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WO1989010760A1 - Peptides synthetiques pour imagerie arterielle - Google Patents

Peptides synthetiques pour imagerie arterielle Download PDF

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Publication number
WO1989010760A1
WO1989010760A1 PCT/US1989/001854 US8901854W WO8910760A1 WO 1989010760 A1 WO1989010760 A1 WO 1989010760A1 US 8901854 W US8901854 W US 8901854W WO 8910760 A1 WO8910760 A1 WO 8910760A1
Authority
WO
WIPO (PCT)
Prior art keywords
synthetic peptide
step further
introducing step
ldl
peptide
Prior art date
Application number
PCT/US1989/001854
Other languages
English (en)
Inventor
Robert S. Lees
Ann M. Lees
Ing Lung Shih
Allan Fischman
Original Assignee
New England Deaconess Hospital Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by New England Deaconess Hospital Corporation filed Critical New England Deaconess Hospital Corporation
Publication of WO1989010760A1 publication Critical patent/WO1989010760A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A61K51/1224—Lipoprotein vesicles, e.g. HDL and LDL proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the technical field of this invention concerns methods and means useful for the early detection of vascular disease, such as atherosclerosis, and in particular, methods and means employing labelled synthetic peptides to detect arterial injury.
  • Atherosclerosis is a disease which causes the thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions or raised fibrous plaques which form within the arterial lumen. The plaques are most prevalent in the abdominal aorta, coronary arteries or carotid arteries and they increase progressively with age. They commonly present dome-shaped, opaque, glistening surfaces which bulge into the lumen.
  • a lesion typically will consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits and exhibit various degrees of necrosis, thrombosis and ulceration.
  • the injury at, or deformities of, the arterial lumen presented by the plaque and associated deposits result in occluded blood flow, and ultimately in angina, cerebral ischemia, renal hypertension, ischemic heart disease, stroke, and diseases of other organs, if untreated.
  • coronary atherosclerosis is still the leading cause of death in the United States, claiming the lives of over a half million Americans annually, roughly twice as many as are killed by cancer.
  • LDLs circulating in the blood are known to bind to atherosclerotic plaques (Lees et al. (1983) J. Nucl. Med. 24.:154-156) . In mammals this binding most likely occurs via apolipoprotein B-100 (apo B-100), the protein moiety of the LDL molecule, which is responsible for the removal of LDL from the circulation by receptor-mediated uptake in a variety of cell types.
  • LDLs conjugated to a radioactive label can be used to provide information on the location and extent of plaque in the vascular system by imaging them with a radiation detector. Alternatively, LDLs can be labelled with a non-radioactive, paramagnetic contrast agent capable of detection in magnetic resonance imaging (MRI) systems.
  • MRI magnetic resonance imaging
  • Yet another object of the present invention is to provide a method, which is non-invasive, of detecting and mapping vascular injury.
  • vascular diseases including asymptomatic atherosclerosis
  • vascular diseases can be diagnosed by administering a labelled synthetic peptide to a patient, and then detecting the location, pattern, and concentration of the peptide which has accumulated within the patient's vascular system.
  • the invention is directed to molecules having an affinity for a site of arterial injury. More specifically, the invention is directed to synthetic peptides which are useful for detecting and imaging this injury.
  • the synthetic peptides administered have an affinity for, and propensity to accumulate at a site of arterial injury, for example, sustantially the same affinity and propensity as does LDL.
  • the synthetic peptides may also have a molecular conformation (or size, shape, and charge) which is substantially analogous to a portion of the molecular conformation of LDL, for example.
  • the synthetic peptide may have an amino acid sequence sufficiently duplicative of that of at least a portion of the apo B moiety of LDL, such that the peptide accumulates at a site of arterial injury in a manner characteristic of LDL. Examples of particularly useful sequences are: (NH 2 ) -Y-R-D-K-E-5-D-G-E-T-I-K-I-(COOH)
  • the synthetic peptide may be linked to a label to enable its monitoring within the patient.
  • Preferable labels include a radioisotope such as 131 I ⁇ 125 ⁇ 123 I# lll In# 99m TC/ 203 Pby 198 H ⁇ j or
  • Such labels may enable the extracorporeal monitoring of synthetic peptide within the vascular system of the subject with, for example, a gamma scintillation camera or an MRI system.
  • the synthetic peptides are useful for detecting and imaging arterial injury in the vascular system of a subject.
  • a preferred detection method includes introducing into a subject a synthetic peptide of the form set forth above.
  • the peptide to be introduced may be administrated by arterial or venous injection.
  • a non-hydrolyzable derivative may be administered orally or nasally.
  • the introduced synthetic peptide is then allowed to circulate within the vascular system of the subject, whereby at least a portion of it accumulates at a site of arterial injury.
  • the portion of the synthetic peptide which has accumulated at a site of arterial injury is then detected.
  • the detection step may further include imaging the region of the -1-
  • An additional step of quantitating the amount of synthetic peptide which has accumulated at a site of vascular injury may also be carried out as part of the method of the present invention.
  • FIG. 1 shows a schematic model of apo B-100 configuration on the LDL molecule and surface-exposed regions
  • FIG. 2 shows a representative plasma decay curve for 12 5i-iabelled synthetic peptide
  • FIG. 3 is an onlay autoradiogram of the abdominal aorta of a rabbit treated with 125 I-labelled synthetic peptide SP-4, showing labelled healing lesions in the balloon de-endothelialized section of the aorta (B) as compared with the unlabelled control portion (A) .
  • This invention provides synthetic peptides which have affinity for, and the propensity to accumulate at a site of arterial injury, and therefore are useful in detecting, diagnosing and monitoring vascular disease.
  • synthetic peptides having these characteristics may have an amino acid sequence that is analogous to portions of known polypeptides which have an affinity for a site of vascular injury, i.e., have a molecular conformation, charge, and/or size which is similar to that part of the polypeptide (e.g., LDL) which is responsible for its affinity for arterial lesions.
  • the synthetic peptides of the present invention may be homologous with portions of the apo B-100 protein moiety of LDL.
  • the primary structure of apo B-100 has become available by virtue of its cloning (Knott et al. (1986) Nature 323:734-742; Lusis et al. (1985) Proc. Natl. Acad.
  • peptides can also be produced by the established procedure of solid phase peptide synthesis. Briefly, this procedure entails the sequentially assembly of the appropriate amino acids into a peptide of a desired sequence while the end of the growing peptide is linked to an insoluble support. Usually, the carboxyl terminus of the peptide is linked to the polymer from which it can be liberated upon treatment with a cleavage reagent.
  • the peptides so synthesized are then labelled with a reagent which enables the monitoring of the peptide after its administration to a patient.
  • synthetic peptides having an amino acid sequence homologous to, or having at least a part of their molecular conformation being substantially analogous to, surface portions of native apo B-100 are used to create radiolabelled diagnostic reagents.
  • the label may be, for example, a radioisotope such as --251 or 99m ⁇ C/ both of which may be imaged extracorporeally by radiation detection means such a gamma scintillation camera.
  • the synthetic peptides can be labelled with a non-radioactive, paramagnetic contrast agent capable of detection in MRI systems.
  • a strong magnetic field is used to align the nuclear spin vectors of the atoms in a patient's body. The field is then disturbed and an image of the patient is read as the nuclei return to their equilibrium alignments.
  • synthetic peptides can be linked to paramagnetic contrast agents such as gadolinium, cobalt, nickel, manganese or iron complexes, to form conjugate diagnostic reagents that are imaged extracorporeally with an MRI system.
  • the labelled synthetic peptide is then administered to a patient.
  • Administration may be accomplished by arterial or venous injection.
  • a non-hydrolyzable derivative of the peptide e.g., a keto methylene derivative
  • administration may be accomplished nasally.
  • the amount of labelled peptide administered is sufficient for later detection.
  • the rabbit model has been imaged both by onlay autoradiography with 12 5i-iabelled LDL and by external imaging with 99m Tc-labelled LDL using a gamma scintillation camera. Human lesions have been imaged with both isotopes using a gamma scintillation camera.
  • onlay autoradiography of the excised rabbit aorta has been reliably predictive of the i vivo results with extracorporeal imaging.
  • LDL accumulates both in the balloon de-endothelialized healing arterial wall of the rabbit and in human atheroma (Camejo (1982) Adv. Lipid Res. 19:1-53) . Accordingly, a rabbit whose abdominal aorta has been balloon de-endothelialized approximately four weeks prior is used as a test model for human arterial disease.
  • other animals or experimental systems can be used as well.
  • each labelled synthetic peptide may be bound to the surface of a lipid emulsion such as a cholesterol ester phospholipid microemulsion.
  • the emulsion is then injected intravenously into the rabbit. Approximately twenty-four hours later, the rabbit is subjected to extracorporeal monitoring appropriate for the specific label on the peptide.
  • the rabbit is sacrificed, and its aorta removed and washed. The aorta is then either cut into sequential portions which are then monitored in a liquid scintillation counter, or is dried, covered with a layer of polyester wrap, and placed on a sheet of x-ray film which is then developed to produce an onlay autoradiogram after suitable storage time in the dark.
  • FIG. 3 An example of such an autoradiogram is shown in FIG. 3. in which the 12 5i-labelled synthetic peptide, SP-4 was used to image arterial injury.
  • Synthetic peptides are designed from the amino acid sequences of various portions of apo B which are shown in FIG. 1. Two representative peptides are (1) SP-1 and (2) SP-4 shown below:
  • Peptides are synthesized by solid phase peptide synthesis according to the established method of Stewart and Young (Solid Phase Peptide Synthesis, 2nd ed., (1984) The Pierce Chemical Co., Rockford, IL pp. 53-123), herein incorporated as reference.
  • the schedule listed below in TABLE 2 is followed, but any one of the other schedules listed in this reference may alternatively be used to generate the desired peptides.
  • the synthetic peptides may be labelled directly with technetium (Tc) , or indirectly through covalent attachment of a chelating group such as diethylenetriamine pentaacetic acid (DTPA), which is known to chelate a variety of metals including radioisotopes such as 111 -indium.
  • Tc technetium
  • DTPA diethylenetriamine pentaacetic acid
  • the radiolabelled synthetic peptide fraction radiolabelled with 1 5 ⁇ Q r 9m Tc is separated from uncoupled technetium and sodium dithionite by molecular sieve chromatography.
  • the column is standardized with blue dextran and potassium iodide to determine the void volume and the column volume, respectively.
  • the reaction mixture is applied to the column, and bicarbonate-EDTA buffer is used to elute column fractions.
  • the macromolecular radioactive peak that elutes at a position characteristic for the synthetic peptide is isolated and is ready for use.
  • a chelating ligand e.g., DTPA as per Hnatowich et al. (1983) Science 220:613. or bromoacetylparaaminobenzyl EDTA (BABE) as per Meares et al. (1984) Analyt. Biochem. 142:142-686) is covalently bound to the N-terminus of the peptide.
  • Technetium is then chelated to the DTPA- or BABE-synthetic peptide by the procedure described above for direct labelling of synthetic peptide.
  • the 99m Tc-labelled peptide is applied neat in solution or bound to a lipid emulsion.
  • the catheter is inflated to a pressure of about 3 psi above the balloon inflation pressure with radiographic contrast medium (Conray, Mallinkrodt, St. Louis, MO). Three passes are made through the abdominal aorta with the inflated catheter to remove the aortic endothelium before removal of the catheter, ligation of the femoral artery, and closure of the wound. The animals are allowed to heal for a period of 4 to 5 weeks before injection of the labelled synthetic peptides. 4. Injection of Labelled Synthetic Peptides:
  • Each labelled synthetic peptide preparation (containing, for example, 150 to 400 mCi of 125 ⁇ _ ⁇ a ⁇ D elled SP-1 or SP-4 bound to lipoprotein) is injected into the marginal ear vein of the ballooned and healing rabbits.
  • Serial blood samples are obtained from the opposite ear during the ensuing 24 hours and are analyzed for radioactivity.
  • the labelled protein concentration in the blood sample that is withdrawn 5 minutes after injection is considered as time zero radioactivity in the calculation of average plasma radioactivity.
  • FIG. 2 shows representative plasma decay curves for l 2 5i-iabelled synthetic peptides.
  • each animal is injected intravenously with 4 ml of a 0.5% solution of Evans blue dye (Allied Chemical Company, National Aniline Division, NY, NY) which stains areas of de-endothelialized aorta blue. After 1 hour, the animal is sacrificed by a lethal injection of pentobarbital. After sacrifice, the aorta is removed completely, and the remaining aorta is washed in formalin.
  • Evans blue dye Allied Chemical Company, National Aniline Division, NY, NY
  • the washed aortas from the animals that had been injected with labelled synthetic peptide were opened along the ventral surface. These segments are then pinned out, immersed in 10% trichloroacetic acid, and photographed. The fixed, opened vessels are then covered with a single layer of plastic (Saran) wrap, placed on high speed x-ray film (Kodak Orthofilm OH-1) , and stored for 2 to 3 weeks in a Kodak "X-Omatic cassette" (24 X 30 cm) before development in a 90 second X-OMAT.
  • Saran high speed x-ray film
  • the mean concentration of synthetic peptide-associated 12 - radioactivity is calculated by numerical integration of the plasma decay curves and division by the time since injection of the isotope.
  • the audioradiograph shown in FIG. 3 demonstrates clear-cut localization of the synthetic peptide on the image at the healing (re-endothelization) edge of the aortic lesions produced by the previous trauma. Since this lesion is known to resemble human arteriosclerosis in many important respects, including accumulation of lipoproteins and other pathological changes, the ability of the synthetic peptides to localize at the trauma site, and to permit the imaging thereof demonstrates the utility of the present invention in imaging vascular disease.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Des maladies vasculaires y compris l'athérosclérose asymptomatiques peuvent être diagnostiquées en administrant un peptide synthétique à un patient puis en détectant le site d'accumulation du peptide dans le système vasculaire du patient. Les peptides synthétiques ont une affinité et une propension à s'accumuler au niveau d'une blessure artérielle. Des exemples spécifiques de tels peptides ont des conformations moléculaires ou des séquences d'acides aminés qui sont homologues à des portions de LDL. Le peptide synthétique peut être marqué avec un radio-isotope ou un agent de contraste paramagnétique, par exemple, permettant ainsi la détection extra-corporelle d'une maladie vasculaire chez le patient.
PCT/US1989/001854 1988-05-02 1989-05-01 Peptides synthetiques pour imagerie arterielle WO1989010760A1 (fr)

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US18913088A 1988-05-02 1988-05-02
US189,130 1988-05-02

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0600869A4 (fr) * 1990-05-03 1993-03-22 New England Deaconess Hospital Peptides synthetiques utilises en imagerie arterielle.
WO1993012819A1 (fr) * 1992-01-03 1993-07-08 Rhomed Incorporated Applications pharmaceutiques a base d'ions metalliques-proteines et peptides
US5443816A (en) * 1990-08-08 1995-08-22 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation and method
US5508020A (en) * 1992-06-05 1996-04-16 Diatech, Inc. Technetium-99M labeled peptides for imaging
US5643549A (en) * 1992-02-20 1997-07-01 Rhomed Incorporated Leukostimulatory agent for in vivo leukocyte tagging
US5776428A (en) * 1992-04-30 1998-07-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5783170A (en) * 1991-11-27 1998-07-21 Diatide, Inc. Peptide-metal chelate conjugates
US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
US5866097A (en) * 1991-11-27 1999-02-02 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5997844A (en) * 1991-02-08 1999-12-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US6782289B1 (en) 1999-10-08 2004-08-24 The Board Of Trustees Of The Leland Stanford Junior University Methods and apparatus for characterizing lesions in blood vessels and other body lumens
US7328058B2 (en) 2000-01-04 2008-02-05 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US7874975B2 (en) 2005-07-20 2011-01-25 Clear Vascular, Inc. Methods and compositions for treating luminal inflammatory disease
US9623129B2 (en) 2005-09-26 2017-04-18 Snip Holdings, Inc. Methods and therapies for treating inflammatory conditions with exposed collagen

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201102189D0 (en) * 2011-02-08 2011-03-23 King S College London Materials and methods relating to cardiovascular imaging

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0135125A2 (fr) * 1983-08-12 1985-03-27 E.I. Du Pont De Nemours And Company Procédé de formation d'images par résonance magnétique nucléaire utilisant des réactifs à déplacement chimique
US4660563A (en) * 1984-12-31 1987-04-28 Massachusetts Institute Of Technology Method and means for detection of arterial lesions
US4668503A (en) * 1982-07-26 1987-05-26 Trustees Of University Of Massachusetts Process for labeling amines with 99m Tc

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668503A (en) * 1982-07-26 1987-05-26 Trustees Of University Of Massachusetts Process for labeling amines with 99m Tc
EP0135125A2 (fr) * 1983-08-12 1985-03-27 E.I. Du Pont De Nemours And Company Procédé de formation d'images par résonance magnétique nucléaire utilisant des réactifs à déplacement chimique
US4660563A (en) * 1984-12-31 1987-04-28 Massachusetts Institute Of Technology Method and means for detection of arterial lesions

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Atherosclerosis. 1979. V. 34, pp. 391-405. HOLLANDER, see entire Article. *
Biochem. Biophys. Res. Comm. 15 Oct. 1986 V. 140 (1), pp 250-257, FORGEZ, see page 254, Table I. *
Journal of Lipid Research, 1983, Vol. 24, pp 1160 1167, ROBERTS, see entire Article. *
Journal of Nuclear Medicine, February 1983, V. 24 (2) pp. 154-156, LEES. See entire Article. *
Proc. Natl. Acad. Sci, USA, July, 1985 V. 82, pp. 4597-4610, LUSIS, see Materials and Methods and figure 2. *
Proc. Natl. Acad. Sci, USA. November 1986, V. 83 pp. 8142-8146, LAW, see figure 2. *
See also references of EP0413766A4 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0600869A4 (fr) * 1990-05-03 1993-03-22 New England Deaconess Hospital Peptides synthetiques utilises en imagerie arterielle.
US5690905A (en) * 1990-08-08 1997-11-25 Rhomed Incorporated Peptide-metal ion pharmaceutical labeling method
US5759516A (en) * 1990-08-08 1998-06-02 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation
US5443816A (en) * 1990-08-08 1995-08-22 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation and method
US6074627A (en) * 1991-02-08 2000-06-13 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5997844A (en) * 1991-02-08 1999-12-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
US5985241A (en) * 1991-11-27 1999-11-16 Diatide, Inc. Peptide-metal chelate conjugate complexes
US5783170A (en) * 1991-11-27 1998-07-21 Diatide, Inc. Peptide-metal chelate conjugates
US5866097A (en) * 1991-11-27 1999-02-02 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5981477A (en) * 1991-11-27 1999-11-09 Diatide, Inc. Peptide-metal chelate conjugates
WO1993012819A1 (fr) * 1992-01-03 1993-07-08 Rhomed Incorporated Applications pharmaceutiques a base d'ions metalliques-proteines et peptides
US5643549A (en) * 1992-02-20 1997-07-01 Rhomed Incorporated Leukostimulatory agent for in vivo leukocyte tagging
US5965107A (en) * 1992-03-13 1999-10-12 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5780007A (en) * 1992-04-30 1998-07-14 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5922303A (en) * 1992-04-30 1999-07-13 Diatide, Inc. Technetium-99M labeled peptides for imaging
US6086849A (en) * 1992-04-30 2000-07-11 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5776428A (en) * 1992-04-30 1998-07-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US6093383A (en) * 1992-04-30 2000-07-25 Diatide, Inc. Bisamine bisthiol radiolabel binding moieties
US5976494A (en) * 1992-06-05 1999-11-02 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5508020A (en) * 1992-06-05 1996-04-16 Diatech, Inc. Technetium-99M labeled peptides for imaging
US6782289B1 (en) 1999-10-08 2004-08-24 The Board Of Trustees Of The Leland Stanford Junior University Methods and apparatus for characterizing lesions in blood vessels and other body lumens
US7328058B2 (en) 2000-01-04 2008-02-05 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US7359747B2 (en) 2000-01-04 2008-04-15 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US7787933B2 (en) 2000-01-04 2010-08-31 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US7813786B2 (en) 2000-01-04 2010-10-12 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US7874975B2 (en) 2005-07-20 2011-01-25 Clear Vascular, Inc. Methods and compositions for treating luminal inflammatory disease
US9623129B2 (en) 2005-09-26 2017-04-18 Snip Holdings, Inc. Methods and therapies for treating inflammatory conditions with exposed collagen

Also Published As

Publication number Publication date
AU3842789A (en) 1989-11-29
EP0413766A1 (fr) 1991-02-27
EP0413766A4 (en) 1991-11-21
AU628357B2 (en) 1992-09-17
JPH03505094A (ja) 1991-11-07

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