EP0894012A2 - Systeme de radiotherapie locale - Google Patents

Systeme de radiotherapie locale

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Publication number
EP0894012A2
EP0894012A2 EP97916290A EP97916290A EP0894012A2 EP 0894012 A2 EP0894012 A2 EP 0894012A2 EP 97916290 A EP97916290 A EP 97916290A EP 97916290 A EP97916290 A EP 97916290A EP 0894012 A2 EP0894012 A2 EP 0894012A2
Authority
EP
European Patent Office
Prior art keywords
radioisotope
radioactivity
local delivery
delivery system
stent
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.)
Withdrawn
Application number
EP97916290A
Other languages
German (de)
English (en)
Inventor
Olivier Bertrand
Rosaire Mongrain
Jean-François Tanguay
Luc Bilodeau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TANGUAY JEAN FRANCOIS
Original Assignee
TANGUAY JEAN FRANCOIS
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 TANGUAY JEAN FRANCOIS filed Critical TANGUAY JEAN FRANCOIS
Publication of EP0894012A2 publication Critical patent/EP0894012A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N5/1002—Intraluminal radiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0095—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof radioactive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to the local delivery of radioactivity.
  • the present invention further relates to the localized inhibition of cell proliferation using radioactivity.
  • Coronary angioplasty is actually a well established technique for the treatment of obstructive coronary disease. More than 500,000 angioplasties are performed every year world-wide. However, two major problems remain unsolved. The first is acute closure, reported to occur in up to 11 % of the cases after balloon angioplasty (Dorros et al., 1983, Circulation 67:723-730). In that context, intracoronary stenting appears as an invaluable procedure for the treatment of extensive dissections occurring after angioplasty. As a scaffolding vessel wall support, it preserves adequate coronary opening and perfusion. The second problem is restenosis which has been shown to occur in 30 to 50% of the cases.
  • Balloon dilation leads to global vascular lesions which include mechanical deformation of the vessel, extensive destruction of the endothelium and immediate formation of thrombus. All of these act through vasoactive hormones, growth factors, circulating cells and presumably lipids on the media muscle cells. It is observed that smooth muscle cells are activated and migrate to the intima where after proliferation and matrix secretion, a "neo-intima" is generated [Hamon et al., 1995, Eur Heart J 16(SUPPI 1 ):33-481. This observation led to the proposal of a cellular mechanism for restenosis (figure 1). The role of elastic recoil and vessel remodelling has also been recognized following angioplasty (Kakuta T.
  • Radioactive catheter External delivery using Gamma or Beta irradiation, showed that at the single high doses used, a decrease in hyperplasia is observed. However, some groups detected fibrosis or necrosis in the irradiated region (Schwartz RS. et al., 1992, J. Am. Coll. Cardiol. 19:1106-1113). Moreover, this type of approach encompasses the irradiation of a large field. 2) Radioactive catheter.
  • Radiotherapeutic treatment such using radioactive stents showed a significant reduction in neointima formation that was dose-dependent, it also suggested a delayed regeneration of endothelial cells. Together with the long-range irradiation of surrounding tissues, this type of stent can be foreseen as having detrimental effects, especially in the long term, on the integrity and functionality of the treated vessel and surrounding tissues.
  • Beta rays also present advantages concerning radioprotection.
  • the use of a Beta-isotope in such systems does not offer an optimal solution.
  • the question of half-life of the isotope used is of crucial importance from a practical, as well as from a biological point of view. It is generally understood that it is preferable to choose an isotope that would irradiate for the minimum while sufficient time required to inhibit the proliferative activity of the targeted cells, thereby minimizing the irradiation of the surrounding tissues.
  • a first aim of the present invention is to provide a radioactivity local delivery system which obviates the drawbacks of the prior-art.
  • a second aim of the invention is to provide a radioactivity local delivery system which permits an optimization of the radiatiotherapeutic treatment.
  • Another aim of the present invention is to provide a radioactivity local delivery system which permits the use of isotopes having a longer half life. As well, the present invention permits the use of radioisotopes with low energy.
  • Another aim of the invention is to provide a radioactivity local delivery system which permits a control of the total dose of local radiation delivery.
  • An additional aim of the present invention is to provide a radioactivity local delivery system which permits an optimization of the duration of local radiation delivery.
  • a further aim of the invention is to provide a radioactivity local delivery system which enables a control of the efficacious dose/rate for inhibiting cellular proliferation.
  • Yet another aim of the invention is to provide a radioactivity local delivery system which eliminates the potential biocompatibility and hemocompatibility problems associated with particle bombardment of a stent or stent-like structure aimed at rendering same radioactive.
  • a further aim of the invention is to provide a radioactivity local delivery system which will also enable the delivery of one or more drugs or biological agents.
  • a radioactivity local delivery system comprising: a) a support of generally tubular structure having an external surface adapted to engage the wall of a vessel of a human patient; b) a radioisotope in releasable association with the support; and c) a chelating agent coupled to the radioisotope, whereby upon placement of the radioactivity local delivery system inside the vessel, the releasable association between the support and the radioisotope enables a release thereof into the circulation of the human patient at a rate controlled by the rate of release of the association, and the chelating agent enables a rapid elimination of the radioisotope from the circulation.
  • kits comprising a support of generally tubular structure having an external surface adapted to engage the wall of a vessel of a human patient and a radioisotope coupled to a chelating agent, wherein the radioisotope is in releasable association with the support for locally delivering to a targeted site of a human vessel a predetermined dose of radiation.
  • a cell proliferation inhibiting composition comprising a radioisotope coupled to a, chelating agent wherein the radioisotope is in releasable association with a pharmaceutically acceptable carrier, whereby upon placement of the cell proliferation inhibiting composition at a targeted site in a human patient, the irradiation by the radioisotope inhibits a proliferation of actively proliferating cells and whereby the releasable association between the radioisotope and the carrier enables a controlled release of the radioisotope from the targeted site at a controlled rate into the circulation of the patient and the chelating agent enables a rapid elimination of the radioisotope from the circulation.
  • a method to decrease the growth of actively proliferating cells at a targeted site in a vessel of a human patient comprising the insertion and positioning at the site of a composition comprising a radioisotope coupled to a chelating agent, wherein the radioisotope is in releasable association with a pharmaceutically acceptable carrier; such that irradiation will inhibit a proliferation of the actively proliferating cells and such that by way of the releasable association between the radioisotope and the carrier, the radioisotope will be removed from the targeted site at a controlled rate into the circulation of the patient and the chelating agent enables a rapid elimination of the radioisotope from the circulation.
  • Fig. 1 shows a simplified model of the restenosis pathway.
  • Fig. 2 is a schematic representation of the exposed tissues using a low energetic radiation; (A) cross sectional view of the vessel with stent in position; (B) cross sectional view along line 1.
  • Fig. 3 is a schematic representation of a frontal view of a Wiktor stent with six radioactive coated struts.
  • Fig. 4 (A) is a schematic representation of a side view of the Wiktor stent with a wire wrapped around it;
  • Fig. 4 (B) shows the wire unwrapped and stretched.
  • the present invention therefore aims at controlling cell proliferation through local isotope irradiation.
  • the present invention is not limited to a use in the reduction of coronary restinosis. Indeed, it is contemplated that the present invention can be used in a variety of clinical situations that include, without being limited thereto, cancer therapy, inhibition of keloide scares and treatment of heterotopic bone formation.
  • the medical practitioner will be able to adapt the present invention to a particular clinical situation. For example, placement of a stent-like structure in a duct or track or even in bronche could locally deliver radiation, thereby inhibiting the proliferation of the targeted cells.
  • the present invention can be adapted by a medical practitioner to enable modification of cancer radiotherapy of a chosen tissue or organ by the use of the present invention.
  • the present invention is aimed at controlling smooth muscle cells proliferation with a radioactive stent to reduce coronary restenosis after balloon angioplasty.
  • a radioactive stent to reduce coronary restenosis after balloon angioplasty.
  • Many arguments suggest the effectiveness of local radioactivity to reduce neointimal proliferation after balloon angioplasty.
  • Coronary stents are increasingly used after angioplasty and indications will probably broaden in the future.
  • the combination of both strategies in some clinical circumstances has previously been disclosed by the group of Fischell and others.
  • the disclosed methods rely on a stent rendered radioactive by activating the metal of the stent with particle bombardment (reactor, cyclotron). In that case, different radioisotopes emitting Gamma and Beta radiations with several energies and half lives can be produced (Herlein C. et al., 1995, Circulation 92:1570-1575). It should be stressed that it remains to be determined whether the biocompatibility and hemocompatibility of the
  • the present invention overcomes the drawbacks of the Fischell strategy by providing a system which can enable a precise control of the dose and dose/rate of irradiation.
  • One such system which is provided consists in putting an available isotope on the stent itself.
  • One way to reversibly fix the isotope is to mix it with a polymer or other carrier that would be bonded on the stent.
  • the degradation thereof will enable the irradiation to be controlled by the rate of degradation of the substance and the half life of the isotope itself, thereby providing a significant increase in the flexibility of the radiation delivery system.
  • the polymer-isotope composition can be chosen so that irradiation will be present during the proliferative activity of the smooth muscle cells and absent thereafter. It is to be understood that the polymer need not necessarily be biodegradable. However, the polymer must provide for a controlled release of the radioisotope mixed therein. Also contemplated in the present invention is the integration of the radioisotope inside the structure of the polymer or carrier forming the stent or support structure itself. In other words, in such an embodiment, the stent or support structure would be both biodegradable and radioactive.
  • Biodegradation thereof would thus play the dual role of eliminating the radioactive source from the targeted area as well as removing the support structure therefrom. It is also conceivable that in certain clinical situations, a stent or support could be withdrawn after a predetermined time.
  • the coupling of the radioactivity isotope in accordance with the present invention with an agent enabling its rapid elimination from the circulation is at the crux of the invention. Such a combination enables a minimization of the potential hazard of irradiation at distant sites from the chosen sites of local radiotherapy. Maximum complex stability is achieved via chelation (Cotton and Wilkinson 1980).
  • a chelate is formed when a metal atom is bound to more than one donor atom of a complexing molecule or ligand, thereby forming a closed-ring structure.
  • the added stability of the metal chelate is often required in order to resist oxidation, hydrolysis or the strong affinity that some metals (especially indium and gallium) display for the plasma protein transferrin.
  • Diethylene- triaminepentaacetic acid (DTPA) was on of the first chelating agents to be used to complex 89 Tc m (Richards and Atkins 1968). Tc-DTPA is primarily excreted from the body via the kidneys and is still used today to assess renal function.
  • Tc complex At least a dozen Tc complex have been described that demonstrate renal accumulation and/or clearance (Eckelman and Volkert 1982).
  • the metal-chelate complexes have characteristic physicochemical properties (i.e. molecular weight, lipid solubility, charge pK B proportion of protein binding, etc.), which will govern their in vivo distribution (Webb Ed., 1993, The Physics of Medical Imaging, Inst. of Physics Publishing, Bristol and Philadelphia). It will be understood that the chelating agent will be dosed so as to promote the execution of the radioisotope following leeching from the carrier or support.
  • the radioactivity local delivery system would significantly reduce neointima formation following angioplasty and proliferation of actively proliferative cells such as for example tumor cells.
  • the medical practitioner can adapt the dose and dose/rate so as to for the treatment to a cancer therapy.
  • the type of isotope, carrier and the like will be adapted to meet the desired needs.
  • the separate sleeve which encompasses the stent and can also serve as a local drug delivery device to prevent restinosis. When combined with a drug, the separate sleeve can further prevent thrombosis and/or restinosis. It should be understood that such a sleeve need not be limited to a use with a stent designed for coronary angioplasty. Indeed, such a sheath can be used with a stent to deliver radioactivity to an arterial wall or lumen, vessel, duct or passage in which the stent has been inserted.
  • the term "vessel” is used broadly to cover lumen, duct, and other types of bodily conduits.
  • drug any compound which has a desired pharmacologic effect.
  • the drug is compatible with the polymer and can be tolerated in a subject.
  • the drug can be an anticoagulant e.g. D-Phe-Pro-Arg chloromethyl ketone, and RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, or platelet inhibitors.
  • the drug could also be a promoter of vascular cell growth, e.g. a growth factor inhibitor, growth factor receptor agonist, transcriptional activator or translational promoter.
  • the drug could be an inhibitor of vascular cell growth, e.g.
  • a growth factor receptor antagonist transcriptional repressor, translational repressor, antisense DNA, antisense RNA, replication inhibitor, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin.
  • Selected examples of days which have been used to inhibit restenosis is include methylprednisome, colchicinie, forskoline, vitamin A, and anti lib / Ilia antibodies.
  • the drug could be a cholesterol-lowering agent, a vaso-dilating agent, and agents which interfere with endogenous vasoactive mechanisms, anticancer agents, chemotherapeutic agents, and agents which selectively affect actively dividing cells.
  • Polymers which can be used as carriers in accordance with the present invention include without being limited thereto natural biodegradable polymers such as fibrin, synthetic biodegradable polymers comprising polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutyrate, polyorthoester, polyethyleneoxide/polybutylene terephtalate, and non biodegradable polymers such as polyurethane, silicone and polyethylene terephtalate. Of course, mixtures of polymers could also be used.
  • natural biodegradable polymers such as fibrin
  • synthetic biodegradable polymers comprising polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutyrate, polyorthoester, polyethyleneoxide/polybutylene terephtalate
  • non biodegradable polymers such as polyurethane, silicone and polyethylene terephtalate.
  • mixtures of polymers could also be used.
  • the methodology to obtain the radioactive stent has been elaborated taking in account radiobiological data concerning dose-rate and tolerance-dose. With that preoccupation, compromises in regard to radiation-type, emission-energy and exposure-time have been determined.
  • ⁇ -irradiation has been put forward, indeed, as compared to ⁇ -irradiation, ⁇ -irradiation has a much lower tissue penetration.
  • a ⁇ -emitter has been selected for its energy spectrum, based on the depth of tissue over which radiation has to be applied, ⁇ -emitters having half-lives of between 1 to 1000 days are contemplated in the present invention in relation with restenosis inhibition.
  • ⁇ -emitters having a modified structure which enables them to be rapidly eliminated from the circulation are contemplated.
  • a chelated isotope is one of many such examples of an isotope modified so as to be rapidly eliminated.
  • a specific example of such a chelated isotope is 45 Ca EDTA (calcium).
  • Delating groups encompassed by the present invention include ethylene diaminetetraacetic acid (EDTA) and diethylene triaminepentaacetic acid (DTPA).
  • the chosen isotope is a pure ⁇ -emitter.
  • One such non-limitative example is 35 S (sulfur), with a linear energy spectrum with a principal (maximum) energy of 167.4 KeV and an average energy of 48.8 KeV (Cross WG. et al., 1983, Phys. Med. Biol. 28:1251-1260).
  • this range of action (maximum energy) reveals itself to be a good compromise for the intended exposure duration and dose tolerance limits.
  • Another advantage is that this substance is commercially available and has a current medical usage in the form of sodium sulfate injection for the measurement of extracellular fluid volume. As a consequence, there is a medical history for this substance with known dosage, biodistribution and side effects (Iturralde Mario P., 1990, Dictionary and Handbook of Nuclear Medecine and Clinical Imaging, CRC Press, Boston).
  • the same principle can be applied to the incorporation of the isotope in another type of carrier such as a gel or sheath or for the incorporation of the isotope in the stent or support itself.
  • This approach presents the double advantage of having a radioactive stent with a practical physical life span and an appropriate biological duration.
  • the isotope can be embedded into a polymer matrix fixed to the stent.
  • the polymer can be an organic or an inorganic polymer.
  • organic and inorganic polymers include fibrin and PLLA/PGLA, respectively (Tanguay et al., 1994, Cardiology Clinics 12:699-713).
  • the rate of degradation of the polymers can control the duration of the radiotherapy.
  • this approach allows to determine the total dose according to a selected effective and safe dose/rate. As presented in the following lines, this dose/rate and total dose are deduced from current values used in radio-oncology procedures. As discussed below, a period of 20 days is considered in the dosimetry calculations.
  • a period of 5 to 60 days is contemplated herein.
  • 10 to 30 days and more preferably 20 days are contemplated.
  • this 20 days of irradiation can be adjusted to take into account a particular clinical situation, and is thus only one example of a chosen time of irradiation. In a first approach, this time range appears reasonable in view of the fact that proliferation of smooth muscle cells occurs during a period of approximately two weeks.
  • High dose/rate is defined herein as dose/rate equal or superior to 1 Gy/min and low dose/rate as dose/rates below 1 Gy/min.
  • 0.1 Gy/hr - 0.1 Gy/min preferably about 0.1 Gy/hr - 0.5 Gy/hr are contemplated. Total doses of between 20 and 200 Gy are contemplated. A dose of 60 Gy in 7 days equivalent is contemplated.
  • the present invention by providing an irradiation at lower doses enables a significantly selective killing of actively dividing cells (such as cancer cells or smooth muscle cells) as opposed to slower dividing cells. This selectivity is explainable by the DNA repair system in the slower dividing cells being able to correct the DNA defects prior to cell division when low dose/rate or fractionated radiation is used.
  • Non-limiting examples of pure ⁇ -emitters include strontium/ltrium 90 , Erbium 169 and Prometheum 147 .
  • a non-limiting example of ⁇ -emitters includes Iodine 125 .
  • Mixed ⁇ - and ⁇ -emitters are also contemplated as encompassed within the scope of the present invention.
  • support is used broadly as encompassing stents, implants, scaffolding structures and other structures permitting a localized delivery of irradiation. It should be understood that biocompatibility is an important arteria for the support of the invention.
  • the first is to fashion the polymer as a thin film completely encasing the stent.
  • the second is to soak the struts with a thin coating of the polymer.
  • EXAMPLE 1 Encasing film With this approach, the spatial range of the ⁇ particles of ⁇ S corresponds to a thick cylinder with an inner and outer diameters of about 2.2 mm and 3.8 mm respectively (figure 2).
  • the dosimetry calculation is performed with the fixed vascular tissue also corresponding to a cylinder annulus with an inner diameter of 3 mm, outer diameter of 3.8 mm and length of 15 mm (stent length) for a mass of about 0.11 g.
  • the radiation is considered as corpuscular radiation.
  • the calculations of the absorbed dose for internally deposited radioisotope follows directly from the definition of the gray (Gy). Over the spatial range (volume) of the considered radiation ( ⁇ ), the absorbed energy should be equal to the concentration of the energy emitted by the radioisotope.
  • the energy absorbed per unit mass per transformation is called the specific effective energy (SEE).
  • the SEE is simply the average energy of the radiation divided by the mass of tissue over which it is active (Cember Herman, 1983, Introduction to Health Physics, 2 nd edition, Pergamon Press, New York). Since what is proposed is a continuous interstitial radiotherapy (brachytherapy) treatment, a low dose rate delivery is required. Based on previous works in brachytherapy, a total dose of 90 Gy has been adopted (which corresponds to the dose that produces an effect equivalent to 60 Gy in 7 days) (Hall EJ. et al., 1991 , Int. J. Radiation Oncology Biol. Phys. 21:1403-1414; Fowler J. et al., 1992, Int. J. Radiation Oncology Biol. Phys.
  • the initial activity on the stent can be related to the dose/rate with the following equation:
  • the activity in Curie is computed with:
  • This initial activity can be assessed using a Beta
  • the accumulated dose over 20 days of 90 Gy corresponds to an energy of about 0.01 Joule to the vascular tissue, as previously mentioned there should be a similar amount of energy brought to the 5 kg of blood tissue which would mean an additional dose of 2 mGy for the blood tissue and eventually when all the polymer matrix would be dissolved there would be a dose distribution of approximately 0.5 mGy to the cartilage, 0.08 mGy to the bone marrow and 0.005 mGy to the whole body.
  • the calculated activity is within an effective range as previously reported in the literature.
  • EXAMPLE 2 Coated struts A method requiring less stringent elastic properties is presented herein below.
  • the same treatment protocol of 90 Gy in 20 days (0.19 Gy/h) can be proposed.
  • the initial activity can be obtained with the following relation:
  • the activity in Curie is given by:
  • the swine implant model has been previously described with respect to balloon damage, stent placement and biologic response to stents.
  • Male or female (Sus scrofa) of 30-40 kgs are utilized.
  • Each animal is identified with ID number tattooed on the ear or by ear tag as per Montreal Heart Institute standard operating procedures.
  • Stents can be placed in the coronary arteries easily and efficiently. Methods of tissue processing and quantification are also well established. Animal health requirements These requirements are to be conform to the Montreal
  • the Protocol for termination is described below. While the number of acute and/or unexpected deaths should be few, if an animal dies before scheduled termination, a necropsy and excision of relevant tissue is to be performed as soon as possible, preferably no longer than 2 hours after death. All information related to the death shall be recorded in the laboratory notebook. The sponsor shall be notified of the death within 24 hours. The animal and tissue are to be treated as described below when possible. Test material: Wiktor coronary prosthesis
  • Sterilized heparin-coated and uncoated Wiktor stents are used. Stents of 3.5 mm in diameter premounted on usual balloon angioplasty catheter shall also be used. The guidewire used will be 0.014 inches. An 8 French (0.077 " min. ID) guiding catheter (hockey stick or Amplatz) are to be used for all coronary implants.
  • Each package containing the endovascular prosthesis is identified with a unique serial number.
  • the devices should not require special storage conditions other than expected for a cardiology lab. Study personnel Selection
  • Aspirin is administered the day before treatment, at treatment and every day thereafter for one week. There will be no prolonged systemic anticoagulation followed by chronic warfarin. Schedule of angiography and sacrifice post endoprosthesis placement.
  • the time points for testing is be as follows: At 28+A-2 days, sacrifice of the pigs. This is to allow analysis of 10 coronary segments with radioactive heparin-coated Wiktor stents, 10 coronary segments with non radioactive heparin-coated Wiktor stents and 10 coronary segments with non radioactive uncoated Wiktor stents.
  • Presurgical regimen is as follows: At 28+A-2 days, sacrifice of the pigs. This is to allow analysis of 10 coronary segments with radioactive heparin-coated Wiktor stents, 10 coronary segments with non radioactive heparin-coated Wiktor stents and 10 coronary segments with non radioactive uncoated Wiktor stents.
  • Intravenous access, anaesthesia, preparation of clinical equipment, and administration of medication is carried out in accordance with the Montreal Heart Institute SOP and accordingly all personnel directly involved in the procedure shall wear appropriate attire.
  • Preoperative medications is administered one day prior to the balloon injury. Young farm swine (Sus scrofa) weighing 25-30 kgs are given 30 mg nifedipine p.o. 1 day prior to the procedure. Ketamine (12 mg/Kg) and Xylazine (8 mg/Kg im) are administered as a premedication prior to anaesthesia, allowing easy endotracheal intubation. Xylazine is an excellent analgesic and is long acting. Anaesthesia is induced and maintained with 1% halothane in a 1 :1 mixture of air or oxygen. A heparin (150 U/Kg) and Xylocaine (100 mg) bolus are administered after percutaneous puncture through the arterial sheath.
  • ACT is measured immediately after administration of heparin and at 30 minutes and 60 minutes thereafter. If the ACT decreases below 300 seconds, an additional 75 U/Kg of heparin will be administered. Saline is administered the day before treatment and during treatment. Balloon damage of vessel and stent placement
  • Each artery LAD, Cx
  • Percutaneous puncture is performed on the right femoral artery, or the carotid artery at the election of the investigator, and the vessel is cannulated with an 8 F vascular sheath.
  • a single bolus of 150 U heparin per Kg and xylocaine (100 mg) is given at this point.
  • PTCA percutaneous transluminal coronary angioplasty
  • Nitroglycerin is used as needed to eliminate spasm at final angiographic and ultrasonic assessment of stent deployment.
  • Each 3.5 mm coronary stent, premounted on the standard PTCA balloon catheter (Gold-X) is used to expand the stent at the intended site.
  • EKGs and blood pressure is continuously monitored during stent implant and post ballooning, and post-procedure, and maintained as per the Montreal Heart Institute SOP.
  • Initial stent deployment is done at 8 atm.
  • Adjunctive high pressure inflations is accomplished using the same
  • Gold-X semi-compliant balloon whose diameter is equal to 3.5 mm.
  • An inflation pressure of at least 12 atmospheres is to be used. Stent position, expansion and apposition to the vessel wall is then confirmed by IVUS.
  • the puncture site is held under pressure by hand until hemostasis is maintained.
  • QCA analysis will include the minimal in-stent diameter and the proximal and distal vessel diameters (1 cm apart of each end of the stent).
  • 10 pigs are sacrificed. Arteriography and IVUS is performed. At sacrifice, the stented arteries are removed en bloc, along with short (1 cm minimum) artery segments proximal and distal to the stents. All specimens are fixed and evaluated by quantitative histopathology in order to quantify thrombus formation, intimal thickening, and arterial remodelling.
  • Quantitative angiography and intravascular ultrasound are used to assess endoprosthesis patency, placement and apposition to the arterial wall.
  • Computerized digital angiographic image analysis (View
  • Termination protocol is performed with the guiding catheter used as reference. In the event that the coronary endoprosthesis is occluded and the animal has survived, the animal will be sacrificed according to the termination protocol. Termination protocol
  • An intravenous commercial solution can be given by intravenous administration for euthanasia (e.g. "Sleepaway", Fort Dodge Laboratories, 10 cc) as per the Montreal Heart Institute SOPs.
  • General physical examination includes body weight and general condition of animal and character of wound healing. Laboratory examination analyses the complete blood count as warranted by DVM, the Serum chemistry as warranted by DVM and ACT, aPTT, and TT immediately pre-sacrifice. Samples for these tests are to be obtained prior to administration of any anticoagulants or drugs required for angiography or sacrifice. Animal sacrifice
  • Heparin approximately 150 U/Kg is to be administered intravenously and the animal is then be sacrificed. Necropsy examination
  • Necropsy examination is to be performed by the designated pathologist A cardiovascular gross examination is done. This is an external examination of the body including all organs in the thoracic cavity. Tissues and organs observed include the mesenteric lymph nodes, lungs and main stem bronchi, heart, aorta and vessels of the left upper leg. The heart is examined with respect to potential emboli.
  • Gross morphology assessment is performed by taking a macroscopic photography of the necropsied heart to show any gross response to stent implant.
  • Explanted vascular prosthesis tissue is to include the entire endoprosthesis and at least 1 cm of native artery attached to each end of the prosthesis.
  • the proximal arterial end is to be marked by the insertion of a black ligature and the distal end by insertion of 2 black ligatures.
  • the appearance of the proximal and distal arterial ends and mid-prosthesis sections is to be described.
  • Native vessel proximal and distal to the explanted segment are also examined. Photographs of the intact explanted endoprosthesis are to be taken, including the entire explanted segments as well as close-ups of the proximal and distal arterial ends and mid-endoprosthesis region. Samples will be pressure fixed in the MJK/2 fixative and will undergo histological preparation and evaluation as described in the section above.
  • Transverse sections are cut at 5 mm intervals starting at the central portion and moving to the distal segment (marked with a ligature). Histopathologic analysis must include sections at the centre of the stent; at the distal edge of the stent with the vessel wall and at the vessel wall 5 mm from the edge of the stent. The diameter of the lumen proximal, distal, and in the stented area is measured. Evaluation of outer diameter enlargement, filling defect, patency of side branches, protrusions of the stent into the vessel lumen, medial or adventitial cells modifications or fibrosis, and neointimal thickening around artery circumference is recorded in the pathology report. Any signs of inflammatory reactions against stents struts is documented.
  • Histological strains include: H&E, Masson's Trichrome, Elastic von Giesson stains. Slides are to be obtained for quantitative histopathological analysis. MJK/2 Fixative
  • the artery sections is observed with quantitative low and high power light microscopy where a movable calibrated reticule is utilized for making lengths measurements in the plane of microscopic view. Careful estimation of the luminal thickening around the arteries circumference of each of the histological sections is made. Quantitative and qualitative findings are to be recorded.
  • stented arteries are cut into slices with a rotating diamond saw.
  • Morphometric analysis should include: maximal intimal thickness, arc length of the medial fracture, lumen area, neo-intima perimeter and total vessel perimeter. The ratio of intimal thickness to length is to be calculated to correct for the extent of the vessel injury.
  • some arteries segments can be examined by scanning electron microscopy in order to assess the reendothelialization of the luminal surface.
  • Immuno-histology To visualize smooth muscle cells and endothelial cell populations, immuno-staining is performed. Specific monoclonal antibodies against proliferative nuclear antigen (PCNA) can assess the limitation of the smooth cell proliferation.
  • PCNA proliferative nuclear antigen

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  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne un système de radiothérapie locale permettant d'utiliser des isotopes ayant une demi-vie plus longue et une énergie moindre. L'invention concerne également un système de radiothérapie locale permettant de régler plus facilement et plus efficacement la dose/le taux et la dose totale du rayonement local. Dans la présente invention, on utilise un radio-isotope couplé à un agent réduisant le temps de circulation tel qu'un agent chélateur, le radio-isotope couplé étant associé à la structure à insérer dans le vaisseau d'un patient humain de manière à pouvoir en être libéré. Le radio-isotope couplé peut faire partie du support lui-même ou lui être associé au moyen d'un excipient pharmaceutique biodégradable ou non biodégradable dont il peut se libérer. On décrit également un procédé et des compositions permettant de réduire la croissance des cellules prolifératives en un site ciblé d'un vaisseau d'un patient humain.
EP97916290A 1996-04-17 1997-04-17 Systeme de radiotherapie locale Withdrawn EP0894012A2 (fr)

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US1578896P 1996-04-17 1996-04-17
US15788 1996-04-17
PCT/CA1997/000262 WO1997038730A2 (fr) 1996-04-17 1997-04-17 Systeme de radiotherapie locale

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US5871436A (en) * 1996-07-19 1999-02-16 Advanced Cardiovascular Systems, Inc. Radiation therapy method and device
US5924973A (en) * 1996-09-26 1999-07-20 The Trustees Of Columbia University In The City Of New York Method of treating a disease process in a luminal structure
DE69821360T2 (de) 1997-04-26 2004-12-09 Universität Karlsruhe Radionuklid-Mikropartikel, gebunden an einen Elastomer-Schlauch für die endovaskuläre Therapie
DE19718339A1 (de) * 1997-04-30 1998-11-12 Schering Ag Polymer beschichtete Stents, Verfahren zu ihrer Herstellung und ihre Verwendung zur Restenoseprophylaxe
US6106454A (en) * 1997-06-17 2000-08-22 Medtronic, Inc. Medical device for delivering localized radiation
CA2301887A1 (fr) * 1997-09-18 1999-03-25 Schering Aktiengesellschaft Methode pour le traitement curatif des affections proliferatives
US6129658A (en) * 1997-12-10 2000-10-10 Varian Associates, Inc. Method and apparatus creating a radioactive layer on a receiving substrate for in vivo implantation
DE19853067A1 (de) * 1998-11-17 2000-05-18 Jomed Implantate Gmbh Radioaktiver Stent
DE19819635A1 (de) * 1998-05-05 1999-11-11 Jomed Implantate Gmbh Radioaktiver Stent
US6296603B1 (en) * 1998-05-26 2001-10-02 Isostent, Inc. Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms
ES2247826T3 (es) * 1998-09-29 2006-03-01 C.R. Bard Inc. Sistemas de administracion de medicamentos.
US6251079B1 (en) 1998-09-30 2001-06-26 C. R. Bard, Inc. Transthoracic drug delivery device
US6620170B1 (en) 1999-04-26 2003-09-16 C. R. Bard, Inc. Devices and methods for treating ischemia by creating a fibrin plug
US6719805B1 (en) 1999-06-09 2004-04-13 C. R. Bard, Inc. Devices and methods for treating tissue
US6277082B1 (en) 1999-07-22 2001-08-21 C. R. Bard, Inc. Ischemia detection system
US6629987B1 (en) 1999-07-30 2003-10-07 C. R. Bard, Inc. Catheter positioning systems
FR2797175A1 (fr) * 1999-08-02 2001-02-09 Jacques Seguin Dispositif permettant de traiter le re-retrecissement de conduits corporels consecutif a la pose d'un stent

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WO1997038730A3 (fr) 1997-12-11
WO1997038730A2 (fr) 1997-10-23

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