WO2001052861A1

WO2001052861A1 - Diagnosis and treatment of mental disorders

Info

Publication number: WO2001052861A1
Application number: PCT/GB2000/000159
Authority: WO
Inventors: Kazuo Miyanaga; Shin Yazawa; Hideyuki Asaoka; Masakazu Adachi
Original assignee: Japan Immunoresearch Laboratories Co Ltd
Current assignee: Japan Immunoresearch Laboratories Co Ltd
Priority date: 2000-01-21
Filing date: 2000-01-21
Publication date: 2001-07-26
Anticipated expiration: 2002-07-21
Also published as: AU2000230653A1

Abstract

The invention provides a method of treatment of schizophrenia, which comprises administering to a human schizophrenia patient an effective amount of an agent that increases the metabolism of GDP-fucose by α-(1→3)-fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase. The invention further provides the use of such agents in the manufacture of a medicament. The invention also relates to methods for the diagnosis of schizophrenia.

Description

Diagnosis and Treatment of Mental Disorders

The present invention relates to the diagnosis and treatment of schizophrenia.

Schizophrenia is a chronic, severe and disabling brain disease that affects approximately 1% of the population. It often affects people from an early age, and there is a strong, though not invariable hereditary factor in its aetiology.

Sufferers of schizophrenia experience a mixture of positive and negative symptoms. Positive symptoms include delusions, hallucinations, and thought disorder whilst negative symptoms generally involve withdrawal from social contacts and flattening of emotional responses. The cause of schizophrenia is still unknown, and a consistent underlying neurochemical disorder has not yet been found. Most biochemical theories have been derived from the analysis of the actions of drugs found by chance to be effective rather than vice versa.

Some schizophrenia patients are treated effectively using available neuroleptic drugs, but relapses are likely if the medication is taken irregularly. Adherence can be a significant problem in schizophrenia, so there is a demand for more easily administered drugs with fewer side effects.

Further, diagnosis of schizophrenia in patients displaying a relapsing or a remitting course is difficult. The present invention relates to two enzymes involved in the metabolism of fucose, namely α- (1—»3) -fucosyl transferase and guanidinediphosphate-fucose (GDP-fucose) hydrolase. The systematic name of α- (1—»3) -fucosyl transferase is GDP-L-fucose : 2 -acetamido-2-deoxy-D-gluco- pyranosyl- (1—»3) -α-L-fucosyl transferase. The enzyme catalyses the transfer of L-fucose from GDP-L-fucose to glucose or N-acetyl glucosamine . The enzyme has been detected inter alia in human milk, submaxillary glands and stomach, plasma or serum, bone marrow and saliva. α(l—»2), α(l—4) and α(l-6) fucosyl transferases are also known. Initial interest in these enzymes was largely related to their involvement in the synthesis of blood group active substances. However elevations in one or more fucosyl transferase activities have been reported in some cancer patients, suggesting that fucosyl transferases could be used as markers for those malignancies, Madiyalakan et al Analytical Biochemistry 152, 22-28 (1986) .

GDP-fucose hydrolase hydrolyses GDP fucose to GDP and fucose.

The present invention is based on the observations that the activity of α- (1—3) -fucosyl transferase in serum of human schizophrenia sufferers is lower than that in humans who do not suffer from schizophrenia and that increasing the activity of that enzyme in schizophrenia sufferers may improve their condition. It has also been found that GDP-fucose hydrolase can be inhibited by certain agents and that administration of a GDP-fucose hydrolase inhibitor to schizophrenia sufferers may lead to an improvement of the schizophrenia condition. Our observations suggest that directing GDP-fucose to metabolism via α- (1—»3) -fucosyl transferase rather than via GDP-fucose hydrolase improves the condition of patients with schizophrenia. The role of GDP-fucose and of its metabolites in the pathology of schizophrenia is not yet known. A direct or downstream metabolite of GDP-fucose via α- (1—»3) -fucosyl transferase may have a positive influence on schizophrenia and/or a direct or downstream metabolite of GDP-fucose via GDP-hydrolase may have a negative effect. Whatever the mode of action, we have found that agents that lead to an increased throughput of GDP-fucose by the α- (1—>3) -fucosyl transferase enzyme are suitable for treatment of schizophrenia. Agents that inhibit GDP-fucose hydrolase are suitable for treatment of schizophrenia. Such agents may act directly by inhibiting the production of the enzyme product and/or indirectly by channelling GDP-fucose via α- (1—»3) -fucosyl transferase.

Accordingly, the present invention provides a method of treatment of schizophrenia, which comprises administering to a human schizophrenia patient an effective amount of an agent that increases the metabolism of GDP- fucose by α- (1—3) -fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase .

The present invention also provides the use of an agent that increases the metabolism of GDP-fucose by α- (l-»3) -fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase in the manufacture of a medicament for the treatment of schizophrenia .

Preferably the agent is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt. More preferably the agent is an adenosine phosphate for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof, for example the disodium salt of ATP.

As shown below, adenosine phosphates both increase the metabolism of GDP-fucose by α- (l->3) -fucosyl transferase and decrease the metabolism of GDP-fucose by GDP-fucose hydrolase by acting as an inhibitor of that enzyme. Alternatively, a different inhibitor of GDP-fucose hydrolase may be used.

In a further embodiment the metabolism of GDP-fucose by α- (1—»3) -fucosyl transferase may be increased by decreasing the metabolism of GDP-fucose by any other enzyme that metabolises that compound in vivo .

The activity of α-(l-3) fucosyl transferase (α- (1—3) FT) was determined in plasma samples from normal human donors i.e. humans not suffering from schizophrenia, and patients with schizophrenia using the assay described in detail in Example 1, measuring transfer of radiolabelled GDP-fucose to N-acetyl-2 ' -O-methyllactosamine, see Madiyalakan et al Analytical Biochemistry 152, 22-28

(1986). It was found that the activity of α- (l-3) FT of normal donors (n=20) was 7,972.92 ± 3,092.8 dpm (disintegrations per minute, mean ± S.D.), whereas the activity in schizophrenic patients was 1,714.0 ± 1,039.7 dpm (mean ± S.D) . Hence, it has been shown that the activity of α-(l—3) FT of schizophrenic patients is strikingly lower than that of normal persons .

The activity of α- (1—»3) FT was determined in plasma samples of 17 normal donors and 26 schizophrenic patients in the presence of added ATP (0.2 μ mol) as described in detail in Example 2. The activity of - (1— >3 ) FT of normal donors was 10,523±3,323 dpm (mean±S.D.), while that of schizophrenic patients was 8,512+5,366 dpm (mean±S.D). Therefore, it has been shown that the activity of α-(l—3) FT of schizophrenic patients in the presence of added ATP (adenosine 5' triphosphate) increases by approximately 5- fold and also that the difference of activity of - (1—>3) FT between normal and schizophrenic patients in the presence of ATP was reduced from 6259 to 2011 dpm, which difference is not statistically significant.

Oral administration of the disodium salt of ATP (ATP-2Na) (60 to 360 mg per day per person) to schizophrenic patients reduced the total Brief Psychiatric Rating Scale (BPRS) and raised the α- (l->3) FT activity.

Accordingly, the invention provides the use in the treatment of schizophrenia of an agent that increases the activity of α- (1—3 ) -fucosyl transferase and also comprises a method of treatment of schizophrenia comprising administering an effective amount of such an agent to a schizophrenia patient.

Preferably, the agent that increases the activity of α- (1—3) -fucosyl transferase is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof. More preferably the inhibitor is an adenosine phosphate for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof.

The main substrates for α- (1—»3 ) -fucosyl transferase are GDP-fucose and N-acetylglucosamine or glucose (alternative synthetic substrates have been described, see for example Madiyalakan et al Analytical Biochemistry 152 , 22-28 (1986)). A second fate for GDP-fucose in the body is its hydrolysis by a GDP-fucose hydrolase. It has now been found that it is possible to inhibit the hydrolase enzyme and that such inhibition leads to an amelioration of the symptoms of schizophrenia.

Accordingly, the invention provides the use of an inhibitor of GDP-fucose hydrolase in the treatment of schizophrenia and also a method of treatment of schizophrenia comprising administering an effective amount of an inhibitor of GDP-fucose hydrolase to a schizophrenia patient. Preferably, the inhibitor of GDP-fucose is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof. More preferably the inhibitor is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof. As indicated above, the activity of α- (1—»3) FT of schizophrenic patients is strikingly lower than that of normal persons. Accordingly, the invention provides a method of diagnosing schizophrenia in a human subject which comprises determining in vi tro the activity level of α- (l-»3) -fucosyl transferase in a sample of a body fluid or tissue of the subject, generally a sample of blood, plasma or serum, and comparing the activity level with that of positive and negative controls to make a diagnosis, a level lower than that of negative controls being indicative of schizophrenia .

Positive controls are obtained from patients diagnosed by other methods as having schizophrenia. Negative controls include samples obtained from humans who do not have schizophrenia.

The diagnostic method of the invention may also be used predict which subjects are likely to respond to treatment according to the present invention. For example, the diagnostic method may be used to screen subjects for suitability for treatment according to the invention. The subjects may be patients already diagnosed as suffering from schizophrenia, which patients may not be responding to their current treatment or may be requiring a change in treatment for any reason. Alternatively, subjects may be simultaneously diagnosed as schizophrenic and screened for suitability for treatment according to the present invention. Methods for determining the level of α- (l—»3) -fucosyl transferase are known in the art (see for example that described in Madiyalakan et al Analytical Biochemistry 152, 22-28 (1986)), and methods of assay design are well known. An immunosorbent assay, a radioactivity-, luminescence- or fluorescence-based assay may be used. Preferably the assay is a radioactivity-based assay. A suitable acceptor for the fucose should be provided, for example, glucose or N-acetylglucosamine . Fucose or an appropriate analogue or derivative thereof should be provided, preferably in labelled form. Radiolabelled fucose may be used.

In a preferred embodiment, the activity of α- (1— >3 ) - fucosyl transferase is determined by assessing the transfer of radioactively-labelled GDP-fucose to 2-acetamido-2- deoxy-4-0- (2-0-methyl-β-D-galactopyranosyl) -D-glucopyranose

(N-acetyl-2 ' -O-methyllactosamine) . A suitable assay has been described by Madiyalakan et al . (Analytical Biochemistry, 1986, Vol. 152, 22-28). The synthesis of

(N-acetyl-2 ' -O-methyllactosamine) is also described in that paper.

The present invention further provides a pharmaceutical preparation comprising a therapeutically effective amount of an agent that increases the metabolism of GDP-fucose by α- (l-3) -fucosyl transferase and/or a therapeutically effective amount of an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase, for example, an inhibitor therof, in admixture or conjunction with a pharmaceutically suitable carrier therefor.

Preferably the agent that increases the metabolism of GDP-fucose by α- (1—3 ) -fucosyl transferase is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt. More preferably the agent is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof, for example the disodium salt of ATP.

Preferably the agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt . More preferably the agent is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or

The present invention further provides a pharmaceutical preparation comprising a therapeutically effective amount of an agent that increases the activity of α- (1—3) -fucosyl transferase, in admixture or conjunction with a pharmaceutically suitable carrier therefor.

Preferably, the agent that increases the activity of α- (1—»3) -fucosyl transferase is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof. More preferably the inhibitor is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof .

The medicaments and pharmaceutical preparations of the present invention may be in a form suitable for enteral administration, for example, oral or rectal administration, or for parenteral administration, for example, for percutaneous, permucous or sublingual administration, or for injection or infusion, for example, for intravenous or intramuscular injection or intravenous infusion. A medicament or pharaceutical preparation of the invention may be, for example, in the form of tablets, dragees, sachets, capsules, syrups, drinkable solutions, suspensions or emulsions, or injectable or infusible suspensions or solutions. A medicament or pharaceutical preparation of the invention may be in a controlled release form.

The active ingredient may generally be used in an amount of more than 10 mg per day, for example, more than 20 mg per day, for example, in an amount of at least 50 mg per day. Generally, the active ingredient may be used in amount of less than 1000 mg per day, for example, less than 800 mg per day, for example, in an amount of less than 600 mg per day. The amount may be, for example, in the range of from 50 mg per day to 500 or 600 mg per day. Examples of daily doses within that range are 60 mg, 120 mg, 180 mg, 240 mg, 300 mg and 360 mg. The daily dosage may conveniently be given in divided doses, for example two, three, four or five times per day.

Brief description of the Figures:

Figure 1. Scatter-graphs showing the α- (1—3-fucosyl transferase activity of plasma samples from schizophrenic patients and healthy controls (a) in the absence of ATP. (b) in the presence of ATP (0.2 μmol) . (DPM = disintegrations per minute.)

Figure 2. Graphs showing the inhibition of GDP-fucose hydrolase by 0.2 μmol adenosine phosphate ester (AMP, ADP and ATP) . pmol/ml/h = pico mol per ml per hour.

Figure 3. Graph showing the activity of GDP-fucose hydrolase in the presence of ATP (0.2, 0.5 and 1.0 μmol) .

Figure 4. Graph showing the α (1—3) -fucosyl transferase activity in plasma samples from schizophrenic patients before and after oral administration of ATP-2Na.

The following non-limiting Examples illustrate the invention.

EXAMPLES ;

Example 1 - Comparison of the activity of α- (1—3) -fucosyl transferase in the plasma of normal and schizophrenic subjects

Plasma was prepared from blood of 35 schizophrenic patients and 20 normal donors using a standard protocol. The activity of α- (1— >3 ) -fucosyl transferase was determined using the following protocol:

A reaction mixture was prepared by combining plasma (10 μl), HEPES-NaOH buffer (pH7.0) (10 μl of a 4 μmol / 10 μl solution), MnCl₂ (10 μl of a 1 μmol / 10 μl solution), sugar acceptor N-acetyl-2 ' -O-methyllactosamine (10 μl of a 10 n ol / 10 μl solution) and sugar donor GDP- [³H] fucose (10 μl of a 78,000 dpm / lOμl solution). The reaction mixture was left to stand for 16 hours at 37°C. Then ethanol (100 μl) was added to the reaction mixture. The sample was then centrifuged at 10,000 rpm for 15 minutes.

The product was separated from the reaction solution by passing through a Sep-Pak Plas C18 column (Waters Co) and eluting with water. The radioactivity was determined by addition of ACS II scintillation fluid and counting in a liquid scintillation counter (Beckman LS6000TA) . The number of disintegrations per minute represents the activity of α- (1—3) -fucosyl transferase. The results are shown in Fig 1 (a) .

The activity of α- (l-3) -fucosyl transferase of normal donors (n=20) was 7,972.92+3,092.8 dpm (disintegrations per minute, mean+S.D.), while that of schizophrenic patients was 1,714.0+1,039.7 dpm (mean+S.D.). The activity of α- (1—>3) -fucosyl transferase of schizophrenic patients is significantly lower than that of normal persons .

Example 2 - Comparison of the activity of - (1—»3) -fucosyl transferase in the plasma of normal and schizophrenic subjects in the presence of ATP The protocol of Example 1 was carried out using plasma from 14 normal donors and 26 schizophrenia patients with the addition of ATP (0.2 μmol) . The results are shown in Fig 1 (b) .

The activity of α- (1—3) -fucosyl transferase of normal donors was 10,523+3,323 dpm (mean+S.D.), while that of schizophrenic patients was 8,512+5,366 dpm (mean+S.D.). Hence, the activity of α- (1—3) -fucosyl transferase of schizophrenic patients in the presence of ATP (adenosine 5' triphosphate) increased by approximately 5- fold. The difference of activity α- (l-3) -fucosyl transferase between normal and schizophrenic patients in the presence of ATP was reduced from 6259 to 2011 dpm, and was no longer statistically significant.

Example 3 - Inhibition of GDP-fucose hydrolase by adenosine phosphates

The reaction mixture was prepared by mixing together plasma (from patients with schizophrenia) (10 μl) , HEPES- NaOH Buffer (pH 7.0) (10 μl of a 4μmol / 10 μl solution), MnCl₂ (10 μl of a 1 μmol / 10 μl solution), GDP- [³H] fucose + GDP-fucose (10 μl of a 10 μmol / 10 μl solution) .

To this mixture was added vehicle, adenosine phosphate ester AMP (adenosine monophosphate) , ADP (adenosine 5 ' -diphosphate) or ATP (adenosine 5'- triphosphate) (10 μl of a 0.2 μmol / 10 μl solution in each case) . The reaction mixture was left to stand for 2 hours at 37°C. Then ethanol (100 μl) was added to the reaction mixture and the mixture was centrifuged at 10000 rpm. The product in the reaction solution ( [³H] fucose) was separated from the reaction mixture by paper chromatography. The radioactivity was measured by addition of ACS II scintillation fluid and coating in a liquid scintillation counter (Beckman LS6000TA) to determine the activity of hydrolase. The results are shown in Fig 2.

The hydrolase activity of GDP-fucose in plasma of schizophrenic patients was inhibited by either AMP, ADP or ATP.

Example 4 - Dose dependence of inhibition of GDP-fucose hydrolase by ATP

The dose dependence of GDP-fucose inhibition by ATP was investigated using the protocol of Example 3 with the addition of ATP at levels of 0.2, 0.5 and 1.0 μmol.

The result of this experiment is shown in Figure 3. A clear dose dependence is observed.

Example 5 - Treatment of Schizophrenic patients with 60 mg / day oral ATP-2Na

Five patients with an ICD-10 diagnosis (International Classification of Disease 10^th Ed.) of schizophrenia were given 20 mg of ATP-2Na (ATP disodium salt) three times per day (total 60 mg daily) for 6 weeks. Measures of clinical psychiatric changes were quantified by the total Brief Psychiatric Rating Scale (BPRS) . After 6 weeks of treatment, 3 of 5 schizophrenic patients showed a reduction in total BPRS score and 2 had a rise in α- (1—3) fucosyl transferase activity as shown in Table 1 and Fig 4.

Example 6 - Treatment of schizophrenic patients with 180 mg per day of ATP-2Na

Five patients with an ICD-10 diagnosis of schizophrenia were given 60 mg of ATP-2Na three times per day (total 180 mg daily) for 4 weeks. Two of the five patients showed a reduction of total BPRS score following treatment. No patient developed any adverse side effects.

Example 7 - Treatment of schizophrenic patients with 360 mg per day of ATP-2Na.

Five patients with an ICD-10 diagnosis of schizophrenia were given 120 mg of ATP-2Na three times per day (total 360 mg daily) for 4 weeks. Four of the five patients showed a reduction of total BPRS score following treatment. No patient developed any adverse side effects. Table 1

I

Claims

CLAIMS :

1. Use of an agent that increases the metabolism of GDP-fucose by α- (1—3 ) -fucosyl transferase in schizophrenic patients and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase in the manufacture of a medicament for the treatment of schizophrenia.

2. Use as claimed in claim 1 wherein the agent that increases the metabolism of GDP-fucose by α-(l-»3) fucosyl transferase is a nucleotide, a nucleotide analogue or a nucleotide derivative, or is a salt thereof.

3. Use as claimed in claim 1, wherein the agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase is a GDP-fucose hydrolase inhibitor.

4. Use as claimed in claim 3, wherein the GDP-fucose hydrolase inhibitor is a nucleotide, a nucleotide analogue or a nucleotide derivative, or is a salt thereof.

5. Use as claimed in claim 2 or claim 4, wherein the agent is a nucleotide phosphate, a nucleotide analogue phosphate, or is a salt thereof.

6. Use as claimed in claim 5, wherein the nucleotide phosphate is an adenosine phosphate, or is a salt thereof.

7. Use as claimed in claim 6, wherein the adenosine phosphate is ADP or AMP, or is a salt thereof.

8. Use as claimed in claim 6, wherein the adenosine phosphate is ATP or a salt thereof.

9. Use as claimed in claim 1, wherein the agent that increases the metabolism of GDP-fucose by α-(l-3)- fucosyl transferase in schizophrenic patients is an agent that decreases the metabolism of GDP-fucose by an enzyme other than α- (1—»3 ) -fucosyl transferase in schizophrenic patients .

10. Use as claimed in claim 9, wherein the agent is an inhibitor of a GDP-fucose-metabolising enzyme other than α- (1—3) -fucosyl transferase.

11. Use as claimed in claim 10, wherein the agent is an inhibitor of GDP-fucose hydrolase.

12. Use as claimed in claim 11, wherein the GDP-fucose hydrolase inhibitor is as defined in any one of claims 4 to

13. A method of treatment of schizophrenia, which comprises administering to a human schizophrenia patient an effective amount of an agent that increases the metabolism of GDP-fucose by α- (1—»3) -fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP- fucose hydrolase.

14. A method as claimed in claim 13, wherein the agent is as defined in any one of claims 2 to 12.

15. A method of diagnosing schizophrenia in a human subject which comprises determining in vi tro the activity level of α- (1—»3) -fucosyl transferase in a sample of a body fluid or tissue of the subject and comparing the activity level with that of positive and negative controls to make a diagnosis .

16. A method as claimed in claim 15, which comprises determining the rate of transfer of GDP-fucose or an analogue or a derivative thereof to a sugar acceptor.

17. A method as claimed in claim 16, wherein the GDP-fucose or analogue or derivative thereof is labelled.

18. A method as claimed in claim 16 or claim 17, wherein the GDP-fucose or analogue or derivative thereof is radioactively labelled.

19. A method as claimed in any one of claims 16 to 18, wherein the sugar acceptor is 2-acetamido-2-deoxy-4-0- (2-0- methyl-β-D-galactopyranosyl) -D-glucopyranose .

20. A diagnostic kit that comprises GDP-fucose or an analogueor a derivative thereof and a sugar acceptor.

21. An inhibitor of GDP-fucose hydrolase for use in the treatment of schizophrenia.

22. An inhibitor of GDP-fucose hydrolase as claimed in claim 21 wherein the inhibitor is as defined in any one of claims 4 to 8.

23. An agent that increases the metabolism of GDP-fucose by α- (l-»3) -fucosyl transferase in schizophrenic patients and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase in schizophrenic patients for use in the treatment of schizophrenia.

24. An agent that increases the metabolism of GDP-fucose by α- (1—»3) -fucosyl transferase in schizophrenic patients and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase in schizophrenic patients for use in the treatment of schizophrenia as claimed in claim 23 wherein the agent is as defined in any one of claims 2 to 12.

25. A pharmaceutical preparation comprising an agent that increases the metabolism of GDP-fucose by α- (1—3) -fucosyl transferase in schizophrenic patients and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase .

26. A pharmaceutical preparation as claimed in claim 25 wherein the agent that increases the metabolism of GDP-fucose by α- (1—»3) -fucosyl transferase is as defined in any one of claims 2 or 5 to 11.

27. A pharmaceutical preparation as claimed in claim 25 wherein the agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase is as defined in any one of claims 2 or 5 to 8.

28. A pharmaceutical preparation comprising an inhibitor of GDP-fucose hydrolase and a pharmaceutically acceptable carrier.

29. A pharmaceutical preparation as claimed in claim 28 wherein the inhibitor is as defined in any one of claims 4 to 8.