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WO1999013920A2 - Methode pour le traitement curatif des affections proliferatives - Google Patents

Methode pour le traitement curatif des affections proliferatives Download PDF

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Publication number
WO1999013920A2
WO1999013920A2 PCT/EP1998/005741 EP9805741W WO9913920A2 WO 1999013920 A2 WO1999013920 A2 WO 1999013920A2 EP 9805741 W EP9805741 W EP 9805741W WO 9913920 A2 WO9913920 A2 WO 9913920A2
Authority
WO
WIPO (PCT)
Prior art keywords
radioactive substance
optionally
catheter
substituted
derivative
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.)
Ceased
Application number
PCT/EP1998/005741
Other languages
German (de)
English (en)
Other versions
WO1999013920A3 (fr
Inventor
Ludger Dinkelborg
Christoph-Stephan Hilger
Dieter Heldmann
Friedhelm Blume
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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
Priority claimed from DE1997141694 external-priority patent/DE19741694C2/de
Priority claimed from DE19741695A external-priority patent/DE19741695C1/de
Priority claimed from DE1997142880 external-priority patent/DE19742880A1/de
Application filed by Schering AG filed Critical Schering AG
Priority to AU11459/99A priority Critical patent/AU745908B2/en
Priority to CA002301887A priority patent/CA2301887A1/fr
Priority to EP98954267A priority patent/EP1011737A2/fr
Priority to JP2000511533A priority patent/JP2001516730A/ja
Publication of WO1999013920A2 publication Critical patent/WO1999013920A2/fr
Publication of WO1999013920A3 publication Critical patent/WO1999013920A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention is in the field of the therapy of proliferative diseases and in particular the therapy of vascular diseases such as atherosclerosis.
  • Ionizing radiation is known to inhibit cell proliferation.
  • a variety of neoplastic and non-neoplastic diseases have been treated in this way (Fletcher, Textbook of Radiotherapy, Philadelphia, P.A: Lea and Febiger, 1980, Hall, Radiobiology for the Radiologist, Philadelphia, P.A: Lippincott, 1988).
  • Atherosclerosis is an inflammatory, fibroproliferative
  • Atherosclerosis is currently treated in different ways.
  • conservative measures e.g. lowering the cholesterol level in the blood
  • bypass operation the mechanical dilatation (angioplasty) and the intravascular removal of atheromatous tissue (atherectomy) of narrowed segments in the peripheral arteries and the coronary arteries have also been shown to be Alternative established in everyday clinical practice.
  • neointimal hyperplasias In addition to radiation therapy, a number of other therapeutic strategies for inhibiting neointimal hyperplasias (restenoses) are also used. These include classic drugs for restenosis suppression such as antithrombotics, antiplatelet agents, calcium antagonists, anti-inflammatory and anti-proliferative substances, but also gene therapy approaches Inhibition of growth stimulators, for example by antisense oligonucleotides, or the amplification of inhibiting factors by expression vector plasmids and virus-mediated gene integration possible. Aptamer oligonucleotides can also be used for inhibition a wide variety of receptor-mediated processes that play a crucial role in restenosis.
  • the object of the present invention was therefore to develop a method for the therapy of proliferative diseases which overcomes the disadvantages of the previously known therapy methods.
  • a method for the therapeutic treatment of proliferative diseases has been developed, which is characterized in that first an application catheter is placed at the site of the lesion and a radioactive substance is applied locally via the catheter, then the catheter is removed again and the radioactive substance at the site of the Lesion remains.
  • the concentration of the radionuclide lasts long enough to inhibit the proliferation of the cells and thus restenosis.
  • the method according to the invention has some essential advantages compared to the known therapy methods.
  • the local application leads to certain Substances and with certain catheters to a surprisingly high radioactive dose at the desired, pathologically changed location.
  • This procedure leads to a high effective radiation dose with low systemic exposure.
  • the radioactive substances have a long residence time at the application site, which leads to a high effective dose on site are mainly and evenly distributed in the pathological region. The unbound radioactive substances are quickly eliminated
  • the method according to the invention is not only suitable for the therapy of atherosclerotic diseases, but also for the therapy of other proliferative diseases, such as tumor diseases
  • radioactive substances are those which have a sufficiently high lipophilicity to adhere to the plaque.
  • radioactively labeled metal complexes are suitable, such as metal complexes of bis-amine oxime derivatives of the general formula I
  • R ⁇ to R- ⁇ 2 are the same or different and each for a hydrogen atom and / or for an unbranched, branched, cyclic or polycyclic Ci -Ci rjo- alkyl, alkenyl, alkynyl, aryl, - Alkylaryl and / or arylalkyl radicals, which optionally have fluorine, chlorine, bromine and / or iodine atoms and / or hydroxyl, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups up to 30 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series N, P, As, O, S, Se, and the radicals R * and R i2 , R 13 and R * 4 , R 15 and R * 6 and Rl and Rl8 together can optionally represent an oxygen atom and n, m and p independently of
  • tetrofosmin tetrofosmin
  • sestamibi tetrofosmin
  • furifosmin derivatives tetrofosmin, sestamibi and furifosmin derivatives.
  • 99m Tc-Tetrofosmin is available under the trade name Myoview TM from Amersham
  • 99m Tc-Sestamibi is sold under the trade name Cardiolite® from DuPont
  • 99m Tc-Furifosmin is under the trade name TechneScan Q-12 from Mallinckrodt Medical to acquire.
  • radionuclides can be introduced which are alpha, beta and / or Gam a emitters, positron emitters, Auger electron emitters and fluorescence emitters, with ⁇ and combined ⁇ / ⁇ emitters for therapeutic Purposes are preferred.
  • radionuclides are known to the person skilled in the art.
  • the radionuclides of the elements of atomic numbers 27, 29 - 32, 37 - 39, 42 - 51, 62, 64, 70, 75, 77, 82 or 83 may be mentioned as examples.
  • nuclides m ⁇ 99 c, L86 R e, 188 Re, 67 Cu, 90 Y, and 107 Ag are preferred which nuclides are especially preferred 186 Re, 188 Re, 67 Cu.
  • Suitable metal complexes have ligands derived from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or a macrocyclic compound such as e.g. Tetraazacyclododecan are derived. The making of this
  • Suitable ligands are, for example, porphyrin derivatives, as described, for example, in DE 42 32 925 AI and DE 43 05 523 AI.
  • Metal complexes suitable for the process according to the invention can also be prepared from these ligands using radionuclides
  • Radioactive thallium compounds of the isotopes 201 T1, 207 T1, 209 T1 and 210 T1 are also suitable; 201 T1C1 is particularly suitable
  • Suitable colloidal solutions are the tin colloids described in the examples. Tin colloids are particularly suitable, which can be produced with the aid of a kit from Amersham ("Amerscan tin colloid ( 99m Tc) - marking kit for liver scintigraphy"). Other suitable colloids are e.g. B radioactive gold sol ( 198 Au colloid) and radioactively labeled sulfur colloid as well as other physiologically acceptable, radioactive colloidal solutions
  • radionuclides for radioactive labeling of the colloidal solutions are known to the person skilled in the art.
  • the radionuclides of the elements Ag, As, At, Au, Ba, Bi, Br, C, Co, Cr, Cu, F, Fe, Ga, Gd, Hg may be mentioned as examples , Ho, I, In, Ir, Lu, Mn, N, O, P, Pb, Pd, Pm, Re, Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb, Tc or Y
  • the nuclides 99m Tc, 186 Re, 188 Re, 67 Cu, 90 Y, 15 Sm, 160 Tb, 162 Tb, 198 Au and 107 Ag are preferred.
  • the colloidal solutions are usually prepared by means of a redox reaction or by changing the pH in an aqueous or alcoholic solution in the presence of a radioactive salt.
  • the colloid can be formed in the presence of a stabilizer or can be added later with a surfactant or other stabilizing amphiphilic Substance added
  • Other manufacturing methods for suitable colloidal solutions are electrochemical methods such as those described, for example, by MT Reetz et al in Angew Chem 1995, Vol 107, p. 2461 ff.
  • the tin colloids are prepared in the examples below and in the instructions for use of the labeling kit described by Amersham
  • the production of a gold colloid for diagnostic purposes is described in the patent specification DE 24 20 531 C3
  • the size of the particles formed is in the range between 5 and 1000 nm, in the case of the tin colloid between 300 and 600 nm.
  • the catheters outlined in FIG. 3 can be used as catheters which are suitable for the local application of the substances according to the invention.
  • Multi-chamber balloon catheters such as Dispatch TM, SciMed
  • microperforated balloon catheters are particularly suitable.
  • the experimental animal a white New Zealand rabbit (internal animal identification number: 1708, male, 3.7 kg body weight) was prepared 4 weeks before the actual application experiment as follows:
  • the local application of the FLMPAO marked with Technetium 99m takes place on the anesthetized test animal (anesthetic type see above) via a coronary perfusion / infusion catheter (Dispatch 3.0, Xtra slippery coating, manufacturer: Boston Scientific Corporation, Ratingen) directly at the lesion in the carotid artery.
  • test animal was placed under a gamma camera (Elscint SP4 HR) to measure the distribution of radioactivity in the body.
  • the activity at the lesion is related to the total activity (measured in the animal at that point in time).
  • this experimental animal there were: 55.38% of the dose at the lesion 5 minutes after application
  • the experimental animal a white New Zealand rabbit (internal animal identification number: 1856, male, 3.3 kg body weight) was prepared 4 weeks before the actual application experiment as follows:
  • test animal is under a gamma camera (Elscint SP4 HR) to measure the distribution of radioactivity in the body.
  • the activity at the lesion is related to the total activity (measured in the animal at this point in time)
  • Experimental animals were at the lesion 5 minutes after application 40 40 74% of the dose
  • test animal is a white New Zealand rabbit (internal animal identification number 1584, male, 3.4 kg body weight)
  • test animal is under a gamma camera (Elscint SP4 HR) to measure the distribution of radioactivity in the body.
  • the activity at the lesion is related to the total activity (measured in the animal at this point in time)
  • test animal was a white New Zealand rabbit (internal animal identification number: 1587, male, 3.5 kg body weight).
  • test animal was placed under a gamma camera (Elscint SP4 HR) to measure the distribution of radioactivity in the body.
  • the activity at the lesion is related to the total activity (measured in the animal at that point in time).
  • gamma camera Elscint SP4 HR
  • test animal was a white New Zealand rabbit (internal animal identification number: 1586, male, 3.3 kg body weight).
  • the test animal was placed under a gamma camera (Elscint SP4 HR) to measure the distribution of radioactivity in the body.
  • the activity at the lesion is related to the total activity (measured in the animal at that point in time).
  • this experimental animal there were: 5 minutes after application 45.56% of the dose at the lesion 4 hours after application 36.39% of the dose at the lesion 24 hours after application 15.24% of the dose at the lesion
  • test animal is a white New Zealand rabbit (internal animal identification number 1852, male, 3.5 kg body weight)
  • Fig. 1 the situation before application was shown in the upper part.
  • the catheter containing the tin colloid was clearly visible Arrow shows the balloon of the catheter, which is located at the desired application site.
  • the same site is shown 1.5 hours after application and removal of the catheter. The amount of tin colloid remaining at the application site can be clearly seen
  • test animal is a white New Zealand rabbit (internal animal identification number 1839, male, 3.7 kg body weight)
  • the test animal is under a gamma camera (Elscint SP4 HR) to show the distribution of radioactivity in the body.
  • the situation before application is shown in the upper part of FIG. 2.
  • the catheter that contains the tin colloid can be clearly seen.
  • the arrow shows the balloon of the catheter that is located at the desired application site. In the lower part of the image, the same site is shown 1.5 hours after application and removal of the catheter Application site to recognize the remaining amount of tin colloid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Radiation-Therapy Devices (AREA)

Abstract

L'invention concerne une méthode pour le traitement curatif des affections prolifératives, qui est caractérisée en ce qu'un cathéter d'application est tout d'abord placé au niveau du siège de la lésion et en ce qu'une substance radioactive est appliquée localement sur le cathéter, ce dernier est ensuite enlevé et la substance radioactive demeure au niveau du siège de la lésion. L'invention concerne également l'utilisation de dérivés de bisaminoxime, de dérivés complexes de N2S2 et de solutions colloïdales radiomarquées pour la préparation d'agents qui sont appliqués localement lors du traitement des affections prolifératives.
PCT/EP1998/005741 1997-09-18 1998-09-10 Methode pour le traitement curatif des affections proliferatives Ceased WO1999013920A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU11459/99A AU745908B2 (en) 1997-09-18 1998-09-10 Method for treating proliferative diseases by therapy
CA002301887A CA2301887A1 (fr) 1997-09-18 1998-09-10 Methode pour le traitement curatif des affections proliferatives
EP98954267A EP1011737A2 (fr) 1997-09-18 1998-09-10 Methode pour le traitement curatif des affections proliferatives
JP2000511533A JP2001516730A (ja) 1997-09-18 1998-09-10 増殖性疾患を治療処置する方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE1997141694 DE19741694C2 (de) 1997-09-18 1997-09-18 Verwendung von Komplexen, deren Ligand ein Bis-Amin-Oxim-Derivat oder ein N¶2¶S¶2¶-Derivat und deren Zentralatom ein Radionuklid ist
DE19741695.0 1997-09-18
DE19741694.2 1997-09-18
DE19741695A DE19741695C1 (de) 1997-09-18 1997-09-18 Verwendung von radioaktiv markierten kolloidalen Lösungen zur Restenoseprophylaxe
DE1997142880 DE19742880A1 (de) 1997-09-23 1997-09-23 Verfahren zur therapeutischen Behandlung proliferativer Erkrankungen
DE19742880.0 1997-09-23

Publications (2)

Publication Number Publication Date
WO1999013920A2 true WO1999013920A2 (fr) 1999-03-25
WO1999013920A3 WO1999013920A3 (fr) 1999-05-06

Family

ID=27217762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005741 Ceased WO1999013920A2 (fr) 1997-09-18 1998-09-10 Methode pour le traitement curatif des affections proliferatives

Country Status (5)

Country Link
EP (1) EP1011737A2 (fr)
JP (1) JP2001516730A (fr)
AU (1) AU745908B2 (fr)
CA (1) CA2301887A1 (fr)
WO (1) WO1999013920A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482943B1 (en) 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
US7312244B2 (en) 1999-04-30 2007-12-25 Cellgate, Inc. Polyamine analog-amino acid conjugates useful as anticancer agents

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1173223A2 (fr) 1999-04-30 2002-01-23 Slil Biomedical Corporation Nouveaux conjugues d'analogue de polyamine et conjugues de quinone, utilises pour le traitement de cancers et de maladies de la prostate
JP2016520650A (ja) * 2013-06-05 2016-07-14 アール−エヌエーヴィ・エルエルシー スズ−１１７ｍでの免疫性、炎症性及び変形性関節炎の治療

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038730A2 (fr) * 1996-04-17 1997-10-23 Olivier Bertrand Systeme de radiotherapie locale
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
US5873811A (en) * 1997-01-10 1999-02-23 Sci-Med Life Systems Composition containing a radioactive component for treatment of vessel wall
DE19718339A1 (de) * 1997-04-30 1998-11-12 Schering Ag Polymer beschichtete Stents, Verfahren zu ihrer Herstellung und ihre Verwendung zur Restenoseprophylaxe
DE19724229C1 (de) * 1997-04-30 1999-04-01 Schering Ag Verfahren zur Herstellung radioaktiver Stents und ihre Verwendung zur Restenoseprophylaxe

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482943B1 (en) 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
US6809176B2 (en) 1999-04-30 2004-10-26 Slil Biomedical, Corporation Quinones as disease therapies
US7253207B2 (en) 1999-04-30 2007-08-07 Cellgate, Inc. Quinones as disease therapies
US7312244B2 (en) 1999-04-30 2007-12-25 Cellgate, Inc. Polyamine analog-amino acid conjugates useful as anticancer agents

Also Published As

Publication number Publication date
JP2001516730A (ja) 2001-10-02
WO1999013920A3 (fr) 1999-05-06
EP1011737A2 (fr) 2000-06-28
CA2301887A1 (fr) 1999-03-25
AU745908B2 (en) 2002-04-11
AU1145999A (en) 1999-04-05

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