | Pachuk Catherine J. | Methods and compositions for silencing genes without inducing toxicity |
US20040126400A1 (en) * | 2002-05-03 | 2004-07-01 | Iversen Patrick L. | Delivery of therapeutic compounds via microparticles or microbubbles |
US20030207907A1 (en) * | 2002-05-03 | 2003-11-06 | Iversen Patrick L. | Delivery of microparticle-conjugated drugs for inhibition of stenosis |
US7754238B2 (en) * | 2002-05-03 | 2010-07-13 | Avi Biopharma, Inc. | Delivery of microparticle-conjugated drugs for inhibition of stenosis |
US20060084617A1 (en) * | 2002-05-06 | 2006-04-20 | Satishchandran C | Methods for delivery of nucleic acids |
AU2003274906A1 (en) * | 2002-07-31 | 2004-02-16 | Nucleonics, Inc. | Double stranded rna structures and constructs, and methods for generating and using the same |
US6921371B2 (en) | 2002-10-14 | 2005-07-26 | Ekos Corporation | Ultrasound radiating members for catheter |
ES2351976T3 (es) | 2003-04-29 | 2011-02-14 | Avi Biopharma, Inc. | Composiciones para mejorar el transporte y la eficacia antisentido de análogos de ácidos nucleicos en células. |
US20050222068A1 (en) * | 2003-10-23 | 2005-10-06 | Mourich Dan V | Method and antisense composition for selective inhibition of HIV infection in hematopoietic cells |
US7025726B2 (en) * | 2004-01-22 | 2006-04-11 | The Regents Of The University Of Nebraska | Detection of endothelial dysfunction by ultrasonic imaging |
US20050288246A1 (en) | 2004-05-24 | 2005-12-29 | Iversen Patrick L | Peptide conjugated, inosine-substituted antisense oligomer compound and method |
DE102004057196A1 (de) * | 2004-11-26 | 2006-06-01 | Rösner Research GmbH & Co.KG | Verfahren zur Herstellung von Albumin-Konjugaten mit Nicht-steroidalen Antirheumatika (NSAR) |
US20060240032A1 (en) * | 2005-03-31 | 2006-10-26 | Hinrichs David J | Immunomodulating compositions and methods for use in the treatment of human autoimmune diseases |
WO2006129080A1 (en) * | 2005-05-31 | 2006-12-07 | The Institute Of Cancer Research: Royal Cancer Hospital | Materials and methods for transducing cells with a viral vector |
US8067571B2 (en) | 2005-07-13 | 2011-11-29 | Avi Biopharma, Inc. | Antibacterial antisense oligonucleotide and method |
US8057408B2 (en) | 2005-09-22 | 2011-11-15 | The Regents Of The University Of Michigan | Pulsed cavitational ultrasound therapy |
US10219815B2 (en) | 2005-09-22 | 2019-03-05 | The Regents Of The University Of Michigan | Histotripsy for thrombolysis |
US20070140965A1 (en) * | 2005-12-02 | 2007-06-21 | Barnes-Jewish Hospital | Methods to ameliorate and image angioplasty-induced vascular injury |
US8715221B2 (en) | 2006-03-08 | 2014-05-06 | Fresenius Medical Care Holdings, Inc. | Wearable kidney |
US8012118B2 (en) | 2006-03-08 | 2011-09-06 | Fresenius Medical Care Holdings, Inc. | Artificial kidney dialysis system |
JP5368305B2 (ja) | 2006-08-24 | 2013-12-18 | フレゼニウス メディカル ケア ホールディングス インコーポレーテッド | 患者の血液から液体を除去するためのデバイス |
US10182833B2 (en) | 2007-01-08 | 2019-01-22 | Ekos Corporation | Power parameters for ultrasonic catheter |
PL2170181T3 (pl) | 2007-06-22 | 2014-08-29 | Ekos Corp | Sposób i aparat do leczenia wylewów wewnątrzczaszkowych |
US20100016215A1 (en) | 2007-06-29 | 2010-01-21 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
AU2008271050B2 (en) * | 2007-06-29 | 2014-11-06 | Sarepta Therapeutics, Inc. | Tissue specific peptide conjugates and methods |
EP2200652B1 (de) | 2007-09-27 | 2018-03-21 | Children's Medical Center Corporation | Mikrobläschen und sauerstoffabgabe-verfahren |
WO2009117688A2 (en) * | 2008-03-21 | 2009-09-24 | The Board Of Trustees Of The University Of Arkansas | Methods for producing microbubbles |
CN102202702B (zh) | 2008-11-03 | 2014-05-21 | 弗雷泽纽斯医疗保健控股有限公司 | 便携式腹膜透析系统 |
CA2746508A1 (en) * | 2008-12-17 | 2010-07-15 | Avi Biopharma, Inc. | Antisense compositions and methods for modulating contact hypersensitivity or contact dermatitis |
US20110269665A1 (en) | 2009-06-26 | 2011-11-03 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
US9061131B2 (en) | 2009-08-17 | 2015-06-23 | Histosonics, Inc. | Disposable acoustic coupling medium container |
EP2470087B1 (de) | 2009-08-26 | 2015-03-25 | The Regents Of The University Of Michigan | Vorrichtungen zur verwendung kontrollierter blasenwolkenhohlräume beim zerbrechen von harnsteinen |
JP5863654B2 (ja) | 2009-08-26 | 2016-02-16 | リージェンツ オブ ザ ユニバーシティー オブ ミシガン | 治療および画像処理超音波変換器用のマイクロマニピュレータ制御アーム |
US10058837B2 (en) | 2009-08-28 | 2018-08-28 | The Trustees Of Columbia University In The City Of New York | Systems, methods, and devices for production of gas-filled microbubbles |
US8539813B2 (en) | 2009-09-22 | 2013-09-24 | The Regents Of The University Of Michigan | Gel phantoms for testing cavitational ultrasound (histotripsy) transducers |
WO2011084694A1 (en) | 2009-12-17 | 2011-07-14 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Stabilized stat3 decoy oligonucleotides and uses therefor |
WO2012065060A2 (en) * | 2010-11-12 | 2012-05-18 | Children's Medical Center Corporation | Gas-filled microbubbles and systems for gas delivery |
US9161948B2 (en) | 2011-05-05 | 2015-10-20 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
KR20120140290A (ko) * | 2011-06-21 | 2012-12-31 | 주식회사 퍼시픽시스템 | 기능성 물질의 전달을 촉진하는 기포 제조 방법 및 이를 이용하는 기능성 물질 전달 장치 |
US9144694B2 (en) | 2011-08-10 | 2015-09-29 | The Regents Of The University Of Michigan | Lesion generation through bone using histotripsy therapy without aberration correction |
US10357450B2 (en) | 2012-04-06 | 2019-07-23 | Children's Medical Center Corporation | Process for forming microbubbles with high oxygen content and uses thereof |
US9049783B2 (en) | 2012-04-13 | 2015-06-02 | Histosonics, Inc. | Systems and methods for obtaining large creepage isolation on printed circuit boards |
WO2013166019A1 (en) | 2012-04-30 | 2013-11-07 | The Regents Of The University Of Michigan | Ultrasound transducer manufacturing using rapid-prototyping method |
US20140100459A1 (en) | 2012-10-05 | 2014-04-10 | The Regents Of The University Of Michigan | Bubble-induced color doppler feedback during histotripsy |
WO2014117232A1 (pt) * | 2013-02-04 | 2014-08-07 | Farret Neto Abdo | Preparação medicinal sob a forma de espuma para a liberação prolongada de medicamentos e sistema para obtenção da preparação medicinal |
US9101745B2 (en) | 2013-03-14 | 2015-08-11 | Sonogene Llc | Sonochemical induction of ABCA1 expression and compositions therefor |
AU2014232195A1 (en) * | 2013-03-15 | 2015-10-15 | Doheny Eye Institute | Management of tractional membranes |
US10577554B2 (en) | 2013-03-15 | 2020-03-03 | Children's Medical Center Corporation | Gas-filled stabilized particles and methods of use |
US10124126B2 (en) * | 2013-04-18 | 2018-11-13 | The Regents Of The University Of Colorado, A Body Corporate | System and methods for ventilation through a body cavity |
WO2015003154A1 (en) | 2013-07-03 | 2015-01-08 | Histosonics, Inc. | Articulating arm limiter for cavitational ultrasound therapy system |
EP4166194A1 (de) | 2013-07-03 | 2023-04-19 | Histosonics, Inc. | Für blasenwolkenbildung mittels schockstreuung optimierte histotripsieerregungssequenzen |
WO2015027164A1 (en) | 2013-08-22 | 2015-02-26 | The Regents Of The University Of Michigan | Histotripsy using very short ultrasound pulses |
US11305013B2 (en) * | 2014-08-26 | 2022-04-19 | Drexel University | Surfactant microbubbles and process for preparing and methods of using the same |
US10052394B2 (en) | 2014-11-21 | 2018-08-21 | General Electric Company | Microbubble tether for diagnostic and therapeutic applications |
US11000476B2 (en) | 2015-05-28 | 2021-05-11 | Pacific System Co., Ltd. | Cavitation seed for drug delivery, and drug delivery method using same |
EP3302489A4 (de) | 2015-06-04 | 2019-02-06 | Sarepta Therapeutics, Inc. | Verfahren und verbindungen zur behandlung von krankheiten und leiden im zusammenhang mit lymphozyten |
CN107708581B (zh) | 2015-06-10 | 2021-11-19 | Ekos公司 | 超声波导管 |
ES2948135T3 (es) | 2015-06-24 | 2023-08-31 | Univ Michigan Regents | Sistemas de terapia de histotripsia para el tratamiento del tejido cerebral |
LT3554553T (lt) | 2016-12-19 | 2022-08-25 | Sarepta Therapeutics, Inc. | Egzoną šalinantys oligomero konjugatai nuo raumenų distrofojos |
US11147890B2 (en) | 2017-02-28 | 2021-10-19 | Children's Medical Center Corporation | Stimuli-responsive particles encapsulating a gas and methods of use |
AU2019389001A1 (en) | 2018-11-28 | 2021-06-10 | Histosonics, Inc. | Histotripsy systems and methods |
EP4096782A4 (de) | 2020-01-28 | 2024-02-14 | The Regents Of The University Of Michigan | Systeme und verfahren zur histotripsie-immunsensibilisierung |
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Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4572203A (en) * | 1983-01-27 | 1986-02-25 | Feinstein Steven B | Contact agents for ultrasonic imaging |
US4718433A (en) * | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
US4634586A (en) * | 1984-05-21 | 1987-01-06 | The Board Of Trustees Of The Leland Stanford Junior University | Reagent and method for radioimaging leukocytes |
US5040537A (en) * | 1987-11-24 | 1991-08-20 | Hitachi, Ltd. | Method and apparatus for the measurement and medical treatment using an ultrasonic wave |
US4844882A (en) * | 1987-12-29 | 1989-07-04 | Molecular Biosystems, Inc. | Concentrated stabilized microbubble-type ultrasonic imaging agent |
US5410516A (en) * | 1988-09-01 | 1995-04-25 | Schering Aktiengesellschaft | Ultrasonic processes and circuits for performing them |
US4957656A (en) * | 1988-09-14 | 1990-09-18 | Molecular Biosystems, Inc. | Continuous sonication method for preparing protein encapsulated microbubbles |
US5703055A (en) * | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
US5542935A (en) * | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US5733572A (en) * | 1989-12-22 | 1998-03-31 | Imarx Pharmaceutical Corp. | Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles |
IN172208B (de) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
US5315997A (en) * | 1990-06-19 | 1994-05-31 | Molecular Biosystems, Inc. | Method of magnetic resonance imaging using diamagnetic contrast |
CA2068334C (en) * | 1990-10-05 | 1996-09-03 | Claude Giddey | Method for the preparation of stable suspensions of hollow gas-filled microspheres suitable for ultrasonic echography |
US5107842A (en) * | 1991-02-22 | 1992-04-28 | Molecular Biosystems, Inc. | Method of ultrasound imaging of the gastrointestinal tract |
EP0732106A3 (de) * | 1991-03-22 | 2003-04-09 | Katsuro Tachibana | Mikrobläschen enthaltende Verstärker zur Ultraschalltherapie von Erkrankungen |
RU2114637C1 (ru) * | 1991-09-17 | 1998-07-10 | Сонус Фармасьютикалз, Инк. | Биосовместимая контрастная среда и способ получения ультразвукового изображения |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
US5304325A (en) * | 1991-11-13 | 1994-04-19 | Hemagen/Pfc | Emulsions containing alkyl- or alkylglycerophosphoryl choline surfactants and methods of use |
US5255683A (en) * | 1991-12-30 | 1993-10-26 | Sound Science Limited Partnership | Methods of and systems for examining tissue perfusion using ultrasonic contrast agents |
IL104084A (en) * | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
US5585479A (en) * | 1992-07-24 | 1996-12-17 | The United States Of America As Represented By The Secretary Of The Navy | Antisense oligonucleotides directed against human ELAM-I RNA |
US5302372A (en) * | 1992-07-27 | 1994-04-12 | National Science Council | Method to opacify left ventricle in echocardiography |
DE4232755A1 (de) * | 1992-09-26 | 1994-03-31 | Schering Ag | Mikropartikelpräparationen aus biologisch abbaubaren Mischpolymeren |
SG52198A1 (en) * | 1993-01-25 | 1998-09-28 | Sonus Pharma Inc | Phase shift colloids as ultrasound contrast agents |
US5439686A (en) * | 1993-02-22 | 1995-08-08 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor |
US5362478A (en) * | 1993-03-26 | 1994-11-08 | Vivorx Pharmaceuticals, Inc. | Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell |
CA2155947C (en) * | 1993-02-22 | 2007-08-21 | Mark W. Grinstaff | Methods for in vivo delivery of biologics and compositions useful therefor |
US5401493A (en) * | 1993-03-26 | 1995-03-28 | Molecular Biosystems, Inc. | Perfluoro-1H,-1H-neopentyl containing contrast agents and method to use same |
US5695740A (en) * | 1993-05-12 | 1997-12-09 | The Board Of Regents Of The University Of Nebraska | Perfluorocarbon ultrasound contrast agent comprising microbubbles containing a filmogenic protein and a saccharide |
US5567415A (en) * | 1993-05-12 | 1996-10-22 | The Board Of Regents Of The University Of Nebraska | Ultrasound contrast agents and methods for their manufacture and use |
US5701899A (en) * | 1993-05-12 | 1997-12-30 | The Board Of Regents Of The University Of Nebraska | Perfluorobutane ultrasound contrast agent and methods for its manufacture and use |
WO1995001187A1 (en) * | 1993-07-02 | 1995-01-12 | Molecular Biosystems, Inc. | Protein encapsulated insoluble gas microspheres and their preparation and use as ultrasonic imaging agents |
US5385147A (en) * | 1993-09-22 | 1995-01-31 | Molecular Biosystems, Inc. | Method of ultrasonic imaging of the gastrointestinal tract and upper abdominal organs using an orally administered negative contrast medium |
NO940711D0 (no) * | 1994-03-01 | 1994-03-01 | Nycomed Imaging As | Preparation of gas-filled microcapsules and contrasts agents for diagnostic imaging |
US5540909A (en) * | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
US5560364A (en) * | 1995-05-12 | 1996-10-01 | The Board Of Regents Of The University Of Nebraska | Suspended ultra-sound induced microbubble cavitation imaging |
EP0888054B1 (de) * | 1996-03-12 | 2003-09-03 | Board Of Regents Of The University Of Nebraska | Zusammensetzung zur zielortspezifischen verabreichung eines medikamentes und verfahren zur anwendung |
US5849727A (en) * | 1996-06-28 | 1998-12-15 | Board Of Regents Of The University Of Nebraska | Compositions and methods for altering the biodistribution of biological agents |
-
1996
- 1996-06-28 US US08/670,999 patent/US5849727A/en not_active Expired - Lifetime
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1997
- 1997-06-20 WO PCT/US1997/010766 patent/WO1998000172A2/en active IP Right Grant
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- 1997-06-20 EP EP97932228A patent/EP0938341B1/de not_active Expired - Lifetime
- 1997-06-20 JP JP50420598A patent/JP4201348B2/ja not_active Expired - Lifetime
- 1997-06-20 CA CA002258882A patent/CA2258882C/en not_active Expired - Lifetime
- 1997-06-20 AT AT97932228T patent/ATE260677T1/de not_active IP Right Cessation
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1998
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2000
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2003
- 2003-01-31 US US10/355,388 patent/US7115583B2/en not_active Expired - Fee Related
- 2003-09-22 US US10/668,448 patent/US7198949B2/en not_active Expired - Fee Related
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JP2000515499A (ja) | 2000-11-21 |
US7198949B2 (en) | 2007-04-03 |
WO1998000172A2 (en) | 1998-01-08 |
ATE260677T1 (de) | 2004-03-15 |
JP4201348B2 (ja) | 2008-12-24 |
US7115583B2 (en) | 2006-10-03 |
US5849727A (en) | 1998-12-15 |
CA2258882A1 (en) | 1998-01-08 |
WO1998000172A3 (en) | 1998-05-14 |
US20040057946A1 (en) | 2004-03-25 |
JP2009029810A (ja) | 2009-02-12 |
US20040013662A1 (en) | 2004-01-22 |
DE69727958T2 (de) | 2005-04-07 |
CA2258882C (en) | 2009-03-17 |
EP0938341A2 (de) | 1999-09-01 |
US6117858A (en) | 2000-09-12 |
US6537814B1 (en) | 2003-03-25 |
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