US20050053548A1 - Use of collagenase to facilitate guide wire crossing in total arterial occlusions - Google Patents

Use of collagenase to facilitate guide wire crossing in total arterial occlusions Download PDF

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US20050053548A1
US20050053548A1 US10/491,424 US49142404A US2005053548A1 US 20050053548 A1 US20050053548 A1 US 20050053548A1 US 49142404 A US49142404 A US 49142404A US 2005053548 A1 US2005053548 A1 US 2005053548A1
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collagenase
proteolytic enzyme
containing formulation
angioplasty
enzyme containing
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Bradley Strauss
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Priority to US12/211,574 priority patent/US8021660B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24003—Microbial collagenase (3.4.24.3)

Definitions

  • the present invention relates to the field of percutaneous interventions of occluded arteries using local infusion of collagenase or a combination of enzymes that include collagenase.
  • CTO Chronic total occlusions
  • PCI cardiovascular disease
  • the main limitations of PCI for CTO are the decreased procedural success rates compared to stenotic (but not totally occluded) arteries, and a high restenosis rate.
  • the restenosis problems have improved with the use of coronary stents 8-10 .
  • procedural success rates have only shown modest improvement in the past 20 years from 50-60% in the 1980's 11,12 to 60-70% range in the 1990's 5,13-15 , due to some improvements in angioplasty equipment, such as hydrophilic guide wires 16,17 .
  • PCI enjoys success rates in excess of 95% in stenotic but non-occluded arteries.
  • thrombolytic therapy is effective in acute coronary occlusions, only a small number of native artery chronic occlusions have been treated with prolonged thrombolytic infusions with limited results and this strategy has largely been abandoned. There are no other published reports of pharmacologic treatments of chronically occluded arteries in order to improve angioplasty results.
  • the myocardial territory supplied by a chronically occluded artery may still be viable, particularly in the situation of a slowly developing occlusion that is associated with extensive collateralization.
  • Myocardial ischemia is a common sequelae of CTO since the blood flow through collaterals is inadequate in situations of increased myocardial demand (exercise, post-prandial, stress). Consequently, significant angina pectoris represents the most common cause of attempted PCI in the setting of CTO.
  • the situation of inadequate blood supply to viable myocardium (termed “hibernating myocardium”) is also a major cause of potentially reversible myocardial dysfunction leading to heart failure.
  • Collagenase formulations have been used in in-vitro cell culture studies for a long period of time. These formulations act to isolate cells from tissue by degrading the surrounding matrix and these cells are then used for cell culture. There are very few reports of using collagenase formulations for in-vivo studies.
  • An experimental model of intracerebral hemorrhage in rats has been developed by systemically infusing bacterial collagenase (type XI and type VII) or a combination of collagenase and heparin directly into the caudate nucleus 48-50 . In this model, erythrocytes accumulate around large caudate blood vessels 10 minutes after injection with extensive bleeding present at 4 hours, presumably due to degrading interstitial and basement membrane collagen in the thin-walled intracerebral vessels 49 .
  • Kerényi and colleagues 51 have previously reported on using several different enzymes including collagenase in a rabbit atherosclerotic model. These enzymes were delivered through a double balloon catheter in which two balloons are inflated and the enzyme is injected into the space between the two inflated balloons. These enzymes were left for a maximum of 30 minutes and then the arteries were immediately removed. In this model, rabbits were fed a high cholesterol diet, which resulted in the development of modest atherosclerotic plaques that were minimally stenotic (approximately 30%) and therefore not occlusive or a barrier to passing a guidewire or angioplasty balloon catheter.
  • Bini teaches a method of causing the degradation of fibrin(ogen) by means of fibrinolytic matrix metalloproteinases, preferably MMP-3 or MMP-7.
  • This patent is relevant to acute arterial occlusions, which contain abundant thrombus and fibrin and are responsible for acute myocardial infarctions and sudden death.
  • the method can be performed in vivo as a method of thrombolytic therapy in which a fibrinolytic matrix metalloproteinase is administered to a subject to degrade thrombus in situ.
  • fibronolytic matrix metalloproteinase is not relevant to the problem of performing angioplasty in chronically occluded arteries, which contain extensive collagen and other extracellular matrix components and very minor amounts of fibrin or fibrinogen.
  • the systemic delivery method is not relevant to local delivery into arterial occlusions.
  • CTO remain an important subset of PCI lesions with quite limited success, predominantly due to inability of crossing the occlusion with a guide wire.
  • the fibrotic, collagen-rich characteristic of these plaques is the underlying impediment to passing a guide wire.
  • the vast majority of patients with symptomatic chronic total occlusions are either treated by medical therapy with often limited effectiveness or undergo invasive bypass surgery.
  • CTO are also associated with poorer left ventricular function and possibly worse survival than stenotic (but not occluded) lesions or successfully dilated chronic occlusions. Stenting of CTO has significantly improved long-term patency, which was the other limitation of angioplasty.
  • the current evidence suggests that opening total occlusions by percutaneous interventions is underutilized and necessitates new approaches.
  • a collagenase containing formulation has been identified for degrading collagen within an occlusive atherosclerotic plaque in a chronically occluded animal tube or cavity. More particularly, a collagenase containing formulation is used as an infusion preparation for administration and retention of a therapeutic dosage of collagenase adjacent to or into the atherosclerotic plaque during a formulation exposure waiting period.
  • a medical-related apparatus for degrading collagen within an occlusive atherosclerotic plaque in a chronically occluded animal tube or cavity comprising a medical-related device having provided thereto a therapeutic amount of a collagen degrading composition comprising a proteiolytic enzyme containing formulation.
  • a method of for treating chronically occluded animal tubes and cavities.
  • the first step in the method is administering a therapeutic effective amount of a proteolytic enzyme-containing formulation adjacent to an occluding atherosclerotic plaque.
  • FIG. 1 shows pathology of a chronically occluded rabbit femoral artery (12 weeks duration).
  • M media
  • A adventita
  • A,B Movat, 10x original
  • C Movat, 20x
  • FIG. 2 shows an embodiment of the method of treating chronically occluded tubes and cavities according to the present invention.
  • FIG. 3 shows angiographic results of wire crossing attempts in the rabbit femoral artery chronic total occlusion model.
  • A-C Successful attempt at 72 hours after collagenase infusion, D-F; Unsuccessful attempt at 72 hours after placebo infusion.
  • BI contrast in bladder.
  • FIG. 4A shows successful wire crossing (region filled by red blood cells) in collagenase treated artery (450 ⁇ g). Evidence of some plaque digestion is evident. Internal elastic lamina (arrow) and medial layer remain intact.
  • FIG. 4B shows placebo treated artery with unsuccessful wire crossing. An extensive and occlusive intimal plaque (P) is present.
  • FIG. 6 shows statistical significant differences (p ⁇ 0.03) in successful guide wire crossings in collagenase treated compared to placebo treated arteries at 72 hours after treatment. The treatments were randomized and the operator was blinded to the treatment allocation.
  • FIG. 7 shows a Western blot analysis for interstitial collagenase (MMP-1) in collagenase and placebo-treated arteries at 24 hours after treatment.
  • Chronic arterial occlusions that undergo either treatment showed the presence of a band at ⁇ 93 kD, confirming the presence of interstitial collagenase (MMP-1).
  • This band was markedly increased in the collagenase-treated arteries (lanes 1 and 2) compared to the placebo-treated arteries (lanes 3 and 4), showing increased interstitial collagenase protein in collagenase-treated arteries.
  • Lane 5 shows the presence of MMP-1 protein in the collagenase formulation and was run as a positive control.
  • FIG. 8 shows a gelatin zymogram from a collagenase treated artery (lane 1) and placebo treated artery (lane 2) at 24 hours after treatment in chronically occluded arteries.
  • MMP-9 92-kD gelatinase
  • Lytic bands were present at 92 and 82 kD, reflecting both the proenzyme and the activated forms of MMP-9 in collagenase-treated arteries.
  • Both collagenase and placebo-treated arteries also had evidence of a 72-kD gelatinase (MMP-2).
  • FIG. 9 shows a Western blot analysis for degraded collagen fragments (carboxy terminus of collagen fragments) at 24 hours after treatment with either collagenase (lanes 1 and 2) or placebo (lanes 3 and 4) in chronically occluded arteries. There was a marked increase in collagen fragments in collagenase treated arteries.
  • FIG. 10 shows effects of collagenase and placebo treatment at 24 hours in the absence of attempts to cross with guide wires.
  • M medial layer
  • Ad adventitial layer.
  • a method of local delivery of a therapeutic effective amount of a proteolytic enzyme-containing so formulation having a matrix-degrading enzyme, belonging to the family of matrix metalloproteinases, serine elastases, trypsin, neutral protease, chymotrypsin, aspartase, cysteinase and clostripain can effectively alter the matrix content of the occluding plaque in a way that significantly facilitates guide wire crossing and substantially improves procedural success rates, without causing adverse effects of these enzymes on medial layers of the occluded artery and in adjacent non-occluded arterial segments.
  • the underlying atherosclerotic plaques in CTO are predominantly fibrocalcific 39 , consisting of smooth muscle cells, extracellular matrix and calcium and variable amounts of intracellular and extracellular lipids 40 .
  • Inflammatory cells are commonly seen 39 .
  • Collagens are the major structural components of the extracellular matrix, comprising up to 50% of the dry weight 41,42 , with predominance of types I and III (and minor amounts of IV, V and VI) in the fibrous stroma of atherosclerotic plaques 43,44 .
  • proteoglycans are also commonly found in the intima.
  • Thrombus formation contributes to a varying degree, depending on the severity of the underlying atherosclerotic plaque, and can result in single or multiple layers of clot.
  • the thrombus becomes organised and converted into a collagen-rich fibrous tissue (known as fibrointimal hyperplasia), which eventually is incorporated into the underlying atherosclerotic plaque 40 .
  • the most recently developed fibrointimal hyerplasia is the most likely structure that the angioplasty guide wire must traverse in order to cross the total occlusion. Older organized collagen-rich fibrous tissue is the barrier to successful crossing with current angioplasty techniques.
  • the presence of the most recently formed fibrous tissue within the lumen is the target of the collagenase therapy of the present invention.
  • Intimal plaque neovascular channels are also common in CTO (>75%), regardless of the occlusion duration 39 .
  • the formation of several new channels through the occlusion (intra-arterial arteries), and/or dilation of the vasa vasorum (i.e. bridge collaterals), provides a vascular supply through the occluded segment for transportation of nutrients and potential agents such as collagenase.
  • these small channels are not sufficient to provide adequate distal coronary perfusion to prevent symptoms.
  • the present invention is directed to a method of treating chronically occluded animal tubes and cavities.
  • animal tubes and cavities refers to both human and other animal species, in that the methods of the present invention have both medical and veterinary applications.
  • the methods of the present invention may be applied to occluded tubes and cavities that contain fibrotic collagen-rich tissue such as root canals, fallopian tubes, bile ducts, sinuses, ureters and urethras, arteries, veins and vein grafts used for arterial conduits.
  • the methods taught herein were primarily developed with regard to the occlusion of coronary arteries, but can be used for occluded noncoronary arteries such as iliac arteries, popliteal arteries, femoral arteries, carotid arteries or subclavian arteries. Routine adaptation of the methods taught herein are contemplated for application to occluded bodily tubes and cavities including veins, vein grafts, root canals, fallopian tubes, bile ducts, sinuses, ureters and urethras.
  • the present invention represents a previously unattempted approach to the treatment of chronically occluded arteries that are not amenable to angioplasty since the lesions cannot be crossed by a guidewire.
  • Experimental models of uniformly organized collagen-rich chronic occlusions have not been previously readily available.
  • the unique properties of chronic occlusions that have made them heretofore difficult to cross include the high collagen content and the length of the occlusion that limit direct contact of parts of the occlusion to therapy.
  • an in-vivo chronic total occlusion animal model was developed ( FIG. 1 ) in accordance with the present invention.
  • the animal model can be established with reference to any typical laboratory testing animal, including but not limited to, rabbits, pigs, dogs, sheep, rats and non-human primates. Dosages and times may require adjustment to account for variations in species and body size.
  • the animal model of the present invention will now be described with respect to Male New Zealand white rabbits, weighing 3.0-3.5 kg.
  • the first step in the method is isolating an arterial segment of an animal artery (such as the femoral artery illustrated in FIG. 1 ) and stopping blood flow with occlusive ligatures in the isolated arterial segment of an animal artery.
  • This step is accomplished in the preferred embodiment of the present invention, by anesthetizing the male rabbits with isofluorane, and then making incisions below the inguinal ligament bilaterally.
  • Ligatures are then placed at least about 5 mm apart to isolate a segment of femoral artery. In the preferred embodiment, the ligatures were placed about 15 mm apart. The ligatures not only isolate, but also physically occlude the arterial segment.
  • the next step in the method is injecting topical thrombin into the arterial segment to form an acute thrombotic occlusion.
  • This step can be carried out by using a 27-gauge needle to inject 100 IU of bovine thrombin solution (ThrombostatTM, Parke-Davis) into the isolated arterial segment.
  • ThrombostatTM bovine thrombin solution
  • the sutures were loosened to determine if an occlusion has formed. This is accomplished by loosening the ligatures (typically sutures) to determine if an whether anterograde blood flow was still present. If anterograde blood flow is still present, one or two additional thrombin injections are performed using the same technique until an acute occlusion is created.
  • the ligatures are applied for total of 60 minutes and then removed.
  • a waiting period follows during which the acute thrombotic occlusion is converted into a chronic fibrotic occlusion.
  • the waiting period is of a duration between about 10 weeks and 25 weeks.
  • the arterial patency is assessed by angiography (using the left carotid artery for arterial access) at a mean duration of 16 ( ⁇ 4) weeks.
  • the present method of developing in-vivo animal models of chronic occlusions can be adapted to other bodily and cavities that contain fibrotic collagen-rich tissue such as root canals, fallopian tubes, bile ducts, sinuses, ureters and urethras, veins and vein grafts.
  • the method would comprise the steps of isolating a segment of the selected animal tube, and stopping fluid flow through the tube with occlusive ligatures placed at least about 5 mm in the isolated segment of an animal tube, then injecting a topical sclerosing agent (such as tetracycline or other agent appropriate to the selected cavity or tube) into the segment to form an acute occlusion; and, waiting while the acute occlusion is converted into a chronic fibrotic occlusion.
  • a topical sclerosing agent such as tetracycline or other agent appropriate to the selected cavity or tube
  • the average occlusion length was approximately 28 mm (range 14 mm-56 mm), which is substantially longer than most clinical coronary occlusions, upon which percutaneous coronary interventions would be attempted. Also, the occluded lumens and overall vessel size were quite small due to the inward remodelling.
  • proteolytic enzyme containing formulation is selected from the group consisting of matrix metalloproteinases, serine elastases, trypsin, neutral protease, chymotrypsin, aspartase, cysteinase and clostripain.
  • Matrix metalloproteinases are is a group of zinc-containing enzymes that are responsible for degradation of extracellular matrix (ECM) components, including fibronectin, collagen, elastin, proteoglycans and laminin. These ECM components are important components of the occluding atherosclerotic plaque.
  • MMPs play an important role in normal embryogenesis, inflammation, wound healing and tumour invasion 45,46 .
  • These enzymes are broadly classified into three general groups: collagenases, gelatinases and stromelysins.
  • Collagenase is the initial mediator of the extracellular pathways of interstitial collagen degradation 47 , with cleavage at a specific site in the collagen molecule, rendering it susceptible to other neutral proteases (e.g. gelatinases) in the extracellular space.
  • the proteolytic enzyme containing formulation comprises a matrix metalloproteinase selected from the group consisting of collagenase, type 1A collagenase, gelatinases, and stromelysins.
  • the proteolytic enzyme containing formulation comprises collagenase, whether alone or in combination with other enzymes. It should be understood that the references to the use of a “collagenase formulation” in this description are intended to be illustrative of the preferred embodiment of the present invention, but are not intended to be limiting.
  • the method of treating chronically occluded animal tubes and cavities, such as coronary arteries that can not be crossed by conventional angioplasty guide wires comprises the steps of administering a therapeutic effective amount of a proteolytic enzyme containing formulation adjacent an occluding atherosclerotic plaque, waiting for a pre-angioplasty waiting period prior to crossing the plaque with an angioplasty guide wire, and then crossing the plaque with an angioplasty guide wire.
  • the step of administering a therapeutic effective amount of a proteolytic enzyme containing formulation is conducted as follows. After determining that a coronary artery is totally occluded by angiography, an over-the-wire angioplasty balloon catheter is advanced on a guide wire into the occluded coronary artery using fluoroscopic guidance. If the occlusion cannot be crossed with conventional 0.014′′ or 0.018′′ coronary angioplasty guide wires ( FIG. 2B ), the wire is removed.
  • the angioplasty balloon is inflated at low pressure, in the range of between about 1 to 5 atmospheres, to prevent proximal run-off of the collagenase formulation during administration. An inflation of the angioplasty balloon to a pressure of about 4 atmospheres is preferable ( FIG.
  • a collagenase-containing formulation is slowly infused into the small space between the inflated balloon and the occlusion. As illustrated in FIG. 2C , the collagenase-containing formulation is being infused directly through the wire port of the angioplasty balloon catheter.
  • the infusion is performed under a pressure in the range of about 0.5 atmospheres to 3.5 atmospheres. It is preferable for the infusion to occur at a low pressure of between about 1 and 2 atmospheres.
  • the formulation may also be infused directly into the proximal part of the occlusion itself through an infusion needle or a catheter.
  • the collagenase containing formulation is retained in position by the inflated angioplasty balloon for a formulation exposure waiting period of between about 10 and 100 minutes.
  • the waiting period is preferably within the range of about 50 to about 80 minutes.
  • the formulation exposure waiting period is about 60 minutes, after which the angioplasty balloon is deflated and then removed.
  • an effective therapeutic amount of proteolytic enzyme containing formulation comprises about 50-2000 ⁇ g of type IA Collagenase.
  • a pre-angioplasty waiting period of between about 1 and 108 hours is needed. It has been found that a waiting period of between about 12 hours and about 86 hours is preferable, with the best results occurring after a waiting period of about 72 hours. The waiting period is required for the enzyme containing formulation to diffuse along the length of the occluded segment and to sufficiently degrade the collagen and “soften” the occluding plaque.
  • the collagenase dose will either be too low to be efficacious or too high to avoid excessive damage and weakening of the arterial wall.
  • newly formed collagen within the occlusive plaque is the most vulnerable to the effects of matrix metalloproteinases.
  • the collagen in the normal arterial medial layer forms early in the development of the vessel wall and is extensively cross-lined with very slow turnover.
  • intimal plaque development which occurs an effect of the organisation of occlusive thrombus is a very dynamic process that contains more recently synthesized collagen with variable cross-linkage and susceptibility to enzymatic degradation by MMP's such as collagenase.
  • the most recently organised thrombus is the most likely part of the lesion that the angioplasty guidewire can traverse in order to cross the total occlusion.
  • this recently formed, relatively loose fibrous tissue within the lumen is the principal target of the therapy methods of the present invention.
  • the patient returns to the catheterization laboratory and the operator again attempts to cross the total occlusion with conventional angioplasty guide wires which is then followed by an angioplasty ( FIG. 2E ).
  • Type IA Collagenase (Sigma), a commercially available bacterial collagenase formulation obtained from the fermentation of clostridium histolyticum . This enzyme formulation is generally used to isolate cells from tissue specimens for cell culture. This formulation also contains small amounts of clostripain, neutral protease and trypsin-like activities.
  • Type IA Collagenase (Sigma) is a bacterial collagenase formulation that is obtained from the fermentation of clostridium histolyticum .
  • the range of doses were based on the results of an in-vitro assay which assessed the effects of a range of doses and incubation periods of the collagenase formulation on the arterial wall structure.
  • Human coronary arteries containing stenotic atherosclerotic plaque were obtained at autopsy. Arterial segments were cut into 3 mm cross-sections and mounted on agar gels in a culture well. This enabled selective delivery of collagenase directly into the lumen with a fine pipette. Thus only the occlusive plaque was in direct contact with the collagenase formulation, similar to the in-vivo approach of intraluminal delivery of the collagenases.
  • an over-the-wire angioplasty balloon catheter (3.0 mm diameter) was advanced through a 5F sheath in the left carotid artery and fluoroscopically guided into the iliac artery proximal to the occluded femoral artery.
  • the angioplasty balloon catheter was then advanced to the occlusion and the occlusion length was measured using the known balloon length (20 mm between markers) as a scaling device.
  • the balloon was inflated to 4 atmospheres to prevent proximal run-off of the enzyme solution.
  • the enzyme formulation was delivered slowly at 1-2 atmospheres.
  • the angioplasty balloon was left inflated for a period up to 60 minutes.
  • the attempt to cross the occlusion at 72 hours was made after accessing the arterial circulation through a right carotid cutdown and placement of the angioplasty balloon catheter as described above.
  • FIGS. 4A and 5A histology confirmed the presence of blood-filled vascular channels where the guide wire traversed the occlusive intimal plaque.
  • FIGS. 4A and 5A There was also evidence of some plaque disruption.
  • the pathology was identical to chronic total occlusion model with dense fibrotic plaques, plaque neovascularization, some inflammatory cell infiltrate and frequent breaks in the internal elastic lamina with interceding fibrous tissue ( FIGS. 4B and 5B ). There was no evidence of wire injury in these cases.
  • MMP-1 Interstitial Collagenase
  • Frozen arteries were pulverised in liquid nitrogen and extracted in ice cold extraction buffer (cocodylic acid 10 mM, NaCl 150 mM, ZnCl 2 20 mM, NaN 3 1.5 mM and SDS 1% w/v).
  • extracts containing 50 ⁇ g protein were fractionated on 4-20% tris-glycine gels under reducing conditions and electrotransferred onto nitrocellulose membranes (Bio-Rad).
  • COL 2 3 ⁇ 4 C short polyclonal rabbit IgG (HDM Diagnostics & Imaging Inc, Toronto) was used as a primary antibody at a dilution of 1:1000 and anti rabbit IgG-HRP (Santa Cruz Biotechnology) was used as a secondary antibody.
  • MMP-1 interstitial collagenase
  • extracts containing 50 ⁇ g of protein were separated under non-reducing conditions and electroblotted onto nitrocellulose membranes.
  • Anti-MMP-1 monoclonal antibody (Calbiochem) was used as a primary antibody at a dilution of 1:100 and anti mouse IgG-HRP (Santa Cruz Biotechnology) was used as a secondary antibody.
  • chemiluminescence detection system (ECL Plus, Amersham) was used followed by autoradiography.
  • the interstitial collagenase (MMP-1) Western blot analyses in both collagenase and placebo-treated arteries showed the presence of a band at ⁇ 93 kD, confirming the presence of interstitial collagenase (MMP-1) ( FIG. 7 ).
  • This band was markedly increased in the collagenase-treated arteries compared to the placebo-treated arteries, showing increased interstitial collagenase (MMP-1) protein in collagenase-treated arteries at 24 hours after treatment.
  • Gelatin zymography was performed as previously described 52 . Gelatin zymography showed an increase of an 92-kD gelatinase (MMP-9) only in collagenase-treated arteries with no activity evident in placebo-treated arteries ( FIG. 8 ). Lytic bands were present at 92 and 82 kD, reflecting both the proenzyme and the activated forms of MMP-9. Both collagenase and placebo-treated arteries had evidence of a 72 kD gelatinase (MMP-2).
  • Degraded collagen was assessed by western blot analysis under reducing conditions with a polyclonal antibody directed against cleaved human type II collagen (col 23/4C, dilution 1/1000, Diagnostic Imaging). Collagen degradation products were identified in both placebo-treated and collagenase-treated arteries, with a marked increase in collagenase treated arteries ( FIG. 9 ).
  • a chronic arterial occlusion model was developed in the femoral arteries of rabbits by applying temporary occlusive ligatures supplemented with thrombin injections to promote acute thrombosis and then waiting an average of 16 weeks for the acute thrombotic occlusion to develop into a chronic fibrotic occlusion, analogous to chronic human arterial occlusions.
  • the local delivery of 450 ⁇ g of a collagenase containing formulation through the wire-port of an over-the-wire angioplasty balloon over a 60 minute period while the balloon is inflated can cause collagen degradation, increased MMP-1 and MMP-9 activity and demonstrable lysis of plaque components within the occluded artery at 24 hours compared to placebo treated arteries.
  • This local delivery of collagenase can increase the success rates of guidewire crossing at 72 hours but not at 1 hour after collagenase administration. Thus, a waiting period of 24-72 hours is required to allow the collagenase to degrade the plaque prior to attempting guidewire crossing.

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US7368270B2 (en) 2000-03-02 2008-05-06 Incyte Corporation Human phospholipases
WO2005097177A1 (en) * 2004-04-08 2005-10-20 Strauss Bradley H Use of collagenase to facilitate guide wire crossing in total arterial occlusions
US20070184083A1 (en) * 2006-02-07 2007-08-09 Medtronic Vascular, Inc. Drug-Eluting Device for Treatment of Chronic Total Occlusions
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US20120259314A1 (en) * 2011-04-11 2012-10-11 Medtronic Vascular, Inc. Apparatus and Methods for Recanalization of a Chronic Total Occlusion
US20160000834A1 (en) * 2013-02-28 2016-01-07 Ventrix, Inc. Methods and compositions for tissue therapy and analysis
CN112638289A (zh) * 2018-06-28 2021-04-09 玛利塞生物技术公司 治疗血栓形成的药物组合物和方法以及医疗设备递送

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HK1076037A1 (en) 2006-01-06

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