WO1995011033A1 - Polyoxometallates utilises dans le traitement des infections associees au flavivirus - Google Patents
Polyoxometallates utilises dans le traitement des infections associees au flavivirus Download PDFInfo
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- WO1995011033A1 WO1995011033A1 PCT/AU1994/000641 AU9400641W WO9511033A1 WO 1995011033 A1 WO1995011033 A1 WO 1995011033A1 AU 9400641 W AU9400641 W AU 9400641W WO 9511033 A1 WO9511033 A1 WO 9511033A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to pharmaceutical compositions containing polyoxometaUates and pharmaceutically acceptable derivatives thereof, and to the use of these compounds in therapy for the treatment or prophylaxis of infections by viruses which are confirmed or probable members of the family Flaviviridae, for example infections such as yellow fever, dengue fever, Australian encephalitis, Japanese encephalitis and Hepatitis C.
- Flaviviruses are well known to be the causative agents of a number of human diseases including the most important arthropod-borne viral afflictions of civilization - dengue, yellow fever, and Japanese encephalitis. In addition, eight flaviviruses cause disease in domestic or wild animals of economic importance. Yellow fever and dengue fever are widespread and well known as mosquito borne diseases of tropical countries. There are between 30 and 60 million flavivirus infections per year including one million Japanese encephalitis infections. The extent of Hepatitis C is not known with any degree of certainty because an infection can exist for many years without the patient being aware of the symptoms. Hepatitis C produces a much higher rate of chronic liver infection than Hepatitis B which is a recognised hazard in many countries.
- Effective vaccines are available for some viruses only, eg for yellow fever, Japanese encephalitis and tick-borne encephalitis. Treatment of dengue fever and Australian encephalitis relies on the patient's own immune defences; infections can be fatal. An antiviral drug to control infections with flaviviruses is thus highly desirable.
- Flaviviridae is a newly-recognised large group (in excess of 70 species) of small, enveloped viruses that contain a single strand of positive-sense RNA of 10 kilobases.
- Prior Art Heteropolytungstate compounds have been known for over 100 years. Most of their applications stem from their redox chemistry and also their high ionic weights and charges. Their redox chemistry has lead to their use as catalysts for the oxidation of organic substrates such as, for example, propylene to acrylic acid, ethylene to acetaldehyde. In the biological field heteropolytungstates have found use as electron dense stains for electron microscopy, as analytical reagents for proteins and several have also been shown to inhibit viral DNA and RNA polymerases (J. C. Cherman, et al., Biochem. Biophys. Res. Commun., 1975, 65, 1229; M. Herve, et al, ibid, 1983, 116, 222.).
- the heteropolytungstates within the scope of this invention include the Keggin and Dawson (also known as the Wells-Dawson) type structures and compounds based on these structures in which one or more of the tungsten atoms are removed and, in the majority of cases, exchanged by other metal atoms.
- Vacancies in the structures are most often created by the extraction of WO 4+ or W 3 O 6 6+ from the Keggin (XW 12 O 40 n" ) or Dawson (P 2 W 18 O 62 6" ) species. Isomers of these unsaturated (lacunary) polyanions are possible, a consequence of the location of the vacancy. (R. Massart R. Contant, J. M. Fruchart, J. M. Ciabrini, M.
- Unsaturated heteropolyanions can behave as ligands by bonding, at their vacant site, with metal ions. These metal ions, when not sterically crowded, can carry ligands such as water, organic coordinating species or organometallic groups. Organometallic moieties can also react with exposed oxygen atoms on, for example, trisubstituted Keggin or Dawson structures (R. G. Finke and M. W. Droege, J. Am. Chem. Soc, 1984, 106, 121 '4 and R. G. Finke, B. Rapko and P. J. Domaille, Organometallics 1986, 5, 175).
- An oxygen atom on the Keggin structure can also be alkylated with reagents such as trimethyloxonium salts (W. H. Knoth and R. L. Harlow, J. Am. Chem. Soc. 1981, 103, 4265). Some of the oxygen atoms on heteropolytungstates can also be exchanged for fluorine atoms (F. Chauveau, P. Doppelt and J. Lefebvre, Inorg. Chem. 1980, 19, 2803; T. L. Jorris, M. Kozik and L. C. W. Baker, Inorg. Chem. 1990, 29, 4584).
- heteropolyanion species are formed by reaction of two W 5 O 18 H 5" ions with metal ions such as the lanthanoids (R. D. Peacock and T. J. R. Weakley, J. Chem. Soc.
- the central atom in the compounds can vary widely, especially in the case of the simpler Keggin type structures.
- the central atom in the Dawson type structures is most often phosphorus.
- PolyoxometaUates containing metals such as molybdenum, niobium and vanadium have also been made.
- polyoxometallate polyanions are active against viruses belonging to the Flaviviridae family. In particular they inhibit the replication of such viruses stopping the development of an infection.
- compositions for use in the treatment or prophylaxis of a flavivirus associated infection having as active ingredient one or more polyoxometallate compounds selected from formula 1 to 17 below or a pharmaceutically acceptable derivative thereof.
- the compounds of the invention are polyanions with associated cations (A) for electrical neutrality. They crystallize with a variable number of molecules of water of crystallization dependent upon the conditions of product recovery and subsequent treatment; all such hydrates come within the scope of this invention.
- a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
- compositions of the present invention may comprise an effective amount of one or more compounds selected from Formulae 1-17 in association with one or more pharmaceutically acceptable carriers or diluents, and optionally other therapeutic agents.
- Each carrier must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
- the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
- compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
- the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- the present invention also extends to a method for the treatment or prophylaxis of a flavivirus associated infection, which comprises the administration of a composition containing an effective amount of one or more compounds selected from Formulae 1-17.
- the compounds may be prepared by the literature methods or adaptions thereof, varying reactants and conditions as required to obtain the target compound.
- General review articles, describing the preparation, structure and properties of many of the compounds, include P. Souchay, "Ions Min ⁇ raux Condenses", Masson, Paris, 1969; M. T. Pope, “Heteropoly and Isopoly Oxometalates", Springer- Verlag, Berlin, 1983; T. J. R. Weakley, Structure and Bonding, Springer-Verlag, Berlin, 1974, 18, 131; M. T. Pope and A. M ⁇ ller, Angew. Chem. Int. Ed. Engl. 1991, 30, 34.
- R an organic residue or one containing an organometallic, metal carbonyl or metal coordinated with a ligand.
- M Ge IV , Si
- Ln lanthanoid metal ion.
- This compound was prepared by reaction of Na 10 [ ⁇ -SiW 9 O 34 ].aq. 14.2 g (5 mmol) with 4.8 g (15 mmol) ZrOCl 2 .8H 2 O in 100 mL H 2 O at 70°C for 4 h. After filtration through Celite filter aid, 25 g KCl was added to give a white precipitate. The mixture was warmed and the precipitate became a clear dense phase which on cooling to room temp, and scratching with a glass rod gave a white solid (10.2 g). This was redissolved in 50 mL H 2 O at 65°C and reprecipitated on addition of 10 g KCl.
- a possible structure for 16/2 may be one similar to that postulated for 16/1, ie one in which two [Zr 2 W 10 SiO 40 ] 8" units are joined through a Zr 4+ .
- IR spectrum (KBr disc, cm -1 ) 997(w), 934(m), 895(s), 792(sh), 755(s).
- This product was obtained by treatment of 100 mmol Na 2 WO 4 .2H 2 O with 10 mmol Na 2 SiO 3 .5H 2 O and ca. 7 mmol acetic acid in 100 mL H 2 O at room temp followed by addition of 20mmol Cp 2 ZrCl 2 and stirring the solution (yellow) for several days. It did not decolourise on treatment with carbon. Addition of excess KCl gave a white precipitate which was dissolved in H 2 O at 60 - 70°C. The white compound that separated on cooling to room temp, was collected and air dried.
- the ir of the yellow crude material had no NO 3 " peak and only a doublet for the PO 4 3" .
- the ir spectrum (KBr disc, cm “1 ) 1076, 1053, 946, 872, 806, 720.
- the brown compound was collected and recrystallised from 100 mL H 2 O (85°C).
- the grey brown powder (11.1 g) was analysed; %W 48.92, %Co 6.77, %Fe 2.59, %Na 2.48 giving the elemental ratio for compound 17/5 of W 7 Fe j 22 Co 3 02 Na 2 8 .
- the oxygen on the transition metal atom(s) may be either doubly protonated (H 2 O), singly protonated (OH), or completely deprotonated (O).
- H 2 O doubly protonated
- OH singly protonated
- O completely deprotonated
- oxygen atoms are necessarily oxo groups and the charge (and hence the number of counter cations (A)) on the polyanion will depend on the number of protons attached to the oxygen atom(s).
- compounds containing groups such as, for example, MOH, may dimerize by an intermolecular condensation reaction. Dimers, where formed, of the compounds listed, are also included in the invention.
- the reduced compounds are also included in this invention.
- the charge on the polyanions can vary, depending upon the extent of protonation of the polyanions, as noted earlier, and upon the oxidation states of the metal atoms.
- the number of associated counter cations (A) will vary correspondingly.
- A may be a proton, an alkali metal ion, an alkali earth ion, or ammonium or alkyl ammonium ion of type R ⁇ JJ H JJ N "1" , where R is an alkyl chain of from 1 to 6 carbon atoms.
- the required cation is generally introduced into the compound either by use of an ion exchange resin or by precipitation with excess of a salt of that cation.
- compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solutions or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
- a binder e.g inert diluent, preservative disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored amd may be formulated so asS to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
- compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- compositions suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the compositions may be presented in unit- dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage compositions are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
- the compounds according to the invention may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
- veterinary compositions include those adapted for:
- oral administration external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
- drenches e.g. aqueous or non-aqueous solutions or suspensions
- tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
- pastes for application to the tongue for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
- parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat;
- topical application e.g. as a cream, ointment or spray applied to the skin;
- compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
- active ingredient means one or more compounds of selected from Formulae 1-17 or a pharmaceutically acceptable derivative thereof.
- Example active ingredients according to the invention were prepared and analysed by ICP spectroscopy.
- the compound formula and the analytical results compared with the composition expected from the formula are given in Table 1 below. Ir and nmr data are also included.
- Example 1 The compounds listed in Example 1 were tested for their ability to inhibit RNA synthesis in an in vitro polymerase assay (Chu and Westaway, 1985, 1987; Brun and Brinton, 1986).
- flavivirus RNA comprising the genomic 44S RNA, a double-stranded replicative form (RF) and a partially-double-stranded replicative intermediate (RI) are detected by the incorporation of [ ⁇ - 32 P]GTP.
- Vero cells were infected at a multiplicity of infection of 7 for Type 2 dengue (DEN-2) virus (New Guinea C strain; Sabin and Schlesinger, 1945) or Kunjin (KUN) virus (strain MRM 61C; Boulton and Westaway, 1972). Extracts containing RNA- dependent RNA polymerase (RDRP) activity derived from DEN-2 virus-infected cells were prepared at 30 to 36 h p.i., when polymerase activity was at a maximum. Similarly, extracts of KUN virus-infected cells were prepared at the time of maximum polymerase activity at 24 h p.i. (Chu and Westaway, 1985).
- DEN-2 Type 2 dengue
- KUN Kunjin virus
- the cells were pelleted by centrifugation and resuspended in 10 mM sodium acetate at a concentration of 2x10 7 cells/ml. They were then disrupted by passaging 20 times through a 21 gauge needle followed by 20 times through a 26 gauge needle. The disrupted cells were centrifuged at 800 g for 7 min to obtain a supernatant fraction and a pellet of the nuclear-associated material. All RDRP assays were performed using the supernatant fraction, hereafter referred to as the cell extract, which was stored at -70°C and used after only one cycle of freeze/thawing.
- the RDRP activity in the cell extract was assayed as previously described with the following modifications (Chu and Westaway, 1985).
- the virus-infected cell extract contained 4.5-6 mg/ml of protein.
- the compound to be tested dissolved in double distilled water and RNasin (0.5 units/ml, Promaga) were added to the cell extract for 10 min prior to the addition of the other components of the RDRP assay.
- the final reaction mixture (total volume of 50 ⁇ l) contained 50 mM Tris-HCl pH 8.0, 10 mM magnesium acetate, 7.5 mM potassium acetate, 10 mM 2-mercaptoethanol, 6 ⁇ g actinomycin D (AMD), 5 mM phosphoenolpyruvate, 3 units/ ⁇ l pyruvate kinase, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM UTP, 25 ⁇ M GTP, 5 ⁇ Ci [ ⁇ - 32 P] GTP (Amersham, specific activity 410 Ci mmol), 0.5 units/ml RNasin, 30 ⁇ l of infected cell extract and the test compound (from 0.5 to 100 ⁇ M).
- the reaction was stopped after 30 min at 37°C by the addition of EDTA to a final concentration of 10 mM.
- An equal volume of TNE-SDS 50 mM Tris-acetate pH 7.6, 0.1 M sodium acetate, 1 mM EDTA and 2% SDS was added to disrupt membranes.
- the RNA was then extracted with phenol and precipitated by ethanol.
- RNA samples were mixed with an equal volume of sample buffer containing 7 M urea in TBE (89 mM Tris-HCl, 89 mM boric acid, 2.5 mM EDTA) and 0.5% bromophenol blue, and were separated by electrophoresis through 3% polyacrylamide gels containing 7 M urea in TBE. The gels were fixed in 10% acetic acid, dried and radiolabelled bands detected by autoradiography.
- the compounds tested inhibited the synthesis of both DEN-2 and KUN RF RNA. There was also a decrease in the amount of RI detected with increasing concentration of drug. The concentrations which give >75% inhibition of RNA synthesis are given in Table 2.
- the compounds were dissolved in doubly distilled water and tested as described above.
- the compounds tested and their antiflavi-viral activity are given in the Table 2 below.
- formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
- the following formulation B may be prepared by direct compression of the admixed ingredients.
- This formulation may be prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet
- a capsule formulation may be prepared by admixing the ingredients of Formulation B in Example 3 above and filling into a two-part hard gelatin capsule.
- Formulation B (infra) may be prepared in a similar manner.
- the following controlled release capsule formulation may be prepared by extruding ingredients a, b and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets may then be coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule
- the active ingredient may be dissolved in most of the water (35°-1)
- the batch may then be made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
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Abstract
L'invention concerne des compositions pharmaceutiques contenant des polyoxométallates ainsi que des dérivés pharmaceutiquement acceptables de ceux-ci. Elle concerne également l'utilisation de tels composés ou compositions dans le traitement thérapeutique ou prophylactique des infections associées aux virus appartenant ou étant supposés appartenir à la famille des Flaviviridae, et notamment au virus de l'hépatite C.
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AU79853/94A AU7985394A (en) | 1993-10-22 | 1994-10-21 | Polyoxometallates in the treatment of flavivirus infections |
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AUPM195093 | 1993-10-22 | ||
AUPM1950 | 1993-10-22 |
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WO1995011033A1 true WO1995011033A1 (fr) | 1995-04-27 |
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Cited By (18)
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WO1999004803A1 (fr) * | 1997-07-24 | 1999-02-04 | Biomolecular Research Institute Limited | Composes d'heteropolytungstate utilises comme inhibiteurs de l'angiogenese |
WO1999021569A1 (fr) * | 1997-10-24 | 1999-05-06 | Starpharma Limited | Composition antifilovirale a base de polyoxometallates |
US6020369A (en) * | 1994-09-26 | 2000-02-01 | Schinazi; Raymond F. | Method compositions and apparatus for treating and preventing respiratory viral infections |
EP1369120A1 (fr) * | 2002-06-03 | 2003-12-10 | National Health Research Institutes | Traitement de l'infection causé par les flavivirus |
US7799351B2 (en) | 1997-09-19 | 2010-09-21 | Ineos Healthcare Limited | Metal compounds, mixed or sulphated, as phosphate binders |
USRE43372E1 (en) | 1999-03-05 | 2012-05-08 | Duke University | C16 unsaturated FP-selective prostaglandins analogs |
US8906962B2 (en) | 2000-03-31 | 2014-12-09 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US9066917B2 (en) | 2009-08-03 | 2015-06-30 | Cytochroma Development Inc. | Mixed metal compound |
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US9346837B2 (en) | 2000-03-31 | 2016-05-24 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
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Cited By (25)
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US6020369A (en) * | 1994-09-26 | 2000-02-01 | Schinazi; Raymond F. | Method compositions and apparatus for treating and preventing respiratory viral infections |
WO1999004803A1 (fr) * | 1997-07-24 | 1999-02-04 | Biomolecular Research Institute Limited | Composes d'heteropolytungstate utilises comme inhibiteurs de l'angiogenese |
US7799351B2 (en) | 1997-09-19 | 2010-09-21 | Ineos Healthcare Limited | Metal compounds, mixed or sulphated, as phosphate binders |
US9242869B2 (en) | 1997-09-19 | 2016-01-26 | Opko Ireland Global Holdings, Ltd. | Metal compounds mixed or sulphated, as phosphate binders |
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