EP0724443A1 - Procedes et comositions d'abaissement de la pression intra-oculaire - Google Patents

Procedes et comositions d'abaissement de la pression intra-oculaire

Info

Publication number
EP0724443A1
EP0724443A1 EP94920077A EP94920077A EP0724443A1 EP 0724443 A1 EP0724443 A1 EP 0724443A1 EP 94920077 A EP94920077 A EP 94920077A EP 94920077 A EP94920077 A EP 94920077A EP 0724443 A1 EP0724443 A1 EP 0724443A1
Authority
EP
European Patent Office
Prior art keywords
quinine
eye
intraocular pressure
pharmaceutical composition
compound
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Withdrawn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
EP94920077A
Other languages
German (de)
English (en)
Other versions
EP0724443A4 (fr
Inventor
Nino Sorgente
Charles Bakhit
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.)
Vide Pharmaceuticals
Original Assignee
Vide Pharmaceuticals
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 US08/096,799 external-priority patent/US5629345A/en
Application filed by Vide Pharmaceuticals filed Critical Vide Pharmaceuticals
Publication of EP0724443A1 publication Critical patent/EP0724443A1/fr
Publication of EP0724443A4 publication Critical patent/EP0724443A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to compositions and methods for lowering intraocular pressure and more particularly to the administration of quinine and quinidine, and ATP-sensitive K + channel inhibitors to the eye to lower intraocular pressure for the treatment of glaucoma.
  • Glaucoma is an ocular disorder that is often manifested as an elevated intraocular pressure, i.e., pressure in the anterior chamber of the eye. It is presently believed that such elevated pressure results from inadequate transport of the intraocular fluid from the anterior chamber, resulting in a detrimental pressure increase. If left untreated, glaucoma will eventually lead to loss of vision in the affected eye.
  • topically applied drugs for the treatment of glaucoma include pilocarpine, a cholinergic; timolol maleate, a /3-adrenergic receptor blocking agent; epinephrine, an ⁇ - and ⁇ -adrenergic receptor agonist; dipivefrin, a pro drug of epinephrine; and demecarium bromide, a cholinesterase inhibitor. While these drugs are generally effective, they can have significant adverse side effects, even when administered topically.
  • Topical administration to the eye results in significant absorption leading to such undesirable systemic effects. Therefore it would be desirable to provide additional drugs useful for the treatment of glaucoma and other disorders related to elevated intraocular pressure, particularly where such drugs have fewer or reduced side effects when compared to present drugs when topically applied.
  • Such drugs should be safe, relatively non-toxic, and be amenable to incorporation in carriers and vehicles suitable for administration to the eye, either topically, by injection, or by ocular insert.
  • compositions for lowering intraocular pressure in the eye of a patient have been discovered.
  • the compositions may comprise at least one quinine compound present in a non-phosphate ophthalmically acceptable carrier in an amount effective to lower intraocular pressure when administered to an eye having elevated intraocular pressure.
  • the quinine compounds are preferably quinine, quinidine, and therapeutically equivalent salts and derivatives thereof, and are preferably present in the compositions in concentrations from about 0.1% to 5% by weight.
  • Particular formulations include those suitable for topical application, for injection, and for combination in an ocular insert.
  • the compositions may comprise at least one ATP- sensitive K + channel inhibiting compound present in an ophthalmically acceptable carrier in an amount effective to lower intraocular pressure when administered to an eye having elevated intraocular pressure.
  • the ATP-sensitive K + channel inhibiting compounds are preferably sulfonylurea compounds, more preferably being selected from the group consisting of glybenclamide, glipizide, tolbutamide, and tolazamide, and therapeutically equivalent salts and derivatives thereof, and are preferably present in the compositions in concentrations from about 0.1% to 5% by weight.
  • Particular formulations include those suitable for topical application, for injection, and for combination in an ocular insert.
  • Methods according to the present invention comprise administering such compositions directly to the eye in an amount effective to lower the intraocular pressure.
  • Suitable administration methods include topical application, injection, and timed release using an ocular insert or equivalent formulation.
  • the methods and compositions of the present invention are particularly useful for the treatment of glaucoma, and overcome many of the limitations of prior glaucoma treatment methods and compositions.
  • the methods and compositions of the present invention are intended for treatment of glaucoma and other conditions which manifest elevated intraocular pressure in the eye of a patient, particularly human patients, but including other mammalian hosts.
  • Glaucoma is a term which embraces a group of ocular diseases characterized by elevated intraocular pressure levels which can damage the eye. Elevated intraocular pressures often exceed 20 mm/Hg and it is desirable that such elevated pressures be lowered to below 18 mm/Hg. In the case of low-tension glaucoma, it is desirable that the intraocular pressure be lowered below that exhibited by the patient prior to treatment.
  • Glaucoma diseases are well- described in the medical literature. See, e.g., Leibowitz et al. (1980) Suirv. Ophthamol . 24 (Suppl.):366-400 and Leske
  • Intraocular pressure can be measured by conventional tonometry techniques.
  • a particularly convenient method for measuring intraocular pressure is the use of the Tono-Pen as described in Minckler et al. (1987) Am . J. Ophthamol . 104:168-173.
  • Quinine compounds useful for the present invention include quinine (6'-methoxycinchonan-9-ol) , quinidine (3-quinine, an enantio eric form of quinine) , and therapeutically equivalent salts and derivatives thereof.
  • quinine and quinidine particularly useful salts and derivatives include quinine sulfate, quinine acid sulfate, quinine bisulfate, quinine urea hydrochloride, quinine carbonate, quinine ethyl carbonate, quinine gluconate, quinine hydroiodide, quinine hydrobromide, quinine hydrochloride, quinidine sulfate, quinidine gluconate, and quinidine polygalacturonate.
  • Quinine and quinidine are well-known drugs, amply described in the patent and medical literature, and biologically equivalent forms of both quinine and quinidine are well-known.
  • ATP-sensitive K + channel inhibiting compounds useful for the treatment of elevated intraocular pressure conditions include sulfonylureas, such as glybenclamide, glipizide, tolbutamide, and tolazamide (each of these compounds is described in the Merck Index, 10th Edition, with suitable source information provided) , and therapeutically equivalent salts and derivatives thereof.
  • Therapeutically equivalent salts and derivatives are those salts and derivatives of the parent compounds which retain biological activity, i.e.
  • the ATP-sensitive K + channel is one of the approximately 15 K + channels that have been identified.
  • the ATP-sensitive K + channel is regulated by intracellular ATP such that it is spontaneously active in the absence of ATP and closed by increasing ATP concentration in the cytoplas ic side of the membrane.
  • the ATP-sensitive K + channel is not activated by intraocular Ca +2 , and gating of the channel is independent of membrane potential.
  • the channel is selective for K + , and it is selectively inhibited by sulfonylurea compounds, such as glybenclamide, glipizide, tolbutamide, and tolazamide, and the like. It is expected that other selective ATP-sensitive K + channel inhibitors will be identified in the future and that they will be useful in the methods of the present invention.
  • ATP-sensitive K + channels have been identified in cardiac cells, skeletal and smooth muscle, neurons and pancreatic ⁇ - cells. It is very likely that ATP-sensitive K + channels are found in many cells, and the data present in the Experimental section hereinafter indicate existence of such a channel in the eye.
  • a decrease in intraocular pressure occurs when the eye is treated with selective inhibitors of the ATP-sensitive K + channel and an increase in intraocular pressure occurs when the eye is treated with a K + channel opener.
  • such quinine and ATP-sensitive K + channel inhibiting compounds will be incorporated into compositions suitable for direct administration to a patient's eye.
  • direct administration it is meant that the compositions will be applied topically, or by injection or instillation, into the eye.
  • Such direct administration does not include systemic forms of administration, such as oral or parenteral administration, e.g., intramuscular, subcutaneous, or intraperitoneal injection.
  • Direct administration of the compositions is intended to introduce the compounds directly into the eye so that they will be transported into the anterior chamber where the compounds will be effective to lower intraocular pressure, most likely by enhancing the transport or release of intraocular fluid from the anterior chamber or by decreasing fluid production.
  • the active compounds will be administered to the eye in amounts and over a schedule effective to lower the intraocular pressure of the eye, particularly when the intraocular was previously elevated, i.e., above about 20 mm/Hg, usually above 18 mm/Hg, or when damage to the optic nerve is noted.
  • the amount of the quinine or ATP-sensitive K + channel inhibiting compound required for such lowering will depend on a number of factors, including degree of initial pressure elevation, condition of the patient, activity of the particular compound which is being administered, and the like, with exemplary amounts typically being in the range from about 50 ⁇ g to 5 mg per dose (i.e., single application of the composition) , usually being from 250 ⁇ g to 1 mg per dose.
  • compositions having the quinine compound present in a suitable ophthalmically acceptable carrier at a concentration in the range from about 0.1 weight percent to 5 weight percent. Concentrations above 5 weight percent are potentially toxic and should generally be avoided. Specific formulations will be described in greater detail hereinafter.
  • Suitable controlled release articles for use with the compositions of the present invention include solid ocular inserts available from commercial vendors such as Alza Corporation, Palo Alto, California (sold under the Ocusert® trade name) and from Oculex Corporation, Palo Alto, California.
  • controlled-release formulations may be based on polymeric carriers, including both water-soluble polymers and porous polymers having desirable controlled-release characteristics.
  • Particularly suitable polymeric carriers include various cellulose derivatives, such as methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, and the like.
  • Suitable porous polymeric carriers can be formed as polymers and copolymers of acrylic acid, polyacrylic acids, ethylacrylates, methyl ethacrylates, polyacrylamides, and the like.
  • Certain natural biopoly ers may also find use, such as gelatins, alginates, pectins, agars, starches, and the like.
  • a wide variety of controlled-release carriers are known in the art and available for use with the present invention.
  • Topical compositions for delivering the quinine or ATP-sensitive K + channel inhibiting compounds of the present invention will typically comprise the quinine compound present in a suitable ophthalmically acceptable carrier, including both organic and inorganic carriers.
  • suitable ophthalmically acceptable carriers include water, buffered aqueous solutions, isotonic mixtures of water and water-immiscible solvents, such as alkanols, arylalkanols, vegetable oils, polyalkalene glycols, petroleum-based jellies, ethyl cellulose, ethyl oleate, carboxymethylcelluloses, polyvinylpyrrolidones, isopropyl yristates, and the like.
  • Suitable buffers include sodium chloride, sodium borate, sodium acetate, gluconates, and the like. Phosphate buffers are not suitable because of the low solubility of quinine in the presence of phosphate ions.
  • the formulations of the present invention may also contain ophthalmically acceptable auxiliary components, such as emulsifiers, preservatives, wetting agents, thixotropic agents (e.g., polyethylene glycols, antimicrobials, chelating agents, and the like.
  • auxiliary components such as emulsifiers, preservatives, wetting agents, thixotropic agents (e.g., polyethylene glycols, antimicrobials, chelating agents, and the like.
  • antimicrobial agents include quaternary ammonium compounds, benzalkonium chloride, phenylmercuric salts, thi erosal, methyl paraben, propyl paraben, benzyl alcohol, phenylethanol, sorbitan, monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopal itylate, dioctyl sodium sulfosuccinate, monothioglycerol, and the like.
  • Ethylenediamine tetracetic acid (EDTA) is a suitable chelating agent.
  • compositions of this invention are exemplary of the compositions of this invention. These formulations are illustrative only and are not intended to limit the scope of this invention and should not be so construed.
  • a sterile solution for topically treating glaucoma or reducing intraocular pressure and which is well tolerated by the eye is prepared as follows: Component Amount Quinine 100 ⁇ g to 20 mg
  • a sterile solution for topically treating glaucoma or reducing intraocular pressure is prepared as described in Formula 1 except that quinidine is used in place of quinine.
  • An injectable solution for use in treating glaucoma or reducing intraocular pressure is prepared as follows:
  • FORMULA 4 A sterile injectable solution for treating glaucoma or decreasing intraocular pressure is prepared as described in Formula 3 except that quinidine is used in place of quinine.
  • FORMULA 5 A sterile solution for topically treating glaucoma or reducing intraocular pressure and which is well tolerated by the eye is prepared as follows: Component Amount Glybenclamide 100 ⁇ g to 20 mg
  • An injectable solution for use in treating glaucoma or reducing intraocular pressure is prepared as follows: Component Amount
  • Formulations of inhibitors of ATP-sensitive K + channels were tested for their ability to decrease intraocular pressure in normal rabbits.
  • Diazoxide a K + channel opener, was tested for its ability to raise intraocular pressure in normal rabbits.
  • Formulations were prepare in NaCl/borate buffer (0.8 mg NaCl, 1.0 mg boric acid, pH 7.2, water to 1 ml) and tested as follows: Seventy New Zealand white rabbits were divided into seven groups; 25 were treated with vehicle; 20 were treated with timolal; 10 were treated with glybenclamide; 5 with tolazamide; 10 with tolbutamide; 5 with chlorpropamide, and 5 with diazoxide.
  • intraocular pressure is at least in part dependent on the ratio of intracellular to extracellular potassium.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des composés à base de quinine sont incorporés à des excipients acceptables pour un usage ophtalmique en vue d'une administration à l'÷il destinée à abaisser la pression intra-oculaire. Ces formulations conviennent en particulier pour traiter le glaucome ou d'autres troubles liés à l'élévation de la pression intra-oculaire.
EP94920077A 1993-06-08 1994-06-03 Procedes et comositions d'abaissement de la pression intra-oculaire Withdrawn EP0724443A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US7380293A 1993-06-08 1993-06-08
US73802 1993-06-08
US96799 1993-07-23
US08/096,799 US5629345A (en) 1993-07-23 1993-07-23 Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
PCT/US1994/006278 WO1994028900A1 (fr) 1993-06-08 1994-06-03 Procedes et comositions d'abaissement de la pression intra-oculaire

Publications (2)

Publication Number Publication Date
EP0724443A1 true EP0724443A1 (fr) 1996-08-07
EP0724443A4 EP0724443A4 (fr) 1997-09-10

Family

ID=26754897

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94920077A Withdrawn EP0724443A4 (fr) 1993-06-08 1994-06-03 Procedes et comositions d'abaissement de la pression intra-oculaire

Country Status (5)

Country Link
EP (1) EP0724443A4 (fr)
JP (1) JPH08511024A (fr)
AU (1) AU7099194A (fr)
CA (1) CA2164733A1 (fr)
WO (1) WO1994028900A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5573758A (en) * 1995-04-28 1996-11-12 Allergan Method for reducing intraocular pressure in the mammalian eye by administration of potassium channel blockers
ID19891A (id) * 1996-08-02 1998-08-20 Senju Pharma Co Komposisi gangguan peredaran anti-okular
US6548535B2 (en) 2000-01-18 2003-04-15 Merck & Co., Inc. Method for treating ocular hypertension
ATE409491T1 (de) 2000-01-18 2008-10-15 Merck & Co Inc Orhthalmologische zusammenstellungen zur behandlung von ocularer hypertension
CA2488752A1 (fr) 2002-06-17 2003-12-24 Merck & Co., Inc. Nouveaux bloqueurs de canaux maxi k, methodes d'utilisation et procedes de fabrication associes
US7528163B2 (en) 2002-11-08 2009-05-05 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
US7196082B2 (en) 2002-11-08 2007-03-27 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
AU2004226479A1 (en) 2003-03-27 2004-10-14 Evotec Oai Ophthalmic compositions for treating ocular hypertension
CN1845914A (zh) 2003-09-02 2006-10-11 默克公司 用于治疗眼压过高的眼用组合物
KR20060090801A (ko) 2003-09-04 2006-08-16 머크 앤드 캄파니 인코포레이티드 고안압증 치료용 안용 조성물
CA2537430A1 (fr) 2003-09-04 2005-03-24 Merck & Co., Inc. Compositions ophtalmiques pour traiter l'hypertension oculaire
JP2008507521A (ja) 2004-07-20 2008-03-13 メルク　エンド　カムパニー　インコーポレーテッド 高眼圧症を治療するための眼科用組成物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0171331A1 (fr) * 1984-08-03 1986-02-12 Laboratoire Vaillant Defresne Nouvelle composition liquide à base de formiate de quinine
GB2177913A (en) * 1984-01-26 1987-02-04 Sanofi Sa Anti malarial compositions
EP0467710A2 (fr) * 1990-07-19 1992-01-22 E.R. Squibb & Sons, Inc. Méthode pour le traitement de la maladie de Parkinson utilisant le bloqueur du canal potassique ATP-dépendant quinine
EP0467709A2 (fr) * 1990-07-20 1992-01-22 E.R. Squibb & Sons, Inc. Utilisation d'un blockeur des canaux de potassium sensibles à l'ATP pour le traitement d'accès neuronal
WO1994002142A1 (fr) * 1992-07-17 1994-02-03 Merck & Co., Inc. Biphenylmethylimidazopyridines substituees

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895807A (en) * 1986-12-31 1990-01-23 Cherksey Bruce D Membrane channel protein and related therapeutic compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2177913A (en) * 1984-01-26 1987-02-04 Sanofi Sa Anti malarial compositions
EP0171331A1 (fr) * 1984-08-03 1986-02-12 Laboratoire Vaillant Defresne Nouvelle composition liquide à base de formiate de quinine
EP0467710A2 (fr) * 1990-07-19 1992-01-22 E.R. Squibb & Sons, Inc. Méthode pour le traitement de la maladie de Parkinson utilisant le bloqueur du canal potassique ATP-dépendant quinine
EP0467709A2 (fr) * 1990-07-20 1992-01-22 E.R. Squibb & Sons, Inc. Utilisation d'un blockeur des canaux de potassium sensibles à l'ATP pour le traitement d'accès neuronal
WO1994002142A1 (fr) * 1992-07-17 1994-02-03 Merck & Co., Inc. Biphenylmethylimidazopyridines substituees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9428900A1 *

Also Published As

Publication number Publication date
WO1994028900A1 (fr) 1994-12-22
AU7099194A (en) 1995-01-03
EP0724443A4 (fr) 1997-09-10
JPH08511024A (ja) 1996-11-19
CA2164733A1 (fr) 1994-12-22

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