WO1990001938A1 - Phosphosugar-based anti-inflammatory and/or immunosuppressive drugs - Google Patents

Phosphosugar-based anti-inflammatory and/or immunosuppressive drugs Download PDF

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WO1990001938A1
WO1990001938A1 PCT/AU1989/000350 AU8900350W WO9001938A1 WO 1990001938 A1 WO1990001938 A1 WO 1990001938A1 AU 8900350 W AU8900350 W AU 8900350W WO 9001938 A1 WO9001938 A1 WO 9001938A1
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phosphosugar
phosphate
mannose
polysaccharide
derivative
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PCT/AU1989/000350
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French (fr)
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Christopher Richard Parish
William Butler Cowden
David Otto Willenborg
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The Australian National University
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Priority to EP89909685A priority Critical patent/EP0429522B1/en
Priority to DE68926746T priority patent/DE68926746T2/en
Publication of WO1990001938A1 publication Critical patent/WO1990001938A1/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • This invention relates to phosphosugars and phosphosugar containing compounds that possess anti-inflammatory and/or immunosuppressive activity, and in particular it relates to the use of these compounds as anti-inflammatory and/or immunosuppressive agents in animals and man.
  • the lysosomes of cells contain a wide range of degradative enzymes which play a central role in the entry of leukocytes into inflammatory sites. Lysosomal enzymes, produced in the rough endoplasmic reticulum, undergo glycosylation followed by a number of 'trimming' and phosphorylation reactions resulting in oligosaccharides rich in mannose-6-phosphate residues (1-3). These mannose-6-phosphate residues are specific recognition markers of lysosomal enzymes (3) . It is this marker on the enzymes that is recognized by a mannose phosphate receptor (MPR) which mediates transport of lysomsomal enzymes to lysosomes.
  • MPR mannose phosphate receptor
  • This receptor functions not only in internal transport of lysosomal enzymes but is also important in their secretory pathway and their expression on cell surfaces (1).
  • Receptor-lysosomal enzyme interactions have been extensively studied (4-6) and shown to be inhibited by exogenous mannose-6-phosphate.
  • Work leading to the present invention has been based on the hypothesis that mannose-6-phosphate and related phosphosugar structures might act as an i-inflammatory agents in vivo, possibly by depleting leukocytes of their lysosomal enzymes although this has not been shown previously.
  • the present invention relates to the use of phosphosugars and phosphosugar- containing oligosaccharides and polysaccharides as anti-inflammatory and/or immunosuppressive agents.
  • a method of anti-inflammatory and/or immunosuppressive treatment of an animal or human patient which comprises administration to the patient of an effective amount of at least one phosphosugar or a derivative thereof, or a phosphosugar- containing oligosaccharide or polysaccharide or a derivative thereof.
  • this invention relates to the use of at least one phosphosugar or phosphosugar-containing oligosaccharide or polysaccharide in the preparation or manufacture of a pharmaceutical or veterinary composition for anti-inflammatdry and/or immunosuppressive treatment.
  • a pharmaceutical or veterinary composition which comprises at least one phosphosugar or a derivative thereof, or a phosphosugar- containing oligosaccharide or polysaccharide or a derivative thereof, together with an acceptable pharmaceutical or veterinary carrier or diluent therefor.
  • Phosphosugars and phosphosugar-containing oligosaccharides or polysaccharides which may be used in accordance with the present invention comprise both naturally occurring and synthetic compounds containing or comprising phosphosugar residues, that is, sugar residues bearing at least one phosphate moiety.
  • Particularly useful phosphosugars include phosphomannoses, phosphofructoses, phosphogalactoses and phosphoglucoses, while particularly useful oligosaccharides or polysaccharides include polysaccharides containing phosphomannose residues.
  • Presently preferred phosphosugars include mannose-6- phosphate and fructose-1-phosphate.
  • Preferred phosphosugar derivatives are the esters including acetate esters, particularly the 1,2,3,4-tetraacetate of mannose-6-phosphate. Whilst it is not intended that the present invention should be restricted in any way by a theoretical explanation of the mode of action of the phosphosugars in accordance with the invention, it is presently believed that these active compounds may exert their own anti-inflammatory effect, by acting as antagonists or competitive inhibitors of the natural ligand of mannose phosphate receptors (MPR) on cells. Accordingly, the active phosphosugars or phosphosugar-containing oligosaccharides or polysaccharides may include any such compounds which are effective antagonists or competitive inhibitors of the natural ligand of the MPR.
  • MPR mannose phosphate receptors
  • the active anti-inflammatory and/or immunosuppressive agents in accordance with the present invention may be used to treat inflammatory diseases or conditions such as multiple sclerosis and rheumatoid arthritis, as well as in the treatment of the inflammatory process associated with the rejection of organ transplants (since massive mononuclear cell infiltrates are usually associated with acute graft rejection).
  • These active agents may be used alone, in combination with one or more other phosphosugars, or in combination with other known anti-inflamma ory or immunosuppressive agents.
  • compositions of phosphosugars and sulphated polysaccharides with heparanase-inhibitory activity may act synergistically and represent a formulation with potent anti-inflammatory activity.
  • the anti-inflammatory activity of these sulphated polysaccharides is disclosed in detail in International Patent Application No. PCT/AU88/00017.
  • Table I presents data from an EAE experiment in rats where mannose-6-phosphate, administered to animals via osmotic pumps, totally inhibited development of disease.
  • the data presented in Table II demonstrates that a four fold reduction in the mannose-6-phosphate dose (40 mg/rat/week to 10 mg/rat/week) still resulted in a substantial reduction in disease severity, i.e. the lowest dose of phosphosugar reduced disease severity to 37.7% that of control animals.
  • Analysis of phosphosugar specificity revealed (Table III) that fructose-1-phosphate was as effective as mannose-6-phosphate at inhibiting disease.
  • Fructose-6-phosphate was also a comparatively effective inhibitor of EAE, whereas galactose-6-phosphate, glucose-6-phosphate and fructose-1,6-diphosphate were partially inhibitory. Glucose-1-phosphate and D-mannose apparently had little or no effect on disease progression.
  • CNS tissue Histological examination of central nervous system (CNS) tissue from untreated animals with EAE and EAE animals which had been treated with either mannose-6-phosphate or mannan containing phosphate moieties, (Table V) revealed that both treatments dramatically inhibited development of CNS lesions. No lesions were detected in mannose-6-phosphate treated animals and a small number of lesions, compared with controls, in mannan treated rats. Such data are consistent with the view that the sugars are inhibiting entry of leukocytes into the CNS.
  • the first data column in the Tables refers to the number of animals in each group which showed any clinical signs of EAE during the entire course of the experiment.
  • 7/10 animals treated with mannose-6-phosphate developed some clinical signs of disease (Table III) the severity of these disease symptoms was extremely mild compared with untreated animals, i.e., ⁇ 10% disease severity of controls when clinical scores and duration of disease are examined.
  • the mannose-6-phosphate data in Tables I and III are almost identical.
  • the estimation of disease severity can be used to rank the anti-inflammatory activity of phosphosugars which only partially inhibit disease, e.g., glucose-6-phosphate and fructose-1,6-diphosphate.
  • EAE induced in Lewis rats with 30 x 10 6 ConA activated EAE effector cells.
  • Miniosomotic pumps containing phosphosugar were implanted subcutaneously on day 3 after cell transfer. Dose was 40 mg/rat delivered over a 7 day period by 2.0 ml pumps.
  • Clinical EAE was graded according to the following scheme: 0, asymptomatic; 1, flaccid distal half of tail; 2, entire tail flaccid; 3, ataxia, difficulty in righting; 4, hind limb weakness; and 5, hind limb paralysis.
  • Mannose-6-phosphate dose represents amount of phosphosugar delivered to rats over a 7 day period via mino-osmotic pumps.
  • Severity represents product of mean clinical score and mean length disease.
  • Yeast mannan from Saccharomyces cerevisiae (Baker's yeast)
  • Rats were killed 9 days after cell transfer and sections of the lower thoracic-upper lumbar spinal cord examined for inflammatory lesions. Animals treated as in Table I.
  • PPME is the purified high molecular weight, acid-resistant fragment, (polysaccharide core fraction) of the isolated exocellular phosphomannan produced by Pichia holstii (Hansenula holstii) as described by Bretthauer et.al. (7), that contains mannose phosphate residues.
  • the pentasaccharide is an isolated monophospho- mannopentaose fragment, 6-phospho-mannose- ⁇ (l-3)- (mannose- ⁇ -(l-3)>2*- ⁇ annose- ⁇ -(l-2)- mannose, of the exocellular phosphomannan produced by Pichia holstii (Hansenula holstii) described by Bretthauer et.al. (7).
  • (DA x Lew)Fl rats were immunized with M.butyricum in light mineral oil given in each foot. Ten days later spleens were removed and incubated as single cell suspension tissue culture medium in + 5 ⁇ g/ml ConA for 75 hrs. Cells were harvested, washed and transferred i.v. at 65 x 10 ⁇ cells/rat into (DA x Lew)F recipients.
  • mice were sensitised by i.v. injection 10 5 of washed sheep red blood cells. 5 days later they were challenged in the right hind footpad with SRBC. Each mouse was given a 0.25ml injection i/p at the same time of either saline, mannose-6-phosphate or the 1,2,3,4-tetraacetate of mannose-6-phosphate and all injections were repeated a further 6 times at approx. k hour intervals.
  • the dose in each injection of mannose-6- phosphate was 0.15mg and of 1,2,3,4- tetraacetate of mannose-6-phosphate was also 0.15mg.
  • Mannose-6-phosphate reduced the swelling by 52.5%, and the 1,2,3,4-tetraacetate of mannose-6- phosphate by 91.5%, as compared with the saline controls.

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Abstract

A method of anti-inflammatory and/or immunosuppressive treatment of an animal or human patient comprises administration to the patient of an effective amount of at least one phosphosugar or derivative thereof, or a phosphosugar-containing oligosaccharide or polysaccharide or derivative thereof.

Description

"Phosphosugar-based an i-inflamma ory and/or immunosuppressive drugs"
This invention relates to phosphosugars and phosphosugar containing compounds that possess anti-inflammatory and/or immunosuppressive activity, and in particular it relates to the use of these compounds as anti-inflammatory and/or immunosuppressive agents in animals and man.
The lysosomes of cells contain a wide range of degradative enzymes which play a central role in the entry of leukocytes into inflammatory sites. Lysosomal enzymes, produced in the rough endoplasmic reticulum, undergo glycosylation followed by a number of 'trimming' and phosphorylation reactions resulting in oligosaccharides rich in mannose-6-phosphate residues (1-3). These mannose-6-phosphate residues are specific recognition markers of lysosomal enzymes (3) . It is this marker on the enzymes that is recognized by a mannose phosphate receptor (MPR) which mediates transport of lysomsomal enzymes to lysosomes. This receptor functions not only in internal transport of lysosomal enzymes but is also important in their secretory pathway and their expression on cell surfaces (1). Receptor-lysosomal enzyme interactions have been extensively studied (4-6) and shown to be inhibited by exogenous mannose-6-phosphate. Work leading to the present invention has been based on the hypothesis that mannose-6-phosphate and related phosphosugar structures might act as an i-inflammatory agents in vivo, possibly by depleting leukocytes of their lysosomal enzymes although this has not been shown previously. As a result of these investigations, it has now been discovered that certain phosphosugars, notably mannose-6-phosphate and fructose-1-ρhosphate, are in fact effective anti-inflammatory agents, continuous infusion of the sugars inhibiting experimental allergic encephalomyelitis (EAE) , an animal inflammatory disease of the central nervous system resembling multiple sclerosis in humans. Polysaccharides containing D-mannose with phosphate residues have also been found to inhibit EAE. Phosphosugars, particularly mannose-6-phosphate, have also been found to exhibit an anti-inflammatory effect on passively induced adjuvant arthritis. Adjuvant-induced arthritis in the rat shares a number of features with arthritis in humans, viz. the presence of a proliferative synovitis and subcutaneous nodules, swelling of extremities, and ultimately cartilage and bone erosion. This animal model has been extensively used for detection of anti-inflammatory and immunosuppressive drugs.
Finally, phosphosugars have been found to be effective as an immunosupp essant in preliminary experiments, particularly in controlling the delayed hypersensitivity reaction.
In a first aspect, therefore, the present invention relates to the use of phosphosugars and phosphosugar- containing oligosaccharides and polysaccharides as anti-inflammatory and/or immunosuppressive agents. In this aspect, there is provided a method of anti-inflammatory and/or immunosuppressive treatment of an animal or human patient which comprises administration to the patient of an effective amount of at least one phosphosugar or a derivative thereof, or a phosphosugar- containing oligosaccharide or polysaccharide or a derivative thereof.
In another aspect, this invention relates to the use of at least one phosphosugar or phosphosugar-containing oligosaccharide or polysaccharide in the preparation or manufacture of a pharmaceutical or veterinary composition for anti-inflammatdry and/or immunosuppressive treatment. In this aspect, there is provided a pharmaceutical or veterinary composition which comprises at least one phosphosugar or a derivative thereof, or a phosphosugar- containing oligosaccharide or polysaccharide or a derivative thereof, together with an acceptable pharmaceutical or veterinary carrier or diluent therefor. Phosphosugars and phosphosugar-containing oligosaccharides or polysaccharides which may be used in accordance with the present invention comprise both naturally occurring and synthetic compounds containing or comprising phosphosugar residues, that is, sugar residues bearing at least one phosphate moiety. Particularly useful phosphosugars include phosphomannoses, phosphofructoses, phosphogalactoses and phosphoglucoses, while particularly useful oligosaccharides or polysaccharides include polysaccharides containing phosphomannose residues. Presently preferred phosphosugars include mannose-6- phosphate and fructose-1-phosphate. Preferred phosphosugar derivatives are the esters including acetate esters, particularly the 1,2,3,4-tetraacetate of mannose-6-phosphate. Whilst it is not intended that the present invention should be restricted in any way by a theoretical explanation of the mode of action of the phosphosugars in accordance with the invention, it is presently believed that these active compounds may exert their own anti-inflammatory effect, by acting as antagonists or competitive inhibitors of the natural ligand of mannose phosphate receptors (MPR) on cells. Accordingly, the active phosphosugars or phosphosugar-containing oligosaccharides or polysaccharides may include any such compounds which are effective antagonists or competitive inhibitors of the natural ligand of the MPR.
The active anti-inflammatory and/or immunosuppressive agents in accordance with the present invention may be used to treat inflammatory diseases or conditions such as multiple sclerosis and rheumatoid arthritis, as well as in the treatment of the inflammatory process associated with the rejection of organ transplants (since massive mononuclear cell infiltrates are usually associated with acute graft rejection). These active agents may be used alone, in combination with one or more other phosphosugars, or in combination with other known anti-inflamma ory or immunosuppressive agents. In particular, compositions of phosphosugars and sulphated polysaccharides with heparanase-inhibitory activity may act synergistically and represent a formulation with potent anti-inflammatory activity. The anti-inflammatory activity of these sulphated polysaccharides is disclosed in detail in International Patent Application No. PCT/AU88/00017.
The anti-inflammatory and/or immunosuppressive activity and use of the phosphosugars in accordance with the present invention is demonstrated in the following Example.
EXAMPLE 1 Inhibition of EAE.
In this Example, a number of phosphosugars and one phospho-polysaccharide were tested for their ability to inhibit development of EAE in rats. (All phosphosugars tested are commercially available and were obtained from Sigma Chemical Co., St. Louis, MO, U.S.A.). Experimental details are included in the footnotes to the Tables setting out the test results.
Table I presents data from an EAE experiment in rats where mannose-6-phosphate, administered to animals via osmotic pumps, totally inhibited development of disease. The data presented in Table II demonstrates that a four fold reduction in the mannose-6-phosphate dose (40 mg/rat/week to 10 mg/rat/week) still resulted in a substantial reduction in disease severity, i.e. the lowest dose of phosphosugar reduced disease severity to 37.7% that of control animals. Analysis of phosphosugar specificity revealed (Table III) that fructose-1-phosphate was as effective as mannose-6-phosphate at inhibiting disease. Fructose-6-phosphate was also a comparatively effective inhibitor of EAE, whereas galactose-6-phosphate, glucose-6-phosphate and fructose-1,6-diphosphate were partially inhibitory. Glucose-1-phosphate and D-mannose apparently had little or no effect on disease progression. These results are displayed graphically in Figure 1. Such phosphosugar specificity closely resembles the monosaccharide specificity of the mannose-6-phosphate receptors on cells (1).
In two separate experiments (Table IV) administration of the D-mannose polysaccharide (mannan) from Saccharomyces cerevisiae, which contains phosphate moieties, totally inhibited EAE, indicating that phospho annans can inhibit disease.
Histological examination of central nervous system (CNS) tissue from untreated animals with EAE and EAE animals which had been treated with either mannose-6-phosphate or mannan containing phosphate moieties, (Table V) revealed that both treatments dramatically inhibited development of CNS lesions. No lesions were detected in mannose-6-phosphate treated animals and a small number of lesions, compared with controls, in mannan treated rats. Such data are consistent with the view that the sugars are inhibiting entry of leukocytes into the CNS.
The first data column in the Tables refers to the number of animals in each group which showed any clinical signs of EAE during the entire course of the experiment. Thus, although 7/10 animals treated with mannose-6-phosphate developed some clinical signs of disease (Table III) the severity of these disease symptoms was extremely mild compared with untreated animals, i.e., <10% disease severity of controls when clinical scores and duration of disease are examined. In this sense, the mannose-6-phosphate data in Tables I and III are almost identical. Similarly, the estimation of disease severity can be used to rank the anti-inflammatory activity of phosphosugars which only partially inhibit disease, e.g., glucose-6-phosphate and fructose-1,6-diphosphate.
Figure imgf000009_0001
EAE induced in Lewis rats with 30 x 106 ConA activated EAE effector cells. Miniosomotic pumps containing phosphosugar were implanted subcutaneously on day 3 after cell transfer. Dose was 40 mg/rat delivered over a 7 day period by 2.0 ml pumps. Clinical EAE was graded according to the following scheme: 0, asymptomatic; 1, flaccid distal half of tail; 2, entire tail flaccid; 3, ataxia, difficulty in righting; 4, hind limb weakness; and 5, hind limb paralysis.
Table II
Effect of Mannose-6-Phosphate Dose on Adoptively Transferred EAE
Treatment Dose No. with Mean Mean Mean Disease (mg) EAE/total Day Clinical Length Severity Onset Score Disease (%Control)
Control 4/4 4.5 3.5 4.5 100% Mannose-6- 40 1/3 5.0 0.3 0.7 1.73 Phosphate
Mannose-6- 20 4/4 5.0 1.5 3.0 .28.-65 Phosphate
Mannose-6- 10 4/4 5.0 1.8 3.3 37.75 Phosphate
Leσend to Table II:
Experimental details as in Table I. Mannose-6-phosphate dose represents amount of phosphosugar delivered to rats over a 7 day period via mino-osmotic pumps. "Disease
Severity" represents product of mean clinical score and mean length disease.
Table III
Figure imgf000011_0001
Fructose-1- 3/5 5.5 1.2 1.6 12.65 phosphate
Fructose-6- 4/5 6.0 1.6 2.4 25.4? phosphate Galactose-6- 5/5 5.2 2.0 3.0 40.5? phosphate
Glucose-6- 5/5 5.4 2.0 3.8 50.3? phosphate
Fructose-1,6- 5/5 5.4 2.4 3.4 54.0? diphosphate
Glucose-1- 5/5 5.2 3.0 3.8 75.5? phosphate
D-mannose 5/5 5.2 2.9 4.4 84.55
Legend to Table III:
Experimental details as in Table I. "Disease Severity" represents product of mean clinical score and mean length disease. Table IV
Inhibition of Adoptively Transferred EAE by Yeast Mannan
Treatment
Figure imgf000012_0001
Expt. 1 Control 5/5 4.8 3.5 4.0
Yeast mannan 0/6 Expt: 2 Control 4/4 5.0 3.1 3.7 Yeast mannan 0/4
Legend to Table IV:
Yeast mannan from Saccharomyces cerevisiae (Baker's yeast)
Experimental details as in Table I
Table V
Histological analysis of EAE Inhibition in Rats
Receiving Mannose-6-Phosphate and Mannan
Treatment No. Sections No.Lesions Lesions/ scanned section
110 11.0
206 25.7
0 0
0 0
284 19.0
303 25.0
20 1.1
Figure imgf000013_0001
92 6.7
Legend to Table V:
Rats were killed 9 days after cell transfer and sections of the lower thoracic-upper lumbar spinal cord examined for inflammatory lesions. Animals treated as in Table I.
EXAMPLE 2 Inhibition of EAE
In further experiments using the EAE model of Example 1, other mannose phosphate-containing compounds were used, including PPME and a pentasaccharide.
PPME is the purified high molecular weight, acid-resistant fragment, (polysaccharide core fraction) of the isolated exocellular phosphomannan produced by Pichia holstii (Hansenula holstii) as described by Bretthauer et.al. (7), that contains mannose phosphate residues. The pentasaccharide is an isolated monophospho- mannopentaose fragment, 6-phospho-mannose-α(l-3)- (mannose-α-(l-3)>2*-πιannose-α-(l-2)- mannose, of the exocellular phosphomannan produced by Pichia holstii (Hansenula holstii) described by Bretthauer et.al. (7).
In these experiments, details of which were as in Table I, the number of cells transferred was 25xl06/rat, while the dose of compound administered was lOmg/rat delivered over a 7 day period by mini-osmotic pumps, commencing on day 3 after cell transfer. The results are set out in Table VI.
Table VI
Control PPME Pentasaccharide EAE/Total 5/5 3/5 1/5 '
EXAMPLE 3 Suppression of Passive Adjuvant Arthritis
(DA x Lew)Fl rats were immunized with M.butyricum in light mineral oil given in each foot. Ten days later spleens were removed and incubated as single cell suspension tissue culture medium in + 5μg/ml ConA for 75 hrs. Cells were harvested, washed and transferred i.v. at 65 x 10^ cells/rat into (DA x Lew)F recipients.
Treated rats were implanted on the day they received cells with miniosmotic pumps which delivered 6mg/rat/day of mannose-6- phosphate for 14 days. Control rats were sham operated. The results are shown in Table VII as % of pre-cell injection foot size. {Average for group; n=4 (mannose-6-phosphate) ; n=6 (control)}.
Day
4
6
7 9
11
14
Figure imgf000015_0001
EXAMPLE 4 Effect on Delayed-Type Hypersensitivity (DTH)
C57B1 mice were sensitised by i.v. injection 105 of washed sheep red blood cells. 5 days later they were challenged in the right hind footpad with SRBC. Each mouse was given a 0.25ml injection i/p at the same time of either saline, mannose-6-phosphate or the 1,2,3,4-tetraacetate of mannose-6-phosphate and all injections were repeated a further 6 times at approx. k hour intervals. The dose in each injection of mannose-6- phosphate was 0.15mg and of 1,2,3,4- tetraacetate of mannose-6-phosphate was also 0.15mg. At 24 hours after challenge the DTH swelling was measured. Mannose-6-phosphate reduced the swelling by 52.5%, and the 1,2,3,4-tetraacetate of mannose-6- phosphate by 91.5%, as compared with the saline controls.
REFERENCES
1. von Figura, K. and Hasilik, A. (1986). Ann. Rev. Biochem. __5. : 167.
2. West, CM. (1986). Mol. Cell. Biochem. 72 : 3.
3. Hickman, S. and Neufeld, E.F. (1972). Biochem. Biophys. Res. Comm. 49 : 992.
4. Varki, A. and Ko,rnfeld, S. (1983). J.Biol. Chem. 258 : 2808
5. Fischer, H.D., Creek, K.E. and Sly, W.S. (1982). J. Biol. Chem. 257 : 9938.
6. Steiner, A.W. and Rome, L.H. (1982). Arch. Biochem. Biophys. 214 : 681.
7. Bretthauer, R.K., Kaczorowski, G.J. and Weise, M.J., (1973), Biochemistry 12(7) : 1251.

Claims

CLAIMS :
1. A method of anti-inflammatory and/or immunosuppressive treatment of an animal or human patient, which comprises administration to the patient of at least one phosphosugar or a derivative thereof, or a phosphosugar-containing oligosaccharide or polysaccharide or a derivative thereof.
2. A method according to claim 1, wherein said phosphosugar is selected from the group consisting of mannose-6-phosphate, fructose-1-phosphate, fructose-6-phosphate, galactose-6- phosphate, fructose-1,6-diphosphate, glucose-6-phosphate and glucose-1-phosphate.
3. A method according to claim 2, wherein said phosphosugar is mannose-6- phosphate.
4. A method according to claim 2, wherein said phosphosguar is fructose-1-phosphate.
5. A method according to claim 1, wherein said phosphosugar derivative comprises an acetate or other ester thereof.
6. A method according to claim 5, wherein said phosphosugar ester is the 1,2,3,4-tetraacetate of mannose-6-phosphate.
7. A method according to claim 1, wherein said phosphosugar-containing oligosaccharide or polysaccharide is an oligosaccharide or polysaccharide containing phosphomannose residues.
8. A method according to claim 7, wherein said oligosaccharide, or polysaccharide is the D-mannose polysaccharide (mannan) from Saccharomyces cerevisiae.
9. A method according to claim 7, wherein said oligosaccharide or polysaccharide is the purified high molecular weight, acid-resistant fragment (polysaccharide core fraction) of the exocellular phosphomannan produced by Pichia holstii (Hansenula holstii), or an oligosaccharide fragment derived therefrom.
10. A method according to claim 9, wherein said oligosaccharide fragment is the monophosphomannopentaose fragment, 6-phospho-mannose-α(l-3)-{mannose-α-(l-3)}2-mannose - -(1-2)-mannose.
11. A method according to claim 1, wherein said treatment comprises treatment of inflammatory disease of the central nervous system.
12. A method according to claim 1, wherein said treatment comprises treatment of arthritis.
13. A method according to claim 1, wherein said treatment comprises treatment to control the delayed-type hypersensitivity reaction.
14. A pharmaceutical or veterinary composition for anti- inflammatory and/or immunosuppressive treatment which comprises at least one phosphosugar or derivative thereof, or a phosphosugar-containing oligosaccharide or polysaccharide or a derivative thereof.
15. Use of at least one phosphosugar or derivative thereof, or a phosphosugar-containing oligosaccharide or polysaccharide or a derivatie thereof for anti-inflammatory or immunosuppressive treatment of an animal or human patient.
16. Use of at least one phosphosugar or derivative thereof, or a phosphosugar-containing oligosaccharide or polysaccharide or a derivative thereof for the preparation of a medicament for anti-inflammatory and/or immunosuppressive treatment of an animal or human patient.
PCT/AU1989/000350 1988-08-19 1989-08-18 Phosphosugar-based anti-inflammatory and/or immunosuppressive drugs WO1990001938A1 (en)

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Cited By (12)

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WO1996009310A1 (en) * 1994-09-20 1996-03-28 Perstorp Ab Derivatives of carbohydrates and compositions containing them
GB2299025A (en) * 1992-03-17 1996-09-25 British Tech Group Formulations of mannose phosphates useful in the treatment of fibrotic disorders
US5587364A (en) * 1982-05-07 1996-12-24 Carrington Laboratories, Inc. Uses of aloe products in the treatment of inflammatory diseases
WO1997005883A1 (en) * 1995-08-04 1997-02-20 The Victoria University Of Manchester Pharmaceutical composition
US5646123A (en) * 1991-06-10 1997-07-08 Alberta Research Council Time dependent administration of oligosaccharide glycosides related to blood group determinants having a type I or type II core structure in reducing inflammation in a sensitized mammal arising form exposure to an antigen
US5747461A (en) * 1994-07-26 1998-05-05 Markov; Angel K. Synergistic administration of cyclosporine and fructose diphosphate
US6093388A (en) * 1996-08-12 2000-07-25 Btg International Limited Mannose-6-phosphate composition and its use in treating fibrotic disorders
US6294521B1 (en) 1996-10-18 2001-09-25 Australian National University Phosphosugars and phosphosugar-containing compounds having anti-inflammatory activity
US6566339B1 (en) 1995-08-04 2003-05-20 Renovo Limited Pharmaceutical composition
WO2005094840A1 (en) * 2004-03-15 2005-10-13 Kimberly-Clark Worldwide, Inc. Compositions comprising mannose phosphate for vaginal treatment
US8119357B2 (en) 2003-12-18 2012-02-21 Procognia, Ltd. Method for analyzing a glycomolecule

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587364A (en) * 1982-05-07 1996-12-24 Carrington Laboratories, Inc. Uses of aloe products in the treatment of inflammatory diseases
US5646123A (en) * 1991-06-10 1997-07-08 Alberta Research Council Time dependent administration of oligosaccharide glycosides related to blood group determinants having a type I or type II core structure in reducing inflammation in a sensitized mammal arising form exposure to an antigen
WO1993018777A1 (en) * 1992-03-17 1993-09-30 British Technology Group Ltd. Use of mannose phosphates for the treatment of fibrotic disorders
GB2265310A (en) * 1992-03-17 1993-09-29 British Tech Group Treatment of fibrotic disorders with mannose phosphates
US5520926A (en) * 1992-03-17 1996-05-28 British Technology Group Limited Method of using mannose phosphates for the treatment of fibrotic disorders
GB2265310B (en) * 1992-03-17 1996-09-25 British Tech Group Treatment of fibrotic disorders with mannose phosphates
GB2299025A (en) * 1992-03-17 1996-09-25 British Tech Group Formulations of mannose phosphates useful in the treatment of fibrotic disorders
GB2299025B (en) * 1992-03-17 1996-11-27 British Tech Group Dispenser containing a formulation of mannose phosphate useful in the treatment of fibrotic disorders of the eye
US5747461A (en) * 1994-07-26 1998-05-05 Markov; Angel K. Synergistic administration of cyclosporine and fructose diphosphate
WO1996009310A1 (en) * 1994-09-20 1996-03-28 Perstorp Ab Derivatives of carbohydrates and compositions containing them
US6310042B1 (en) 1994-09-20 2001-10-30 Lars Persson Derivatives of carbohydrates and compositions containing them
WO1997005883A1 (en) * 1995-08-04 1997-02-20 The Victoria University Of Manchester Pharmaceutical composition
US6140307A (en) * 1995-08-04 2000-10-31 The Victoria University Of Manchester Pharmaceutical composition
US6566339B1 (en) 1995-08-04 2003-05-20 Renovo Limited Pharmaceutical composition
US6900181B2 (en) 1995-08-04 2005-05-31 Renovo Limited Pharmaceutical composition
US6093388A (en) * 1996-08-12 2000-07-25 Btg International Limited Mannose-6-phosphate composition and its use in treating fibrotic disorders
US6294521B1 (en) 1996-10-18 2001-09-25 Australian National University Phosphosugars and phosphosugar-containing compounds having anti-inflammatory activity
US8119357B2 (en) 2003-12-18 2012-02-21 Procognia, Ltd. Method for analyzing a glycomolecule
WO2005094840A1 (en) * 2004-03-15 2005-10-13 Kimberly-Clark Worldwide, Inc. Compositions comprising mannose phosphate for vaginal treatment
US7276486B2 (en) 2004-03-15 2007-10-02 Kimberly-Clark Worldwide, Inc. Compositions for vaginal treatment

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DE68926746D1 (en) 1996-08-01
DE68926746T2 (en) 1996-11-28

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