WO1999025336A1 - Methodes de prevention de la restenose utilisant des tocotrienols - Google Patents
Methodes de prevention de la restenose utilisant des tocotrienols Download PDFInfo
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- WO1999025336A1 WO1999025336A1 PCT/US1998/024606 US9824606W WO9925336A1 WO 1999025336 A1 WO1999025336 A1 WO 1999025336A1 US 9824606 W US9824606 W US 9824606W WO 9925336 A1 WO9925336 A1 WO 9925336A1
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- tocotrienol
- tocotrienols
- composition
- coronary artery
- composition comprises
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
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- 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
Definitions
- This invention relates to the prevention of restenosis using tocotrienols. Specifically, this invention relates to the use of individual tocotrienols (such as P 25 tocotrienol), mixtures of tocotrienols and mixtures of one or more tocotrienols with other substances (such as the TRF 25 mixture).
- the methods of this invention are particularly well suited for preventing restenosis in patients having undergone or prior to undergoing angioplasty or arterial bypass surgery.
- An artery that is constricted or narrowed is referred to as being stenosed.
- the artery may be clogged by the buildup over time of fat, cholesterol and other substances that adhere to the interior of arterial walls. Procedures designed to unblock such clogged arteries result in localized arterial trauma. The result of such damage to the artery is an increased risk for atheroma formation at the site of trauma (restenosis).
- PTCA percutaneous transluminal coronary angioplasty
- balloon angioplasty involves the use of a balloon-tipped catheter that is inserted directly into the heart's vessels to open partially blocked, or stenotic, coronary arteries.
- Over 400,000 PTCA procedures were performed in 1994 alone in the United States. The average cost of the PTCA procedure well exceeds $20,000.
- PTCA often does not yield long term success in unblocking clogged arteries.
- About one-third of patients undergoing PTCA develop restenosis of the widened segment within about six months of the procedure.
- Restenosis can also occur following other procedures that cause damage or trauma to an artery, such as arterial bypass operations (including coronary artery bypass procedures).
- Arterial bypass surgery reroutes the flow of blood around clogged arteries via an arterial transplant or graft to improve the supply of blood and oxygen to the heart and other vital organs.
- stenosis sometimes occurs in the transplanted blood vessel ' segment.
- angioplasty or atherectomy may be required to widen the passage. Because of the arterial trauma associated with arterial bypass surgery, restenosis is a substantial risk after such procedures.
- the present invention satisfies the need for therapeutic agents effective in the prevention of restenosis.
- this invention provides methods for preventing restenosis in a patient comprising the step of administering to the patient a prophylactically effective amount of a composition comprising a tocotrienol, a mixture of tocotrienols or a mixture of one or more tocotrienols with other substances.
- This invention also provides a method for preventing restenosis in a patient undergoing an arterial angioplastic procedure comprising the steps of:
- the tocotrienols useful in the methods of this invention include those compounds possessing the following three structural characteristics: (1) a hydrogen donor group (or a group that can be hydrolyzed to a hydrogen donor group) attached to an aromatic ring system; (2) a side chain attached to the aromatic ring system comprising one or more isoprenoid or isoprenoid-like units and (3) a methylene unit or a functional group having at least one lone pair of electrons positioned adjacent to the atom to which the side chain is attached to the aromatic ring, said electrons being conjugated to the aromatic ring system.
- tocotrienols useful in the methods of this invention include desmethyl-tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, Pig tocotrienol and P 25 tocotrienol.
- Figure 1 shows the effects of ⁇ - tocotrienol (GT301) on superoxide production in human peripheral blood neutrophils.
- composition refers to a preparation for administration via any acceptable route known to those of ordinary skill in the art. Such routes include, but are not limited to oral, parenteral, intravenous or topical administration. “Composition” encompasses pharmaceutical compositions as well as dietary supplements, foodstuffs, food additives and the like.
- Desmethyl-tocotrienol refers to the compound 3,4-dihydro-2-methyl-2-(4,8,12- trimethyltrideca-3'(E), 7'(E), 11 '-trienyl)-2H-benzopyran-6-ol. This specific tocotrienol has been referred to as "tocotrienol” in some of the published literature cited herein.
- Patient refers to a warm-blooded mammal and preferably, a human.
- Patients in need of prophylactic therapy to prevent restenosis are those patients possessing one or more risk factors for the development of restenosis.
- patients who have undergone angioplasty or arterial bypass surgery are at particular risk for the development of restenosis.
- patients may also receive prophylactic restenosis therapy according to this invention (short or long-term) prior to undergoing angioplasty or arterial bypass surgery.
- 'P 18 tocotrienol refers to a tocotrienol having the formula
- P 18 tocotrienol and Pj 8 are trademarks of Bionutrics, Inc. (Phoenix, Arizona).
- P 25 tocotrienol refers to the tocotrienol 3,4-dihydro-2-(4,8,12-trimethyltrideca- 3'(E),7'(E), 1 l"-trienyl)-2H-l-benzopyran-6-ol) which has the formula
- P 25 tocotrienol and P 25 are trademarks of Bionutrics, Inc. (Phoenix, Arizona).
- “Prophylactically effective amount” refers to an amount of active ingredient sufficient to prevent restenosis or the symptoms of restenosis in a patient for a period of at least about six months. “Prophylactically acceptable means” refers to means effective to impart a prophylactic effect.
- Preferred tocotrienols for use in the methods of this invention are those which are naturally occurring. These naturally occurring tocotrienols may be conveniently isolated from biological materials or synthesized from commercially available starting material. Preferably, the tocotrienols for use in the methods of this invention are obtained from biological materials that have been stabilized and extracted, such as by the processes described in PCT publication WO 91/17985 (the entire disclosure of which is hereby incorporated by reference).
- tocotrienols examples include stabilized brans and especially, stabilized rice bran.
- Specific preferred tocotrienols of this invention include those of formula (I):
- R] and R 3 are each independently selected from the group consisting of H, halogen, OH,
- OCH 3 and C r C 6 branched or unbranched alkyl preferably, H, halogen and C C 3 branched or unbranched alkyl and more preferably, H and methyl;
- R 2 is a hydrogen donor group selected from the group consisting of OH, NHRg, CO 2 Y,
- R ⁇ s is selected from the group consisting of H and C ⁇ -C 6 branched or unbranched alkyl
- R 7 is selected from the group consisting of isoprenoid and isoprenoid-like side chains, and more preferably from the group consisting of side chains of formulas (a)-(c):
- each R ⁇ 0 is independently selected from the group consisting of H, NH 2 and Cp C 6 branched or unbranched alkyl and Ri ⁇ is selected from the group consisting of H, C ⁇ -
- R 7 is a side chain of formula (a), wherein R 10 and R ⁇ are each independently is selected from the group consisting of H and C ⁇ -C 3 branched or unbranched alkyl and more preferably, H and methyl); each R 8 and R 9 is independently selected from the group consisting of H and C ⁇ -C 6 branched or unbranched alkyl (preferably, H and C r C 3 branched or unbranched alkyl and more preferably, H and methyl);
- Y is H or and - g branched or unbranched alkyl (preferably H and C C 6 branched or unbranched alkyl and more preferably, H and CpC 4 branched or unbranched alkyl); Z is selected from the group consisting of H, halogen, OH, CH 2 OH, CH 3 , OCH 3 and
- COCH 3 (preferably H and CH 3 ); n is an integer selected from the group consisting of 0, 1, 2, 3 and 4 (preferably 0 and 1); and m is an integer selected from the group consisting of 1-30 (preferably 1-20, more preferably 3-10 and most preferably, 3-7).
- More preferred tocotrienols of this invention include desmethyl-tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, Pig tocotrienol and P 25 tocotrienol.
- This invention expressly encompasses the prodrug form of tocotrienols. Upon administration to a patient, such a prodrug undergoes biotransformation to their active form.
- Prodrugs include the esterified form of the tocotrienols used in this invention which comprise a carboxylic acid functionality.
- the tocotrienols for use in the methods of this invention may be in their isomerically pure form or be present as mixtures of isomers.
- the tocotrienols of this invention may exist as the d- or 1-isomer or the d,l-racemic mixture.
- the naturally occurring isomer (usually the d-isomer) and the d,l-racemic mixture are preferred.
- TRF refers to a tocotrienol rich fraction obtained by the stabilization and extraction of a biological source.
- TRF typically contains varying amounts of desmethyl-tocotrienol,. ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol and ⁇ - tocotrienol and may also contain quantities of the newly discovered tocotrienols, P t8 tocotrienol and P 25 tocotrienol.
- TRF will be comprise at least about 50% to about 90% tocotrienols w/w (preferably, at least about 60% to about 90% and more preferably, at least about 70% to about 90%).
- TRF 25 refers to a TRF comprising a significant weight percentage of P 25 tocotrienol.
- TRF 25 comprises at least about 5% P 25 , more preferably, at least about 10% P 25 , and even more preferably, at least about 15% P 25 w/w.
- An example of the preparation of a specific TRF 25 is set forth in A. A. Qureshi et al., Nutr. Biochem.. 8, pp. 290-98 (1997).
- TRF 25 is a preferred component of the compositions and methods described herein.
- TRF 25 is a trademark of Bionutrics, Inc. (Phoenix, Arizona).
- One embodiment of this invention provides a method for preventing restenosis in a patient comprising the step of administering to the patient a prophylactically effective amount of a composition comprising a tocotrienol, a mixture of tocotrienols or a combination of one or more tocotrienols with one or more additional substances.
- This embodiment of the invention provides an effective means for administering tocotrienols systemically or locally to a patient in need of restenosis prophylaxis.
- composition (b) performing the arterial angioplastic procedure such that a prophylactically effective amount of the composition is transferred to the interior surface of the artery.
- a coating also may be applied to implantable and non-implantable vascular instruments (e.g., stents).
- This alternate embodiment of the invention provides an effective means for delivering tocotrienols directly to the site of damage where restenosis is likely to develop without necessitating further invasive procedures. Delivery of the tocotrienols in this way reduces the severity of endothelial damage caused as a result of the trauma and also reduces further damage resulting from the subsequent inflammatory response.
- the methods described herein may be used alone or in conjunction with conventional prophylactic methods (such as those described above). Accordingly, the methods 'of this invention, used alone or together with other methods, provide a safe and effective means for reducing or eliminating the risk of restenosis in a patient in need of such prophylactic treatment.
- tocotrienols are useful in preventing restenosis due to their unique combination of antioxidant, antiinflammatory and antithrombotic properties. As opposed to conventional therapeutics that target a single mechanism, tocotrienols target multiple mechanisms leading to restenosis.
- the tocotrienols of this invention inhibit the production of free arachidonic acid (a major mediator of inflammatory response). This inhibition is believed to occur by either the inhibition of phospholipase A 2 or alternatively, through the increase in corticosterone levels in the blood. Phospholipase A 2 cleaves at C-2 of phosphate head groups, resulting in the release of free arachidonic acid.
- Free arachidonic acid can then be converted to a variety of biologically important molecules, such as prostaglandins and thromboxanes (via the cyclooxygenase pathway) and the leukotrienes (via the lipoxygenase pathway). These factors are associated with the increased platelet aggregation and vasoconstriction in restenosis.
- tocotrienols inhibit the production of a variety of cytokines (including TNF, IL-1 and growth factors). These cytokines contribute to the proliferation of smooth muscle and propagation of the inflammatory response associated with restenosis. Furthermore, tocotrienols reduce the levels of superoxide production. Superoxide and nitric oxide react to form peroxynitrite, which is a causative factor in endothelial damage and arteriosclerosis. By reducing superoxide and cytokine production, tocotrienols reduce the cell proliferation, chemotaxis, inflammation and endothelial damage that are responsible for restenosis. As a result of their unique combination of properties, tocotrienols are capable of combating the root causes and lessen the severity of the arterial response to injury that often leads to restenosis.
- cytokines including TNF, IL-1 and growth factors.
- compositions of this invention are prepared by combining one or more tocotrienols with an acceptable carrier.
- the carrier must be pharmaceutically acceptable (i.e., a carrier which is non-toxic to the patient at the administered level and which does not destroy the activity of the active component(s) of the composition).
- Acceptable carriers, including pharmaceutically acceptable carriers, are well known to those of ordinary skill in the art.
- compositions of this invention may be used or administered by any prophylactically acceptable means to a patient in need of restenosis prophylaxis.
- pharmaceutical compositions of this invention may be administered orally, topically, transdermally, parenterally, intravenously or by inhalation. These compositions may be formulated so as to impart a time-released benefit.
- Oral compositions may take the form of tablets, capsules, caplets, emulsions, liposomes, suspensions, powders and the like.
- Topical compositions include, but are not limited to, gels, lotions and creams.
- Parenteral compositions take the form of sterile solutions and emulsions and the like.
- Intravenous compositions include, but are not limited to sterile solutions.
- the preferred routes of administration are parenteral injection of a sterile solution or emulsion (if being administered to a patient immediately prior to undergoing angioplasty or arterial bypass surgery) and oral or transdermal administration (if being administered to patients who have already undergone angioplasty or arterial bypass surgery or who will be treated for a prolonged period of time prior to any such procedure).
- Suitable carriers for use in the alternate embodiment of this invention are pharmaceutically acceptable carriers that are sufficiently viscous to adhere to the exterior surface of an angioplastic balloon but that are readily transferred to the interior surface of the treated artery upon inflation during the angioplastic procedure.
- the exterior surface of the angioplastic balloon can be pretreated or altered (such as by mechanical or chemical roughening or increasing the surface porosity) to enhance the ability of the tocotrienol composition to adhere to the surface.
- Suitable carriers include glycols, such as propylene glycol, parabens (such as methyl and propyl), glycerin, alcohols, petrolatum, oils (including rice bran and other bran oils) and waxes. Propylene glycol and rice bran oil are preferred carriers for this method.
- a formulation comprising about 0.1 - 5000 mg of a tocotrienol composition (comprising from about 0.1% to about 50%), preferably from about 1% to about 25% and more preferably, about 5% to about 15% w/w tocotrienol) and about 0.1 to about 100 g of a suitable carrier (preferably about 1 to about 50 g and more preferably, from about 1 to about 25 g of a suitable carrier) is used to coat the balloon prior to the angioplastic procedure.
- the balloon may be coated immediately preceeding surgery or may be pre-coated and stored for later use.
- Dosage levels and requirements are well-recognized in the art and may be chosen by those of ordinary skill in the art from publicly available sources. Typically, dosage levels will range between about 0.1 and about 10,000 mg of tocotrienol or mixture of tocotrienols per dose. Preferably, the range is between about 0.1 and about 5,000 mg of active ingredient per dose. If being administered to patients who have undergone angioplasty or arterial bypass surgery, multiple doses may be required over a period of time to obtain maximum benefit. For example, a patient may receive oral administration of between about 0.1 and about 5000 mg/day for a period of several weeks to several months following angioplasty or bypass surgery.
- Patients receiving prophylactic treatment prior to undergoing angioplasty or arterial bypass surgery may be administered, for example, one or more doses of between about 0.1 and about 5000 mg/day by parenteral injection for one or more days or weeks prior to the procedure.
- a concentration should be selected such that a prophylactically effective amount of the tocotrienol composition is transferred to the interior surfaces of the treated artery.
- Specific dosage and treatment regimens will depend upon factors such as the patient's overall health status, the severity and course of the patient's disorder or disposition thereto and the judgment of the treating physician. Higher or lower doses may be employed as needed.
- Tocotrienols and mixtures thereof may be used in combination with conventional therapeutics in the methods described herein.
- the conventional therapeutics may be administered separately from the tocotrienols and mixtures thereof, or they may be formulated together in a single dosage form.
- Such combination therapy advantageously utilize lower dosages of those conventional therapies and reduce or avoid possible toxicity incurred when those agents are used as monotherapies.
- the tocotrienols used in the methods of this invention may be used in conjunction with any anti-inflammatory or anti-oxidative agent.
- the tocotrienols are used in conjunction with non-steroidal anti-inflammatory agents (NSAIDS) or with one or more of the following restenosis prophylactic agents: ReoPro (Centacor, Inc.), DAB389EGF (Seragen, Inc.), gene-based anti -restenosis agents (such as those being developed by Antivirals, Inc.), nitrogen oxide based anti-restenosis agents (such as those being developed by NitroMed, Inc.), acyclovir, acyclovir with the thymidine kinase gene (CardioGene Therapeutics, Inc.) or cyclodextrins (such as the sulfated cyclodextrins being developed by Atlantic Pharmaceuticals, Inc.).
- Particularly preferred combination therapies employ the co-administration of the tocotrienol compositions of this invention with aspirin, naproxen salts and ibuprofen (and more preferably, aspirin).
- Protocol II Dry Heat followeded Bv Wet Heat Stabilization Dry Heat Stage: Protocol I Wet Heat Stage: Extruder: Anderson 4 inch
- Protocol III Drving/Cooling Procedure
- the wet heat stabilized product of protocol II (15% moisture) was discharged onto aluminum trays and placed in a tray oven at 101.1 °C until the moisture content was 8- 10% (approximately 1.5 hrs). The trays were then placed on tray racks and allowed to cool at ambient temperature (approximately 20°C).
- Protocol V Dewaxing
- tocotrienols in the form of the TRF mixture and individual tocotrienols
- plasma levels of thromboxane B 2 and platelet factor 4 in chickens were determined. These levels are known to correlate with the levels of inflammatory cytokines.
- the following feeding conditions were used:
- Each group of six chickens (6-week old female white leghorn chickens) was administered a chick mash control diet or a control diet containing one or more additives.
- the amount of feed consumed by all groups was comparable to the control group.
- the feeding period was 4 weeks.
- the birds were fasted for a period of 14 hours prior to sacrifice (at 0800 hours).
- the chicken mash control diet contained the following ingredients:
- Results are reported as mean ⁇ standard deviation. Percentages of control are reported in parentheses. The following results were obtained:
- tocotrienols in the form of the TRF mixture and individual tocotrienols
- plasma levels of thromboxane B 2 and platelet factor 4 in swine were determined. These levels are known to correlate with the levels of inflammatory cytokines.
- the following feeding conditions were used:
- Each group of three swine (5-month old swine carrying Lpd 5 and Lpu 1 mutant alleles) were administered a control diet or a control diet supplemented with one or more additives. After a 12 hour fast, plasma samples were taken at 42 days from the start of the feeding period.
- the swine control diet contained the following ingredients:
- Neufrophils are an extracellular source of oxygen free radicals and, together with nitric oxide, form peroxynitrite (responsible for endothelial damage).
- Activated monrophils attach to endothelial tissue, where they release the potent toxin, superoxide.
- Superoxide amplifies the inflammatory response and impairs local blood circulation.
- the duties tested were isolated by density centrifugation on Ficoll-Hypaque gradients using conventional methods (see E. Serbinova et al., Free Rad. Bio, and Med.. 10, pp. 263-75 (1991)). The damrophils were then placed in a 96-well plate, ⁇ -tocotrienol and phorbol myrstate acetate were added to the wells at the same time. The secretion of superoxide was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome C. The results of this study are displayed in Figure 1. The amount of released superoxide was reduced from 19.7 nmole (5xl0 5 cells/hour) in the control to 8.0 and 0.0 nmole at ⁇ -tocotrienol concentrations of 10 ' and 10 " , respectively.
- ApoE deficient mice develop atherosclerotic lesions that are similar to those in humans. Using apoE deficient (-/-) C57BL/6 mice, atherosclerotic lesions develop after about 16 weeks when fed a standard low fat mouse diet. ApoE heterozygous (+/-)C57BL/6mice only develop atherosclerotic lesions when fed an atherogenic high fat diet.
- the mice can be subjected to angioplasty and the effects of tocotrienols can then be measured by administering unsupplemented feed or feed supplemented with between about 5 and about 100 ppm of tocotrienols and tocotrienols mixtures (such as P ⁇ 8 , P 25 and TRF 25 ).
- the effect of the tocotrienols on the prevention of restenosis can be measured using a standard low fat mouse feed or a high fat atherogenic diet. Feeding protocols can be carried out for a period of about 4 to about 40 weeks.
- One or more of these models can be used to establish the efficacy of tocotrienol compositions useful in the methods of this invention to prevent restenosis.
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Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15902/99A AU746369B2 (en) | 1997-11-17 | 1998-11-17 | Methods for preventing restenosis using tocotrienols |
JP2000520770A JP2001522880A (ja) | 1997-11-17 | 1998-11-17 | トコトリエノールを用いて再狭窄を予防する方法 |
EP98960259A EP1037628A4 (fr) | 1997-11-17 | 1998-11-17 | Methodes de prevention de la restenose utilisant des tocotrienols |
CA002310232A CA2310232A1 (fr) | 1997-11-17 | 1998-11-17 | Methodes de prevention de la restenose utilisant des tocotrienols |
Applications Claiming Priority (2)
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US97170397A | 1997-11-17 | 1997-11-17 | |
US08/971,703 | 1997-11-17 |
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WO1999025336A1 true WO1999025336A1 (fr) | 1999-05-27 |
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PCT/US1998/024606 WO1999025336A1 (fr) | 1997-11-17 | 1998-11-17 | Methodes de prevention de la restenose utilisant des tocotrienols |
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EP (1) | EP1037628A4 (fr) |
JP (1) | JP2001522880A (fr) |
AU (1) | AU746369B2 (fr) |
CA (1) | CA2310232A1 (fr) |
ID (1) | ID26335A (fr) |
WO (1) | WO1999025336A1 (fr) |
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DE4333794A1 (de) * | 1993-10-04 | 1995-04-06 | Carl Heinrich Dr Weischer | Neue Acetyl-Salicylsäure-Derivate zur Bekämpfung von Entzündungs- und Schmerzzuständen sowie zur Thromboseprophylaxe und -terapie |
EP0669132A1 (fr) * | 1994-02-23 | 1995-08-30 | van der Kraaij, Antonius Marinus Maria | Composition pharmaceutique à la vitamine E et à l'acetylsalicylate pour le traitement et la prévention de l'atherosclerosis |
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1998
- 1998-11-17 JP JP2000520770A patent/JP2001522880A/ja active Pending
- 1998-11-17 AU AU15902/99A patent/AU746369B2/en not_active Ceased
- 1998-11-17 ID IDW20001179A patent/ID26335A/id unknown
- 1998-11-17 EP EP98960259A patent/EP1037628A4/fr not_active Withdrawn
- 1998-11-17 CA CA002310232A patent/CA2310232A1/fr not_active Abandoned
- 1998-11-17 WO PCT/US1998/024606 patent/WO1999025336A1/fr not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
EP1037628A4 (fr) | 2002-08-21 |
CA2310232A1 (fr) | 1999-05-27 |
AU1590299A (en) | 1999-06-07 |
ID26335A (id) | 2000-12-14 |
JP2001522880A (ja) | 2001-11-20 |
AU746369B2 (en) | 2002-04-18 |
EP1037628A1 (fr) | 2000-09-27 |
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