CA2046037A1 - Long-term prophylaxis against diseases caused by viruses or by unconventional viruses - Google Patents
Long-term prophylaxis against diseases caused by viruses or by unconventional virusesInfo
- Publication number
- CA2046037A1 CA2046037A1 CA002046037A CA2046037A CA2046037A1 CA 2046037 A1 CA2046037 A1 CA 2046037A1 CA 002046037 A CA002046037 A CA 002046037A CA 2046037 A CA2046037 A CA 2046037A CA 2046037 A1 CA2046037 A1 CA 2046037A1
- Authority
- CA
- Canada
- Prior art keywords
- viruses
- unconventional
- long
- diseases caused
- derivatives
- 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.)
- Abandoned
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Abstract
Abstract of the disclosure Long-term prophylaxis against diseases caused by viruses or by unconventional viruses Sulfated polysaccharides and derivatives thereof are suitable for the long-term prophylaxis of diseases caused by viruses or by unconventional viruses.
Description
~ ~à ~
HOECHST AKTIENGESELLSCHAET HO2 90/F 203 Dr. WN/fe De~cription Long-t~rm prophylaxis against disease~ caused by viru~es or by unconventional viru~es S The present invention relates to long-te~m prophyla~is against diseases caused by viruses or by unconv~ntional viruæes. It has already been disclosed that sulfated polysaccharides and derivatives thereof have antiviral activity (DE 3,601,136, EP Or270,317). It has also been disclosed that dextran sulfate and other sulfated poly-saccharides have activity against scrapie (Ehlers, Diringer, J. ~en. Virol. 65/2 (423-428), 1984). There is a report in J. Gen. Virol. 65/8 (1325-1330~, 1984 tha~
there is an increase which, although extremely small, is still significant in the incubation time after scrapie infections when dextran 8ulfate has been administered 10 weeks before the infection.
It has now been found, surprisingly, that administration of sul~ated polysaccharides or derivatives thereof prevents onset of a disease caused by viruses or uncon-ventional viruses when the administration of the agent takes place a long interval of time before the infection.
Administration of said agents protects the animals from onset of the infection for a long time, the result being that prophylactic administration of the agents resembles a vaccination (p~eudovaGcination). Thi~ i~ particularly surprising because no such observation have to date been made either with the chemotherapeutic treatment of viral diseases or with the treatment of unconventional viral diseases.
The method, according to the invention, for controlling viral diseases and unconventional viral diseases has the advantage that the c~mpounds which can be used according to the invention are less toxic than other antiviral ,J ~ ~ ~
HOECHST AKTIENGESELLSCHAET HO2 90/F 203 Dr. WN/fe De~cription Long-t~rm prophylaxis against disease~ caused by viru~es or by unconventional viru~es S The present invention relates to long-te~m prophyla~is against diseases caused by viruses or by unconv~ntional viruæes. It has already been disclosed that sulfated polysaccharides and derivatives thereof have antiviral activity (DE 3,601,136, EP Or270,317). It has also been disclosed that dextran sulfate and other sulfated poly-saccharides have activity against scrapie (Ehlers, Diringer, J. ~en. Virol. 65/2 (423-428), 1984). There is a report in J. Gen. Virol. 65/8 (1325-1330~, 1984 tha~
there is an increase which, although extremely small, is still significant in the incubation time after scrapie infections when dextran 8ulfate has been administered 10 weeks before the infection.
It has now been found, surprisingly, that administration of sul~ated polysaccharides or derivatives thereof prevents onset of a disease caused by viruses or uncon-ventional viruses when the administration of the agent takes place a long interval of time before the infection.
Administration of said agents protects the animals from onset of the infection for a long time, the result being that prophylactic administration of the agents resembles a vaccination (p~eudovaGcination). Thi~ i~ particularly surprising because no such observation have to date been made either with the chemotherapeutic treatment of viral diseases or with the treatment of unconventional viral diseases.
The method, according to the invention, for controlling viral diseases and unconventional viral diseases has the advantage that the c~mpounds which can be used according to the invention are less toxic than other antiviral ,J ~ ~ ~
agents, and some of them are even virtually non-toxic.
Furthermore, it is po~sible, ~or tha long-texm prophyl-axis according to the invention, to divide the administrations of the polysaccharides into relatively small doses ~o be given more or less regularly, which allows unwanted side effects of ~he polysaccharide~ to be substantially or completely suppres6Qd.
Accordingly, the present inven~ion relates to the use of sulfated polysaccharide~ or derivatives thereof for the long-term prophylaxis of diseases caused by viru~es or unconventional viruses.
Preferred for the use according to the invention are polysaccharides which have a polysaccharide framework which is compo~ed of uniform or different monomer units selected from the following group of compounds, or comprises the following compounds: xyloRe~ arabinose, rhamnose, fucose, gluco~e, mannose, galactos~, fructose, glucosamine, galactosamine, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid, carrageenans, fucoids, laminaran, alginate, lentinan, pluran, xylan, dextran, heparin, keratan sulfate, chondroitin 4- and 6-sulfate, dermatan sulfate, heparin ~ulfatet hyaluronic acid, teichuronic acid and partial hydrolyzates of starch, cellulose, glycogen, chitin or pectin. Said compounds can be both of synthetic and of natural, i.e.
in particular vegetable or microbial, origin.
Furthermore preferred for the use according to the invention are sulfated polysaccharide~ with lipophilic substituents. By sulfated polysaccharides with lipophilic substituents are meant in this connection particularly sulfated polysaccharides which can be linear or branched, are composed of uniform of different natural or ~nthetic monomers, which can al80 contain a replaced or unsub-stituted amino group per monomer unit, and whose OH
groups are on average between 5 and 80 % replaced by a group of the formula -X-B-Y where ~ J/~ Ji x is an oxy group o~ a group of the formula I
-C (I) o-whose carbon atom is bonded ~o B, B is a non-aromatic hydrocarbon radical which has 2 ~o 30 carbon atoms and in whose alkyl chain up to 3 methylene units can be replaced by oxy groups, in which up to three C-C double bonds can be present and which can be substituted by up to three Cl-C4-alkyl radicals and 10 Y can - if x is an oxy group - be hydrogen, CQOR or OSO3Rl, in which R is a physiologically tolerated singly or doubly charged cation, or a hydrocarbon radical with up to 20 carbon atoms or a mono- or ~isether residue with 3 to 10 caxbon atoms, R1 is a physiologically tolerated cation, or Y is - if X is a radical of the formula I - hydrogen or COOR in which R has the abovementioned m~anings, and where the OH groups of the abovementioned polysac-charides are between 10 and 95 % replaced by a group of the formula OS03M where M i8 a physiologically tolerated cation and between O and 40 ~ of the OH groups are not replaced.
In the case of lipophilic polysaccharides whose polysac-charide framework already occurs in nature in ~ulfated ~5 form, it is possible for the sulfated polysaccharides to be used both with their natural sulfate content and after additional sulfation. The polysaccharide frameworks pre~
ferred for the lipophilic sulfated polysaccharides are the sulfated polysaccharides alread~ mentioned above.
The OH groups of the lipophilic polysaccharide~ according to the invention are preferably 5 to 80 ~, particularly preferably S to 50 ~ and especially 10 to 40 ~ replaced 'J ~) ~J
by a group of the formula -X-B-Y and, furthermore, preferably 10 to 95 %, particularly preferably 45 to 95 %
and especially 50 to 90 ~ replaced by a group of the formula OS03M, where preferably between O and 40 ~, particularly preferably between O and 20 % and especially between O and 10 ~ of the OH groups are not replaced.
Preferred radicals B have 2 to 20 carbon atoms, have one or no double bond and are unsubstituted or monosubsti-tuted by a Cl-C4-alkyl group.
Where X is an oxy group, Y is preferably H, COOR, OSO3Rl, where R is an alkali metal cation, especially potassium or sodium or a branched or unbranched Cl-C8-alkyl group, Rl is preferably an alkali metal cation, especially sodium.
If X is a radical of ~he formula I, Y is preferably H or a radical of the formula COOR, where R is an alkali metal cation, preferably sodium or potassium, a branched or unbranched Cl-C8-alkyl group or a mono- or bisether residue with 6 to 9 carbon atoms.
Examples of radicals of the formula -X-B-Y are ethyloxy, propyloxy, isopropyloxy, butyloxy, hexylo~y, octylo~yI
decyloxy, dodecyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, octanoyloxy, decanoyloxy, dodecanoyloxy, palmitoyloxy, st~aroyloxy, 2-methylbutyryloxy, 9-octadecenoyloxy, linoleyloxy, linolenoyloxy, cholesteryloxy, hydroxyoxalyloxy, hydroxymalonyloxy, hydroxysuccinyloxy, hydroxyglutaryloxy, hydroxyadipoyloxy, crotonoyloxy, mesaconoyloxy or the esters of said dlcarbo~ylic acid derivatives with unbranched Cl-C~alcohol~ or (1,3-diisopropoxy-2-propyloxycarbonyl)propanoyloxy.
The dodecanoyloxy and the stearoyloxy radicals have particular importance, especially on a xylan polysac-charide framework.
- 5 - ~p,~
The polysaccharides according to th2 invention in a form which is unsubstituted or has lipophilic substituents may have an average molecular weight which covers a wide range. The substituted polysaccharides preferably have an average molecular weight of up to 100 kD, particularly preferably of up to 40 kD, e~pecially between 1 and 22 kD. Particularly important are ~ubsti~uted polysac-charides according to the invention who~ polysaccharide framework is composed of xylan ox dextran and which have an average molecular weig~t of 1 to 22 kD.
Pentosan polysulfate is very particularly preferxed (polysulfated ~ 4~-D-xylopyranoside with an avexage molecular weight of 3,500-5,000 D) .
The preparation of the sulfated polysaccharides is state of the art and is described, for example in EP 0,240,098, US 2,715,091, CH 293,566 or Carbohydr. Chem. 2, 298 (1963). The abovementioned sulfated polysaccharides with lipophilic substituents are prepared, for example, in ~he case of polysaccharides which are substituted by a group XBY where X is an oxy ~roup, by partially etherifying the polysaccharides with an alkyl halide or an ~-halogeno carboxylic acid salt, with basic catalysis, followed, immediately or after alkoxylation, by total or partial sulfation.
If x is a group of the formula I, the polysaccharides are, for example, partially acylated with carboxylic acids or carboxylic acid derivatives, and the remaining OH groups of the polysaccharides are totally or partially sulfated.
3Q Further details of the preparation of lipophilic sulfated polysaccharides are disclosed in ~erman Patent Appli-cation P 3,921,761.2, to which express reference is made at this point. The compound~ described as preferred in said patent application are also preferred for the present use according to the invention.
Also suitable for the use according to the invention are polyelectrolyte complexes of a polyacid and a polyba~e.
Preferred polyacids are the ~ulfated poly~accharides already described above, in substitu~ed or un~ubstituted form. Particularly preferred sulfated polysaccharides have a degree of sulfation of more ~han 10 %, particular-ly preferably 90 to 100 %~
The average molecular weight of the unsubstituted and substituted polysaccharides for the polyelectrolyte complexes should be between 500 and 80,000 D, preferably between l,00D and 40,000 D, especially between 4,000 and 15,000 D.
The polyelectrolyte complexes according to the invention can be formed with the aid of different polybases. It is possible to employ, inter alia, proteins as polybases, such as, for example, hemoglobin. Further suitable examples are polylysine, lysine alkyl esters, chitosan, poly-(2-N,N-dimethylaminoethyl)-D,L-aspartamidel amino acids, poly(amino acids), aminated oligo- and polysac-charides (for example aminated dextrans), poly-C~
(spermidinyl) D,L-a~partamide], gelatin and derivative (for example Polygeline~, Behringwerke AG, Marburg), quaternary ammonium compounds (for example Lu~iquat~, BASF AG, Ludwigshafen or Micrapol ~15~, Miranal Chem. Co., Inc. South Brunswick, New Jersey), C1z-alkyls~ernamine, ~ bis-(N-propylamino)polyethylene glycol and aminated polyethylene glycol derivatives. It is also po~sible to use as pol~bases covalent compounds of pol~mers containing OH groups (for example dextran~ and nitrogen crGwn ethers, and the metal complexes thereof.
It is additionally pos~ible to optimize the absorbability of the polyelectrolyte complexes according to the inven-tion by varying the substituen~ on the polyacids and polybases. Thus, for example, it i5 possible to provide the polyacids with different substituents as already explained above. The polybases can likewise be modified by substitution reactions. Particularly suitable sub-stituents for the polybases are hydrophobizing in naturP, such as, for example, alkyl chains, especially branched or unbranched alkyl chains with 10-20 carbon atoms, such as, for example, lysine octadecyl ester or cetyltri-methylammonium bromide. Other suitable substituent~ are, for example, steroid residues, especially cholesterol bonded via the alcohol group, or the cholesteryl ester of succinic acid or analogous steroids.
It is furthermore possible to employ tailored polyelec-trolyte complexes prepared by reaction of a polyacid or a mixture of polyacids with a polybase or a mixture o~
polybases.
The polyelectrolyte complexes are prepared, for example, by adding either a) the polybase or b) the polyacid dropwise, preferably in aqueous solution at a ~uitable temperature and at a suitable pH to a) the polyacid or b) the polybase, preferably in aqueous solution.
Further details of the polyelectrolyte comple~es are described in German Pat~nt Application P 3,937,283.9, to which express reference is made a~ this point. The polyelectrolyte complexes which emerged as preferred in said patent application are also preferred for the present use according to the invention.
~5 The compounds which can be used according to the inven-tion are employed for tha prophylaxis of disea~es caused by viruses or unconventional viruses. They are particu-larly important for the long~term prophylaxis of diseases caused by herpesviruses or by retroviruses such as, fox example, HTLV I and II, HIV, BLV, FLV, Fe~V, FIV, Visna-Maedi viruses, goat arthritis viruses, human spumaviruses or by unconventional viruses.
They are very particularly important for the control of retroviral diseases and diseases connected with y ~ ~
unconventional viruses, especially scrapie, bovine spongiform encephalopathy (BSE virus) and Creu~zfeldt-Jakob syndrome.
Long-term prophylaxis means in the present connection that the relevant compounds are given at least one, preferably three, especially five days before a potential infection.
However, it is preferable to administer the relevant agents long before a potential infection after admini-stxation of one or more initial doses at regular inter-vals in a relatively low dose which has few side effects to the organisms a~ risk of infection. In this way the relevant organisms are optLmally protected against the onset of an infection without unwanted side effects occurring. The compounds can be administered preferably at an interval of 90 days, particularly preferably of 80 days, especially of 60 days. The dosage of the indivi-dual administrations is, in terms of amount, below the dose which would be required to control an infection after onset. The preferred initial dose is 0.1-10, particularly preferably 3-9, especially about 4 mg/kg body weight of a mammalian organism. The preferred maintenance dose, which should be administered after a time interval as explained above, is 0.1-5, particularly preferably 0.5-2, especially about 1.5 mg/kg body weigh~.
The described dosages apply to administration ~y injection; it may be necessary to increase the doses, for example by 5-10 times, for a different mode of administration.
The compounds which can be used according to th2 inven-tion can be administered, for example, orally, intraven-ously, intramuscularly, intraperitoneally, subcutaneously or rectally.
The present invention also relates to pharmaceuticals for the long-term prophylaxis of disea~es caused by viruses _ 9 _ 2 or unconventional viruses, which contain compounds which can be used according to ~he invention. The pharmaceuti-cals according to the învention are prepared by convert-ing at least on2 substituted polysaccharide or one of its derivatives, where appropriate with other auxiliaries and/or excipients, into a ~uitable dosage fo~m. The auxiliaries and excipien~s are derived from the group comprising vehicles, preservatives and other customary auxiliaries.
For example, it is possi~le to use for ora~ dosage forms auxiliaries such as starches, for example potato, corn or wheat starch, cellulose or derivatives thereof, e~pecial-ly microcrystalline cellulose, silica, various sugars such as lactose, magnesium carbonate and/or calcium phosphates. It is furthermore advantageous to add to the oral dosage forms auxiliaries which improve the toler-ability of the medicamen~s, such as, for example, &well-ing agents and resins. It is al~o possible for the purpose of improving tolerability to administer the medicaments in the form of enteric capsules. It may furthermore be advantageou~ to add a retarding agent to the dosage form, where appropriate in the form of perme-able membranes, for example those based on cellulo~e or polystyrene resin, or ion exchangers. It may furthermore be worthwhile to administer the compounds which can be used according to the invention in the form of an implant.
The intention of the exemplary embodLments which follow is to explain the present invention in more detail.
The present invention i6 explained by the following exemplary embodiments and by the patent claims.
~ample 1:
Effect of prophylactic administration of pentosan poly-sulfate (MW about 5,000 dalton) on splenomegaly after ~/3 ,l~ J ~, infection with Friend leukemia virus (FLV).
3 groups each of 10 female NMRI mice, body weight 18-20 g, were treated in each case 50, ~0 and 30 days before infection by intraperitoneal in~ection of pentosan polysulfate in physiological saline as follows:
Group 1: 0 mg/kg (control) Group 2: 50 mg/kg Group 3: 250 mg/kg Group 4: 500 mg/kg The infection was brought about by intravenous in~ection of 0.2 ml of a 1:10,000 dilution of serum from ~LV-infected NMRI mice. 14 Days after infection~ the spleens of the experimental animals were weighed. The ~pleen weight served as a measurement unit for the replication of FLV in the experimental animals (Chirgos M.A., Luber, E., March, ~., Pettigrew, H. (1965) Antiviral chemotherapeutic assay with Friend leukemia virus in mice. Cancer Chemother. Rep. 45, 29-33). The result i8 summarized in the following table (1):
Group DosageSpleen weight Survivor mg/kg ~ S.D.
1 0 2.54 i 0.37 10 2 50 1.77 ~ 0.61 3 250 1.67 + 0.89 4 4 5~0 1.56 ~ 0.53 Whereas the spleen weight of uninfected mice i8 about 0.1 g, FLV-infected mice develop splenomegaly with spleen weights above 2 g (Group 1) within 2 weeks.
Pretreatment with pentosan polysulfate resulted in a dose-dependent and statistically significant (p s 0.05~
reduction in the spleen weight compared with the un-treated control (Group 1). It can be concluded from thi~
that pretreatment of the mice with pentosan polysulfate has influenced subsequent infection with FLV. The deaths fl~ Y,, 3 .
observed among the experimental animals during the experiment occurred as a consequence of ~he an~icoagulant effect of pentosan polysulfate at high dosage even before the infection.
Example 2 Prophylactic effect of pentosan polysulfate (MW:
Furthermore, it is po~sible, ~or tha long-texm prophyl-axis according to the invention, to divide the administrations of the polysaccharides into relatively small doses ~o be given more or less regularly, which allows unwanted side effects of ~he polysaccharide~ to be substantially or completely suppres6Qd.
Accordingly, the present inven~ion relates to the use of sulfated polysaccharide~ or derivatives thereof for the long-term prophylaxis of diseases caused by viru~es or unconventional viruses.
Preferred for the use according to the invention are polysaccharides which have a polysaccharide framework which is compo~ed of uniform or different monomer units selected from the following group of compounds, or comprises the following compounds: xyloRe~ arabinose, rhamnose, fucose, gluco~e, mannose, galactos~, fructose, glucosamine, galactosamine, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid, carrageenans, fucoids, laminaran, alginate, lentinan, pluran, xylan, dextran, heparin, keratan sulfate, chondroitin 4- and 6-sulfate, dermatan sulfate, heparin ~ulfatet hyaluronic acid, teichuronic acid and partial hydrolyzates of starch, cellulose, glycogen, chitin or pectin. Said compounds can be both of synthetic and of natural, i.e.
in particular vegetable or microbial, origin.
Furthermore preferred for the use according to the invention are sulfated polysaccharide~ with lipophilic substituents. By sulfated polysaccharides with lipophilic substituents are meant in this connection particularly sulfated polysaccharides which can be linear or branched, are composed of uniform of different natural or ~nthetic monomers, which can al80 contain a replaced or unsub-stituted amino group per monomer unit, and whose OH
groups are on average between 5 and 80 % replaced by a group of the formula -X-B-Y where ~ J/~ Ji x is an oxy group o~ a group of the formula I
-C (I) o-whose carbon atom is bonded ~o B, B is a non-aromatic hydrocarbon radical which has 2 ~o 30 carbon atoms and in whose alkyl chain up to 3 methylene units can be replaced by oxy groups, in which up to three C-C double bonds can be present and which can be substituted by up to three Cl-C4-alkyl radicals and 10 Y can - if x is an oxy group - be hydrogen, CQOR or OSO3Rl, in which R is a physiologically tolerated singly or doubly charged cation, or a hydrocarbon radical with up to 20 carbon atoms or a mono- or ~isether residue with 3 to 10 caxbon atoms, R1 is a physiologically tolerated cation, or Y is - if X is a radical of the formula I - hydrogen or COOR in which R has the abovementioned m~anings, and where the OH groups of the abovementioned polysac-charides are between 10 and 95 % replaced by a group of the formula OS03M where M i8 a physiologically tolerated cation and between O and 40 ~ of the OH groups are not replaced.
In the case of lipophilic polysaccharides whose polysac-charide framework already occurs in nature in ~ulfated ~5 form, it is possible for the sulfated polysaccharides to be used both with their natural sulfate content and after additional sulfation. The polysaccharide frameworks pre~
ferred for the lipophilic sulfated polysaccharides are the sulfated polysaccharides alread~ mentioned above.
The OH groups of the lipophilic polysaccharide~ according to the invention are preferably 5 to 80 ~, particularly preferably S to 50 ~ and especially 10 to 40 ~ replaced 'J ~) ~J
by a group of the formula -X-B-Y and, furthermore, preferably 10 to 95 %, particularly preferably 45 to 95 %
and especially 50 to 90 ~ replaced by a group of the formula OS03M, where preferably between O and 40 ~, particularly preferably between O and 20 % and especially between O and 10 ~ of the OH groups are not replaced.
Preferred radicals B have 2 to 20 carbon atoms, have one or no double bond and are unsubstituted or monosubsti-tuted by a Cl-C4-alkyl group.
Where X is an oxy group, Y is preferably H, COOR, OSO3Rl, where R is an alkali metal cation, especially potassium or sodium or a branched or unbranched Cl-C8-alkyl group, Rl is preferably an alkali metal cation, especially sodium.
If X is a radical of ~he formula I, Y is preferably H or a radical of the formula COOR, where R is an alkali metal cation, preferably sodium or potassium, a branched or unbranched Cl-C8-alkyl group or a mono- or bisether residue with 6 to 9 carbon atoms.
Examples of radicals of the formula -X-B-Y are ethyloxy, propyloxy, isopropyloxy, butyloxy, hexylo~y, octylo~yI
decyloxy, dodecyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, octanoyloxy, decanoyloxy, dodecanoyloxy, palmitoyloxy, st~aroyloxy, 2-methylbutyryloxy, 9-octadecenoyloxy, linoleyloxy, linolenoyloxy, cholesteryloxy, hydroxyoxalyloxy, hydroxymalonyloxy, hydroxysuccinyloxy, hydroxyglutaryloxy, hydroxyadipoyloxy, crotonoyloxy, mesaconoyloxy or the esters of said dlcarbo~ylic acid derivatives with unbranched Cl-C~alcohol~ or (1,3-diisopropoxy-2-propyloxycarbonyl)propanoyloxy.
The dodecanoyloxy and the stearoyloxy radicals have particular importance, especially on a xylan polysac-charide framework.
- 5 - ~p,~
The polysaccharides according to th2 invention in a form which is unsubstituted or has lipophilic substituents may have an average molecular weight which covers a wide range. The substituted polysaccharides preferably have an average molecular weight of up to 100 kD, particularly preferably of up to 40 kD, e~pecially between 1 and 22 kD. Particularly important are ~ubsti~uted polysac-charides according to the invention who~ polysaccharide framework is composed of xylan ox dextran and which have an average molecular weig~t of 1 to 22 kD.
Pentosan polysulfate is very particularly preferxed (polysulfated ~ 4~-D-xylopyranoside with an avexage molecular weight of 3,500-5,000 D) .
The preparation of the sulfated polysaccharides is state of the art and is described, for example in EP 0,240,098, US 2,715,091, CH 293,566 or Carbohydr. Chem. 2, 298 (1963). The abovementioned sulfated polysaccharides with lipophilic substituents are prepared, for example, in ~he case of polysaccharides which are substituted by a group XBY where X is an oxy ~roup, by partially etherifying the polysaccharides with an alkyl halide or an ~-halogeno carboxylic acid salt, with basic catalysis, followed, immediately or after alkoxylation, by total or partial sulfation.
If x is a group of the formula I, the polysaccharides are, for example, partially acylated with carboxylic acids or carboxylic acid derivatives, and the remaining OH groups of the polysaccharides are totally or partially sulfated.
3Q Further details of the preparation of lipophilic sulfated polysaccharides are disclosed in ~erman Patent Appli-cation P 3,921,761.2, to which express reference is made at this point. The compound~ described as preferred in said patent application are also preferred for the present use according to the invention.
Also suitable for the use according to the invention are polyelectrolyte complexes of a polyacid and a polyba~e.
Preferred polyacids are the ~ulfated poly~accharides already described above, in substitu~ed or un~ubstituted form. Particularly preferred sulfated polysaccharides have a degree of sulfation of more ~han 10 %, particular-ly preferably 90 to 100 %~
The average molecular weight of the unsubstituted and substituted polysaccharides for the polyelectrolyte complexes should be between 500 and 80,000 D, preferably between l,00D and 40,000 D, especially between 4,000 and 15,000 D.
The polyelectrolyte complexes according to the invention can be formed with the aid of different polybases. It is possible to employ, inter alia, proteins as polybases, such as, for example, hemoglobin. Further suitable examples are polylysine, lysine alkyl esters, chitosan, poly-(2-N,N-dimethylaminoethyl)-D,L-aspartamidel amino acids, poly(amino acids), aminated oligo- and polysac-charides (for example aminated dextrans), poly-C~
(spermidinyl) D,L-a~partamide], gelatin and derivative (for example Polygeline~, Behringwerke AG, Marburg), quaternary ammonium compounds (for example Lu~iquat~, BASF AG, Ludwigshafen or Micrapol ~15~, Miranal Chem. Co., Inc. South Brunswick, New Jersey), C1z-alkyls~ernamine, ~ bis-(N-propylamino)polyethylene glycol and aminated polyethylene glycol derivatives. It is also po~sible to use as pol~bases covalent compounds of pol~mers containing OH groups (for example dextran~ and nitrogen crGwn ethers, and the metal complexes thereof.
It is additionally pos~ible to optimize the absorbability of the polyelectrolyte complexes according to the inven-tion by varying the substituen~ on the polyacids and polybases. Thus, for example, it i5 possible to provide the polyacids with different substituents as already explained above. The polybases can likewise be modified by substitution reactions. Particularly suitable sub-stituents for the polybases are hydrophobizing in naturP, such as, for example, alkyl chains, especially branched or unbranched alkyl chains with 10-20 carbon atoms, such as, for example, lysine octadecyl ester or cetyltri-methylammonium bromide. Other suitable substituent~ are, for example, steroid residues, especially cholesterol bonded via the alcohol group, or the cholesteryl ester of succinic acid or analogous steroids.
It is furthermore possible to employ tailored polyelec-trolyte complexes prepared by reaction of a polyacid or a mixture of polyacids with a polybase or a mixture o~
polybases.
The polyelectrolyte complexes are prepared, for example, by adding either a) the polybase or b) the polyacid dropwise, preferably in aqueous solution at a ~uitable temperature and at a suitable pH to a) the polyacid or b) the polybase, preferably in aqueous solution.
Further details of the polyelectrolyte comple~es are described in German Pat~nt Application P 3,937,283.9, to which express reference is made a~ this point. The polyelectrolyte complexes which emerged as preferred in said patent application are also preferred for the present use according to the invention.
~5 The compounds which can be used according to the inven-tion are employed for tha prophylaxis of disea~es caused by viruses or unconventional viruses. They are particu-larly important for the long~term prophylaxis of diseases caused by herpesviruses or by retroviruses such as, fox example, HTLV I and II, HIV, BLV, FLV, Fe~V, FIV, Visna-Maedi viruses, goat arthritis viruses, human spumaviruses or by unconventional viruses.
They are very particularly important for the control of retroviral diseases and diseases connected with y ~ ~
unconventional viruses, especially scrapie, bovine spongiform encephalopathy (BSE virus) and Creu~zfeldt-Jakob syndrome.
Long-term prophylaxis means in the present connection that the relevant compounds are given at least one, preferably three, especially five days before a potential infection.
However, it is preferable to administer the relevant agents long before a potential infection after admini-stxation of one or more initial doses at regular inter-vals in a relatively low dose which has few side effects to the organisms a~ risk of infection. In this way the relevant organisms are optLmally protected against the onset of an infection without unwanted side effects occurring. The compounds can be administered preferably at an interval of 90 days, particularly preferably of 80 days, especially of 60 days. The dosage of the indivi-dual administrations is, in terms of amount, below the dose which would be required to control an infection after onset. The preferred initial dose is 0.1-10, particularly preferably 3-9, especially about 4 mg/kg body weight of a mammalian organism. The preferred maintenance dose, which should be administered after a time interval as explained above, is 0.1-5, particularly preferably 0.5-2, especially about 1.5 mg/kg body weigh~.
The described dosages apply to administration ~y injection; it may be necessary to increase the doses, for example by 5-10 times, for a different mode of administration.
The compounds which can be used according to th2 inven-tion can be administered, for example, orally, intraven-ously, intramuscularly, intraperitoneally, subcutaneously or rectally.
The present invention also relates to pharmaceuticals for the long-term prophylaxis of disea~es caused by viruses _ 9 _ 2 or unconventional viruses, which contain compounds which can be used according to ~he invention. The pharmaceuti-cals according to the învention are prepared by convert-ing at least on2 substituted polysaccharide or one of its derivatives, where appropriate with other auxiliaries and/or excipients, into a ~uitable dosage fo~m. The auxiliaries and excipien~s are derived from the group comprising vehicles, preservatives and other customary auxiliaries.
For example, it is possi~le to use for ora~ dosage forms auxiliaries such as starches, for example potato, corn or wheat starch, cellulose or derivatives thereof, e~pecial-ly microcrystalline cellulose, silica, various sugars such as lactose, magnesium carbonate and/or calcium phosphates. It is furthermore advantageous to add to the oral dosage forms auxiliaries which improve the toler-ability of the medicamen~s, such as, for example, &well-ing agents and resins. It is al~o possible for the purpose of improving tolerability to administer the medicaments in the form of enteric capsules. It may furthermore be advantageou~ to add a retarding agent to the dosage form, where appropriate in the form of perme-able membranes, for example those based on cellulo~e or polystyrene resin, or ion exchangers. It may furthermore be worthwhile to administer the compounds which can be used according to the invention in the form of an implant.
The intention of the exemplary embodLments which follow is to explain the present invention in more detail.
The present invention i6 explained by the following exemplary embodiments and by the patent claims.
~ample 1:
Effect of prophylactic administration of pentosan poly-sulfate (MW about 5,000 dalton) on splenomegaly after ~/3 ,l~ J ~, infection with Friend leukemia virus (FLV).
3 groups each of 10 female NMRI mice, body weight 18-20 g, were treated in each case 50, ~0 and 30 days before infection by intraperitoneal in~ection of pentosan polysulfate in physiological saline as follows:
Group 1: 0 mg/kg (control) Group 2: 50 mg/kg Group 3: 250 mg/kg Group 4: 500 mg/kg The infection was brought about by intravenous in~ection of 0.2 ml of a 1:10,000 dilution of serum from ~LV-infected NMRI mice. 14 Days after infection~ the spleens of the experimental animals were weighed. The ~pleen weight served as a measurement unit for the replication of FLV in the experimental animals (Chirgos M.A., Luber, E., March, ~., Pettigrew, H. (1965) Antiviral chemotherapeutic assay with Friend leukemia virus in mice. Cancer Chemother. Rep. 45, 29-33). The result i8 summarized in the following table (1):
Group DosageSpleen weight Survivor mg/kg ~ S.D.
1 0 2.54 i 0.37 10 2 50 1.77 ~ 0.61 3 250 1.67 + 0.89 4 4 5~0 1.56 ~ 0.53 Whereas the spleen weight of uninfected mice i8 about 0.1 g, FLV-infected mice develop splenomegaly with spleen weights above 2 g (Group 1) within 2 weeks.
Pretreatment with pentosan polysulfate resulted in a dose-dependent and statistically significant (p s 0.05~
reduction in the spleen weight compared with the un-treated control (Group 1). It can be concluded from thi~
that pretreatment of the mice with pentosan polysulfate has influenced subsequent infection with FLV. The deaths fl~ Y,, 3 .
observed among the experimental animals during the experiment occurred as a consequence of ~he an~icoagulant effect of pentosan polysulfate at high dosage even before the infection.
Example 2 Prophylactic effect of pentosan polysulfate (MW:
5,000 dalton) on scrapie infections in mice.
In 2 independent experiments, groups each of 6-8 mice were pretreated by intraperitoneal administration of, in each case, 10 mg/mouse of pen~osan polysulfate on the following days before the infection with the ~crapie agent:
Experiment 1 Experiment 2 - 77 - 6~
Corresponding control groups were treated at the ~tated times with phosphate-buffered saline.
The infection was brought about by intraperitoneal injection of 0.1 ml of homogenate from scrapie-infected mice in a dilution of 1:100 to 1:1 million. The observa-tion period lasted 384 (Experiment 1) or 307 days (Experiment 2)~ during which the experimental animals were examined twice a week, each day on onset of the symptoms, for their state of health and possible signs of scrapie infection. The survival time and the number of surviving anLmals served as a measure of the effect of the prophylaxis with pentosan polysulfate.
The result of the experiment is summarized in the follow-ing Table ~2):
J ,;J
Incubation ~ime (days) and survival rate InfectiveExperiment 1 Experiment 2 dose Control Treated Control Treated 10-2 155+1239+~ 167~2 220i6 10-3 160+2248+9 174~32~8~15 0 / ~1 t 6 0 / 7 5 / 8 10-4 184+5 ~ 187+3 267t 10-5 187+4 - 18~2 ~) n = 3, one animal died prematurely with other symptoms It was possible to show that in both experiments the pretreatment with pentosan polysulfate extended the incubation time compared with the relevant control or, with a lower infective dose, prevented the on~et of scrapie.
Further analyses of the animals from Experiment 2 showed that the animals which did not become di eased during the experimental period had no amyloid protein ~hereas amyloid was detectable~ in all the controls and the treated diseased mice. Accumulation of amyloid protein in the brain is regarded as an Lmportant criterion for the presence of scrapie.
In 2 independent experiments, groups each of 6-8 mice were pretreated by intraperitoneal administration of, in each case, 10 mg/mouse of pen~osan polysulfate on the following days before the infection with the ~crapie agent:
Experiment 1 Experiment 2 - 77 - 6~
Corresponding control groups were treated at the ~tated times with phosphate-buffered saline.
The infection was brought about by intraperitoneal injection of 0.1 ml of homogenate from scrapie-infected mice in a dilution of 1:100 to 1:1 million. The observa-tion period lasted 384 (Experiment 1) or 307 days (Experiment 2)~ during which the experimental animals were examined twice a week, each day on onset of the symptoms, for their state of health and possible signs of scrapie infection. The survival time and the number of surviving anLmals served as a measure of the effect of the prophylaxis with pentosan polysulfate.
The result of the experiment is summarized in the follow-ing Table ~2):
J ,;J
Incubation ~ime (days) and survival rate InfectiveExperiment 1 Experiment 2 dose Control Treated Control Treated 10-2 155+1239+~ 167~2 220i6 10-3 160+2248+9 174~32~8~15 0 / ~1 t 6 0 / 7 5 / 8 10-4 184+5 ~ 187+3 267t 10-5 187+4 - 18~2 ~) n = 3, one animal died prematurely with other symptoms It was possible to show that in both experiments the pretreatment with pentosan polysulfate extended the incubation time compared with the relevant control or, with a lower infective dose, prevented the on~et of scrapie.
Further analyses of the animals from Experiment 2 showed that the animals which did not become di eased during the experimental period had no amyloid protein ~hereas amyloid was detectable~ in all the controls and the treated diseased mice. Accumulation of amyloid protein in the brain is regarded as an Lmportant criterion for the presence of scrapie.
Claims (10)
1. The use of sulfated polysaccharides or derivatives thereof for the long-term prophylaxis of diseases caused by viruses or unconventional viruses.
2. The use as claimed in claim 1, wherein the sulfated polysaccharide is composed of or comprises uniform or different monomer units selected from the following group of compounds: xylose, arabinose, rhamnose, fucose, glucose, mannose, galactose, fructose, glucosamine, galactosamine, mannosamine, glucoronic acid, galacturonic acid, mannuronic acid, carrageenans, fucoids, laminaran, alginate, lentinan, pluran, xylan, dextran, heparin, keratan sulfate, chondroitin 4- and 6-sulfate, dermatan sulfate, heparin sulfate, hyaluronic acid, teichuronic acid and partial hydrolyzates of starch, cellulose, glycogen, chitin or pectin.
3. The use as claimed in claim 1, wherein the derivative of the sulfated polysaccharide is a lipophilic sulfated polysaccharide.
4. The use as claimed in claim 1, wherein the derivative of the sulfated polysaccharide is a polyelectrolyte complex.
5. The use as claimed in one or more of claims 1-4, wherein the virus is a retrovirus, especially HIV.
6. The use as claimed in one or more of claims 1-5, wherein the unconventional virus is the causative agent of scrapie, of Creutzfeldt-Jakob syndrome or of spongi-form encephalopathy.
7. The use of sulfated polysaccharides or derivatives thereof for preparing a long-term prophylactic against diseases caused by viruses or by unconventional viruses.
8. A pharmaceutical containing a sulfated polysaccharide or one of its derivatives for the long-term prophylaxis of diseases caused by viruses or by unconventional viruses.
9. A method for the long-term prophylaxis of diseases caused by viruses or unconventional viruses, which comprises administering a sulfated polysaccharide or one of its derivatives.
10. The use as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4021066A DE4021066A1 (en) | 1990-07-03 | 1990-07-03 | LONG-TERM PROPHYLAXIS AGAINST DISEASES CAUSED BY VIRUSES OR BY UNCONVENTIONAL VIRUSES |
| DEP4021066.9 | 1990-07-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2046037A1 true CA2046037A1 (en) | 1992-01-04 |
Family
ID=6409520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002046037A Abandoned CA2046037A1 (en) | 1990-07-03 | 1991-07-02 | Long-term prophylaxis against diseases caused by viruses or by unconventional viruses |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0464759A3 (en) |
| JP (1) | JPH04230325A (en) |
| KR (1) | KR920002153A (en) |
| AU (1) | AU7947091A (en) |
| CA (1) | CA2046037A1 (en) |
| DE (1) | DE4021066A1 (en) |
| IE (1) | IE912320A1 (en) |
| PT (1) | PT98185A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083933A (en) * | 1999-04-19 | 2000-07-04 | Stellar International Inc. | Treatment of cystitis-like symptoms with chondroitin sulfate following administration of a challenge solution |
| US6562836B1 (en) | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
| WO2006114019A1 (en) * | 2005-04-26 | 2006-11-02 | Versitech Limited | Polysaccharide extract from lycium barbarum as neuroprotective agent against beta-amyloid peptide neurotoxicity |
| US7244764B2 (en) | 2003-06-23 | 2007-07-17 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7414076B2 (en) | 2003-06-23 | 2008-08-19 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7772210B2 (en) | 2003-02-19 | 2010-08-10 | Stellar Pharmaceuticals Inc. | Cystitis treatment with high dose chondroitin sulfate |
| US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
| US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
| US9499480B2 (en) | 2006-10-12 | 2016-11-22 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040208875A1 (en) | 1995-03-15 | 2004-10-21 | Queen's University At Kingston | Method for treating amyloidosis |
| US5972328A (en) * | 1993-03-29 | 1999-10-26 | Queen's University At Kingston | Method for treating amyloidosis |
| US5840294A (en) * | 1993-03-29 | 1998-11-24 | Queen's University At Kingston | Method for treating amyloidosis |
| US5643562A (en) * | 1993-03-29 | 1997-07-01 | Queen's University Of Kingston | Method for treating amyloidosis |
| ITPD940054A1 (en) * | 1994-03-23 | 1995-09-23 | Fidia Advanced Biopolymers Srl | SULPHATED POLYSACCHARIDES |
| DE69809892T2 (en) | 1997-04-04 | 2003-08-28 | Fidia Advanced Biopolymers Srl | N-SULFATED HYALURONIC ACID COMPOUNDS, THEIR DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| GB2334211A (en) * | 1997-12-12 | 1999-08-18 | Stephen Francis Dealler | The use of anionic polysaccharides to prevent prion infection |
| US6310073B1 (en) | 1998-07-28 | 2001-10-30 | Queen's University At Kingston | Methods and compositions to treat glycosaminoglycan-associated molecular interactions |
| DE10053053A1 (en) * | 2000-10-19 | 2002-05-16 | Knoell Hans Forschung Ev | Pharmaceutical formulations for the inhibition of inflammatory arthritis |
| TW200716088A (en) | 2005-04-15 | 2007-05-01 | Neurochem Int Ltd | Formulations and methods for treating amyloidosis |
| ATE481094T1 (en) | 2005-12-22 | 2010-10-15 | Kiacta Sarl | TREATMENT OF DIABETIC NEPHROPATHY |
| FR2899815B1 (en) * | 2006-04-14 | 2008-07-11 | Goemar Lab Sa | NEW MEDICINES FOR TREATMENTS AGAINST RETROVIRUSES |
| IT1397247B1 (en) * | 2009-05-14 | 2013-01-04 | Fidia Farmaceutici | NEW REGULATORY AGENTS OF CYTOKINIC ACTIVITY |
| FR3096579B1 (en) * | 2019-05-27 | 2023-05-05 | Organes Tissus Regeneration Reparation Remplacement | composition for the protection and repair of the hematoencephalic barrier (BBB) |
| EP4117781A1 (en) * | 2020-03-09 | 2023-01-18 | Organes Tissus Régénération Réparation Remplacement | Composition for the treatment of lesions of the respiratory system |
| US20230136817A1 (en) * | 2020-04-09 | 2023-05-04 | Paradigm Biopharmaceuticals Ltd. | Treatment of acute respiratory disease syndrome (ards) with polysulfated polysaccharides |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3601136A1 (en) * | 1986-01-16 | 1987-07-23 | Max Planck Gesellschaft | INHIBITORS OF REVERSE TRANSCRIPTASE FOR PROPHYLAXIS AND THERAPY OF RETROVIRUS INFECTIONS IN MAMMALS |
| ZA878877B (en) * | 1986-11-29 | 1988-05-24 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Treatment of diseases caused by viruses |
| DE3725554A1 (en) * | 1987-08-01 | 1989-02-09 | Hoechst Ag | PHARMACEUTICAL COMBINATION PREPARATION AND ITS MANUFACTURE AND USE |
| EP0312222B1 (en) * | 1987-10-14 | 1992-08-05 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Treatment of diseases caused by viruses |
| DE3734962C1 (en) * | 1987-10-15 | 1989-01-05 | Luitpold Werk Chem Pharm | Use of chondroitin polysulfate for the preventive, soothing or curative treatment of AIDS and ARC |
| DE3744119A1 (en) * | 1987-12-24 | 1989-07-06 | Basf Ag | USE OF POLYSULFATED HEPARINES |
| DE3919644A1 (en) * | 1989-06-16 | 1990-12-20 | Diagen Inst Molekularbio | Organic and/or inorganic polymers - have anionic gps. bound to carrier, used for prophylaxis and treatment of viral infections |
| DE3921761A1 (en) * | 1989-07-01 | 1991-01-03 | Hoechst Ag | SUBSTITUTED POLYSACCHARIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE PROPHYLAXIS AND THE TREATMENT OF VIRUS DISEASES |
| DE3937283A1 (en) * | 1989-11-09 | 1991-05-16 | Hoechst Ag | POLYELECTROLYTE COMPLEXES FOR TREATING AND PROPHYLAXIS OF VIRUS DISEASES, NEW POLYELECTROLYTE COMPLEXES AND METHOD FOR THE PRODUCTION THEREOF |
-
1990
- 1990-07-03 DE DE4021066A patent/DE4021066A1/en not_active Withdrawn
-
1991
- 1991-07-01 EP EP19910110901 patent/EP0464759A3/en not_active Withdrawn
- 1991-07-02 IE IE232091A patent/IE912320A1/en unknown
- 1991-07-02 PT PT98185A patent/PT98185A/en not_active Application Discontinuation
- 1991-07-02 AU AU79470/91A patent/AU7947091A/en not_active Abandoned
- 1991-07-02 KR KR1019910011144A patent/KR920002153A/en not_active Application Discontinuation
- 1991-07-02 JP JP3161381A patent/JPH04230325A/en active Pending
- 1991-07-02 CA CA002046037A patent/CA2046037A1/en not_active Abandoned
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083933A (en) * | 1999-04-19 | 2000-07-04 | Stellar International Inc. | Treatment of cystitis-like symptoms with chondroitin sulfate following administration of a challenge solution |
| US7393875B2 (en) | 1999-05-24 | 2008-07-01 | Neurochem (International) Limited | Methods and compounds for inhibiting amyloid deposits |
| US6562836B1 (en) | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
| US7786174B2 (en) | 1999-05-24 | 2010-08-31 | Bellus Health (International) Limited | Methods and compounds for inhibiting amyloid deposits |
| US8778908B2 (en) | 2003-02-19 | 2014-07-15 | Stellar International Inc. | Cystitis treatment with high dose chondroitin sulfate |
| US7772210B2 (en) | 2003-02-19 | 2010-08-10 | Stellar Pharmaceuticals Inc. | Cystitis treatment with high dose chondroitin sulfate |
| US8084441B2 (en) | 2003-02-19 | 2011-12-27 | Stellar Pharmaceuticals, Inc. | Cystitis treatment with high dose chondroitin sulfate |
| US8334276B2 (en) | 2003-02-19 | 2012-12-18 | Stellar Pharmaceuticals Inc. | Cystitis treatment with high dose chondroitin sulfate |
| US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
| US7244764B2 (en) | 2003-06-23 | 2007-07-17 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7414076B2 (en) | 2003-06-23 | 2008-08-19 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
| US8835654B2 (en) | 2004-12-22 | 2014-09-16 | Bhi Limited Partnership | Method and compositions for treating amyloid-related diseases |
| WO2006114019A1 (en) * | 2005-04-26 | 2006-11-02 | Versitech Limited | Polysaccharide extract from lycium barbarum as neuroprotective agent against beta-amyloid peptide neurotoxicity |
| US9499480B2 (en) | 2006-10-12 | 2016-11-22 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US10238611B2 (en) | 2006-10-12 | 2019-03-26 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US10857109B2 (en) | 2006-10-12 | 2020-12-08 | Bellus Health, Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US11020360B2 (en) | 2006-10-12 | 2021-06-01 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| IE912320A1 (en) | 1992-01-15 |
| EP0464759A3 (en) | 1992-06-03 |
| AU7947091A (en) | 1992-01-09 |
| JPH04230325A (en) | 1992-08-19 |
| KR920002153A (en) | 1992-02-28 |
| EP0464759A2 (en) | 1992-01-08 |
| DE4021066A1 (en) | 1992-01-09 |
| PT98185A (en) | 1994-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2046037A1 (en) | Long-term prophylaxis against diseases caused by viruses or by unconventional viruses | |
| Bianculli et al. | Antiviral polymers: past approaches and future possibilities | |
| Ghosh et al. | Focus on antivirally active sulfated polysaccharides: from structure–activity analysis to clinical evaluation | |
| KR0128287B1 (en) | Pharmaceutical composition for the inhibition of angiogenesis | |
| Sosa et al. | N-Carboxymethylchitosan-N, O-sulfate as an anti-HIV-1 agent | |
| CA2694189A1 (en) | Method for blocking ligation of the receptor for advanced glycation end-products (rage) | |
| JPH027577B2 (en) | ||
| H Pomin | Antimicrobial sulfated glycans: Structure and function | |
| AU617850B2 (en) | Heparin fragments and fractions with anti-hiv action | |
| US6020323A (en) | Compositions and methods for regulation of active TNF-α | |
| EP0669827B1 (en) | Compositions for the regulation of cytokine activity | |
| US4820693A (en) | Method and composition for arresting angiogenesis and capillary, cell or membrane leakage | |
| CA2066155A1 (en) | Antiviral agent for human immunodeficiency virus | |
| Barzu et al. | Preparation and anti-HIV activity of O-acylated heparin and dermatan sulfate derivatives with low anticoagulant effect | |
| IE902384A1 (en) | Substituted polysaccharides, processes for their preparation¹and their use for the prophylaxis and treatment of virus¹diseases | |
| JPH08277224A (en) | Antiinflammatory agent | |
| EP0338092A1 (en) | Anti-hiv agent | |
| US3679795A (en) | Antiinfectious compositions and process for their preparation | |
| EP1059304A1 (en) | Novel polysaccharide derivatives, process for the production thereof and medicinal compositions containing the same as the active ingredient | |
| US20150099703A1 (en) | Treatment of postpartum haemorrhage with chemically modified heparin or heparan sulphate and a uterotonic agent | |
| EP1423130A1 (en) | Antithrombotic compositions comprising low molecular weight heparin and low molecular weight dermatan sulphate | |
| IE904033A1 (en) | Polyelectrolyte complexes for the treatment and prophylaxis¹of virus diseases, novel polyelectrolyte complexes and a¹process for their preparation | |
| EP0676206B1 (en) | Antimalarial | |
| EP0544321A1 (en) | Use of substituted cinnamic acid polymers to treat AIDS | |
| US20030171333A1 (en) | Pharmaceutical composition containing at least a polymer combined with or conjugated to at least a phenylalkylcarboxylic acid salt, conjugate polymers and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |