METHOD FOR DIAGNOSING INTERSTITIAL CYSTITIS

Abstract

A method for diagnosing interstitial cystitis includes measuring at least any one kind of lysophosphatidylcholine. A system and program for diagnosing a possibility of interstitial cystitis or bladder pain syndrome is also provided.

Claims

1-23. (canceled)

24. A method for diagnosing interstitial cystitis, the method comprising measuring at least any one kind of lysophosphatidylcholine.

25. The method according to claim 24, wherein the method comprises measuring any one or more of 1-myristoyl-glycerophosphocholine, 2-myristoyl-glycerophosphocholine, 1-myristoleoylglycerophosphocholine, 1-oleoyl-glycerophosphocholine, 1-linoleoyl-glycerophosphocholine, 2-linoleoyl-glycerophosphocholine, 1-linolenoyl-glycerophosphocholine, 2-linolenoyl-glycerophosphocholine, and 1-eicosadienoyl-glycerophosphocholine.

26. The method according to claim 24, wherein the method comprises measuring any one or more of 1-linoleoyl-glycerophosphocholine, 2-linoleoyl-glycerophosphocholine, 1-linolenoyl-glycerophosphocholine, and 2-linolenoyl-glycerophosphocholine.

27. The method according to claim 24, wherein the measuring is a measurement by chromatography-mass spectrometry.

28. The method according to claim 24, comprising measuring a ratio of 1-linoleoylglycerophosphocholine to phospholipid in blood, serum, or plasma.

29. A system, the system configured to: receive an input of a value obtained from a content of at least any one kind of lysophosphatidylcholine included in the blood, serum, or plasma; compare a predetermined threshold with the input value; and determine whether the input value is higher or lower than the predetermined threshold, wherein the predetermined threshold is a value for diagnosing a possibility of interstitial cystitis or bladder pain syndrome.

30. The system according to claim 29, wherein the system is configured to: receive an input of a value obtained from a content of at least any one of 1-myristoyl-glycerophosphocholine, 2-myristoyl-glycerophosphocholine, 1-myristoleoylglycerophosphocholine, 1-oleoyl-glycerophosphocholine, 1-linoleoyl-glycerophosphocholine, 2-linoleoyl-glycerophosphocholine, 1-linolenoyl-glycerophosphocholine, 2-linolenoyl-glycerophosphocholine, and 1-eicosadienoyl-glycerophosphocholine included in the blood, serum, or plasma; compare a predetermined threshold with the input value; and determine whether the input value is higher or lower than the predetermined threshold, wherein the predetermined threshold is a value for diagnosing a possibility of interstitial cystitis or bladder pain syndrome.

31. The system according to claim 30, wherein an indicator of a possibility of interstitial cystitis or bladder pain syndrome is a value obtained from a content of 1-linoleoylglycerophosphocholine.

32. The system according to claim 29, wherein an indicator of a possibility of interstitial cystitis or bladder pain syndrome is a ratio of 1-linoleoylglycerophosphocholine to phospho lipid.

33. The system according to claim 29, wherein the system is configured to determine a possibility of interstitial cystitis or bladder pain syndrome in stages with a plurality of thresholds.

34. A program for a computer, wherein the program is configured to control the computer to: receive a value obtained from a content of at least any one kind of lysophosphatidylcholine included in the blood, serum, or plasma, and a predetermined threshold; compare the predetermined threshold with the value; and determine whether the value is higher or lower than the predetermined threshold, wherein the predetermined threshold is a value for diagnosing a possibility of interstitial cystitis or bladder pain syndrome.

35. The program according to claim 34, wherein the program is configured to control the computer to: receive a value obtained from a content of at least any one kind of 1-myristoyl-glycerophosphocholine, 2-myristoyl-glycerophosphocholine, 1-myristoleoylglycerophosphocholine, 1-oleoyl-glycerophosphocholine, 1-linoleoyl-glycerophosphocholine, 2-linoleoyl-glycerophosphocholine, 1-linolenoyl-glycerophosphocholine, 2-linolenoyl-glycerophosphocholine, and 1-eicosadienoyl-glycerophosphocholine included in the blood, serum, or plasma, and a predetermined threshold; compare the predetermined threshold with the value; and determine whether the value is higher or lower than the predetermined threshold, wherein the predetermined threshold is a value for diagnosing a possibility of interstitial cystitis or bladder pain syndrome.

36. The program according to claim 34, wherein an indicator of a possibility of interstitial cystitis or bladder pain syndrome is a value obtained from the content of 1-linoleoylglycerophosphocholine.

37. The program according to claim 34, wherein an indicator of possibility of interstitial cystitis or bladder pain syndrome is a value of a ratio of 1-linoleoylglycerophosphocholine to phospholipid.

38. The program according to claim 34, wherein the program is configured to determine a possibility of interstitial cystitis or bladder pain syndrome in stages with a plurality of thresholds.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In the drawings:

[0020] FIG. 1 is a plot of the content of 1-linoleoylglycerophosphocholine in the blood (μg/mL) in 25 healthy subjects and 25 patients with interstitial cystitis with Hunner lesion;

[0021] FIG. 2 is a plot of an ROC curve for the data of FIG. 1;

[0022] FIG. 3 is a plot of a comparison of the healthy subjects and patients with interstitial cystitis with Hunner lesion of FIG. 1 compared by age and shows an example of the cutoff value in which the sensitivity and the specificity are balanced;

[0023] FIG. 4 is a plot of the ratio (weight ratio) of 1-linoleoylglycerophosphocholine to phospholipid for 25 healthy subjects and 25 patients with interstitial cystitis with Hunner lesion;

[0024] FIG. 5 is a plot of an ROC curve for the data of FIG. 4; and

[0025] FIG. 6 is a plot of a comparison of the healthy subjects and patients with interstitial cystitis with Hunner lesion of FIG. 4 compared by age and shows an example of the cutoff value in which both the sensitivity and the specificity are balanced.

ADVANTAGEOUS EFFECTS OF INVENTION

[0026] The present invention enables an objective, simple and clear diagnosis or determination of interstitial cystitis to be made. Therefore, the present invention is useful not only for initial screening, early diagnosis, and early start of treatment, but also for development of therapeutic agents for interstitial cystitis. In diagnosis, the present invention is also easily combined with symptoms, cystoscopic findings, denial of other similar diseases, and the like. Thus, the present invention is useful in helping patients with interstitial cystitis who are overlooked.

DESCRIPTION OF EMBODIMENTS

[0027] The sensitivity and specificity, likelihood ratio, P-value, and content (increase/decrease relative to that of healthy subjects) of each substance for interstitial cystitis, as determined by liquid chromatography-mass spectrometry, are shown in the following Tables, and all of them have been demonstrated to be useful for diagnosis (population (blood): 10 healthy subjects and 20 patients with interstitial cystitis).

TABLE-US-00001 TABLE 1 LPC: Relative to lysophosphatidylcholine SE SP LI P-value healthy subject 1-myristoyl-GPC (14:0) 1-myristoyl- 55 90 5.5 0.0073 Reduce glycerophosphocholine 2-myristoyl-GPC (14:0) 2-myristoyl- 60 90 5.5 0.0122 Reduce glycerophosphocholine 1-myristoleoyl 1-myristoleoyl 60 90 6 0.0197 Reduce glycerophosphocholine glycerophosphocholine (14:1) 1-oleoyl-GPC (18:1) 1-oleoyl- 70 90 7 0.0024 Reduce glycerophosphocholine 1-linoleoyl-GPC (18:2) 1-linoleoyl- 75 90 7.5 0.0024 Reduce glycerophosphocholine 2-linoleoyl-GPC (18:2) 2-linoleoyl- 75 90 7.5 0.0013 Reduce glycerophosphocholine 1-linolenoyl- 1-linolenoyl- 80 90 8 0.0007 Reduce glycerophosphocholine glycerophosphocholine (18:3n3) 2-linolenoyl- 2-linolenoyl- 70 90 7 0.0083 Reduce glycerophosphocholine glycerophosphocholine (18:3n3) 1-eicosadienoyl-GPC (20:2) 1-eicosadienoyl- 55 90 5.5 0.0028 Reduce glycerophosphocholine SE = Sensitivity; SP = Specificity; LI = Likelihood (The same is true in the following Tables)

TABLE-US-00002 TABLE 2 P- Relative to γ-glutamyl amino acid SE SP LI value healthy subject gamma- γ-glutamylalanine 60 90 6 0.0073 Increase glutamylalanine gamma- γ-glutamyl glutamic 70 90 7 0.0021 Increase glutamylglutamate acid gamma- γ-glutamylglutamine 80 90 8 0.0007 Increase glutamylglutamine gamma- γ-glutamylhistidine 45 90 4.5 0.0823 Increase glutamylhistidine gamma- γ-glutamylisoleucine 70 90 7 0.0056 Increase glutamylisoleucine gamma- γ-glutamylleucine 60 90 6 0.0529 Increase glutamylleucine gamma- γ-glutamylmethionine 60 90 6 0.0042 Increase glutamylmethionine gamma- γ-glutamylthreonine 55 90 5.5 0.1405 Increase glutamylthreonine gamma- γ-glutamylvaline 80 90 8 0.0008 Increase glutamylvaline gamma-glutamyl-2- γ-glutamyl-2- 85 90 8.5 0.0006 Increase aminobutyrate aminobutyric acid

TABLE-US-00003 TABLE 3 MAG: Relative to Monoacylglycerol SE SP LI P-value healthy subject 1-linoleoylglycerol 1-linoleoylglycerol 60 90 6 0.0249 Increase (18:2) 1-linolenoylglycerol 1-linolenoylglycerol 45 90 4.5 0.1183 Increase 1-arachidonoylglycerol 1-arachidonoylglycerol 75 90 7.5 0.0028 Increase

TABLE-US-00004 TABLE 4 Relative to FFA: free fatty acid SE SP LI P-value healthy subject 10-heptadecenoate heptadecenoic acid 55 90 5.5 0.1036 Increase (17:1n7) oleate (18:1n9) oleic acid 40 90 4 0.1236 Increase vaccinate (18:1n7) vaccenic acid 40 90 4 0.1726 Increase 10-nonadecenoate nonadecenoate 60 90 6 0.1236 Increase (19:1n9) docosapentaenoate docosapentaenoic 45 90 4.5 0.1132 Increase (DPA: 22:5n3) acid docosahexaenoate docosahexaenoic 45 90 4.5 0.1036 Increase (DHA: 22:6n3) acid linoleate (18:2n6) linoleic acid 45 90 4.5 0.1466 Increase linolenate (18:3n3 or linolenic acid 45 90 4.5 0.1869 Increase 3n6) dihomolinolenate dihomolinolenic 50 90 5 0.1869 Increase (20:3n3 or 3n6) acid arachidonoate (20:4n6) arachidonic acid 60 90 6 0.0646 Increase docosapentaenoate docosapentaenoic 45 90 4.5 0.0784 Increase (n6 DPA: 22:5n6) acid dihomolinoleate dihomolinoleic acid 50 90 5 0.1466 Increase (20:2n6) propionylcarnitine (C3) propionylcarnitine 75 90 7.5 0.0073 Increase 3-hydroxybutyrate hydroxybutyric acid 50 90 5 0.0946 Increase (BHBA) 3-hydroxydecanoate hydroxydecanoic 70 90 7 0.0197 Increase acid 3-hydroxylaurate hydroxylaurate 65 90 6.5 0.0107 Increase

TABLE-US-00005 TABLE 5 LPE: Lysophosphatidyl- P- Relative to ethanolamine SE SP LI value healthy subject 1-margaroyl Margaroylglycero- 65 90 6.5 0.0008 Reduce Glycerophospho- phosphoethanolamine ethanolamine 1-oleoyl-GPE (18:1) 1-oleoyl-glycerophospho- 60 90 6 0.0122 Reduce ethanolamine 2-oleoyl-GPE (18:1) 2-oleoyl-glycerophospho- 65 90 6.5 0.0122 Reduce ethanolamine 1-linoleoyl-GPE (18:2) 1-linoleoyl-glycerophospho- 40 90 4 0.0138 Reduce ethanolamine 2-linoleoyl-GPE (18:2) 2-linoleoyl-glycerophospho- 50 90 5 0.0064 Reduce ethanolamine

[0028] In the above, 1-linoleoyl-glycerophosphocholine, 2-linoleoyl-glycerophosphocholine, 1-linolenoyl-glycerophosphocholine, 2-linolenoyl-glycerophosphocholine, 1-linoleoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, γ-glutamyl glutamic acid, γ-glutamylglutamine, γ-glutamylisoleucine, γ-glutamylvaline, γ-glutamyl-2-am inobutyric acid, 1-arachidonoylglycerol, and propionylcarnitine have sensitivity of 70% or more, specificity of 90% or more, likelihood ratio of 7 or more, and P value in the level of 1%, and are effective and further suitable for diagnosis for interstitial cystitis.

[0029] Furthermore, the contents of γ-glutamylisoleucine, 1-linoleoyl-glycerophosphocholine, and 1-arachidonoylglycerol in the blood in 5 patients with interstitial cystitis and 5 healthy subjects (see Table 6 below) were determined by high-performance chromatography-mass spectrometry.

TABLE-US-00006 TABLE 6 Interstitial cystitis Healthy subjects patient group group Hunner type: age 80 age: 22 Hunner type: age 42 age: 25 Hunner type: age 68 age: 22 Hunner type: age 67 age: 23 non-Hunner type: age 34 age: 25

[0030] The results are shown in the following Tables 7-9.

TABLE-US-00007 TABLE 7 γ-glutamylisoleucine [average ± standard deviation] Patient with Healthy 5 subjects interstitialcystitis subjects each 13.50 ± 4.50 9.974 ± 2.962 Unit: ng/mL

TABLE-US-00008 TABLE 8 1-linoleoylglycerophosphocholine [average ± standard deviation] Patient with Healthy 5 subjects interstitialcystitis subjects each 20020 ± 7008 30980 ± 9800 Unit: ng/mL

TABLE-US-00009 TABLE 9 1-arachidonoylglycerol [average ± standard deviation] Patient with Healthy 5 subjects interstitialcystitis subjects each 0.5456 ± 0.3383 0.2840 ± 0.1242 Unit: ng/mL

[0031] As mentioned above, the patients with interstitial cystitis have higher concentrations of γ-glutamylisoleucine and 1-arachidonoylglycerol in the blood and lower concentrations of 1-linoleoylglycerophosphocholine in the blood as compared with the healthy subjects. In addition, since 1-linoleoylglycerophosphocholine is overwhelmingly large in the detected amount per unit, it is assumed that linoleoylglycerophosphocholine is advantageous in cost and efficiency in the detection.

[0032] From the above results, the content of 1-linoleoylglycerophosphocholine in the blood (μg/mL) in 25 healthy subjects and 25 patients with interstitial cystitis with Hunner lesion were obtained and compared in order to seek the criteria for facilitating determination of interstitial cystitis (see FIG. 1). An ROC curve was also calculated (see FIG. 2).

[0033] Furthermore, both were compared by age. FIG. 3 shows an example of the cutoff value in which the sensitivity and the specificity are balanced.

[0034] As shown in FIGS. 1-3, the content of 1-linoleoylglycerophosphocholine can be one of the indicators for diagnosis. In other words, if the content of a predetermined cutoff value or less, it can be understood that interstitial cystitis is suspected. Therefore, when the content is used as an indicator at the initial stage determining the necessity of cystoscopy. From the above results, the cutoff value can be 20 or more and less than 40, but more preferably 25 to 35 from the viewpoint that the balance between the sensitivity and the specificity is desirable. For example, when the cutoff value is 40, the sensitivity is increased but the specificity is largely reduced.

[0035] In addition, based on the above findings, a possibility that examining the ratio with respect to phospholipid in subjects is useful was found, and experiments were carried out. Specifically, the ratio (weight ratio) of 1-linoleoylglycerophosphocholine to phospholipid was obtained for 25 healthy subjects and 25 patients with interstitial cystitis with Hunner lesion and compared (see FIG. 4). An ROC curve was also calculated (see FIG. 5).

[0036] In addition, both were compared by age. FIG. 6 shows an example of the cutoff value in which both the sensitivity and the specificity are balanced.

[0037] As shown above, when determination is carried out based on the ratio of 1-linoleoylglycerophosphocholine to phospholipid, it is found that that the indicator has higher sensitivity and specificity as compared with the case where determination is carried out using a simple substance of 1-linoleoylglycerophosphocholine as the indicator. The cutoff value seems to be desirably 10 or more and less than 20, and particularly desirably 15 or more and less than 16 in view of the balance between the sensitivity and specificity. When the cutoff value is, for example, 20, the sensitivity is increased, but the specificity is reduced.

[0038] Treatment strategies for interstitial cystitis vary widely depending on the presence or absence of Hunner lesion. Cystoscopy is necessary for the diagnosis of Hunner lesion, but it is important to accurately determine the need for it because of the psychological and physical burden on patients.

[0039] As mentioned above, the ratio of 1-linoleoylglycerophosphocholine to phospholipid can be an indicator (in particular, suspicion indicator) of “interstitial cystitis”. In addition, high sensitivity and specificity are achieved. In the current situation where the diagnosis of interstitial cystitis itself is not reached so often, the ratio is particularly useful as an early diagnostic indicator.

[0040] The present invention can be made as a system or a program using the above-mentioned compound or the indicator as a criterion. In other words, the present invention can be made as a system or a program having means for receiving an input of a value (one type or more values) obtained from a content of lysophospholipid, γ-glutamyl amino acid, monoacylglycerol, free fatty acid, or lysophosphatidylethanolamine included in the blood, serum, or plasma; comparing a predetermined threshold with the input value; and determining whether the input value is higher or lower than the predetermined threshold, wherein the predetermined value is a value applicable to diagnosis of interstitial cystitis. The threshold is not limited to a particular numerical value as long as it is a value useful as an indicator for diagnosis for interstitial cystitis, in view of interstitial cystitis and feature of the present invention, particularly, it is preferable to select a value useful as an indicator for initial diagnosis.

[0041] Specifically, when the content, for example (μg/mL), of the above-mentioned compounds, preferably 1-linoleoylglycerophosphocholine, and more preferably a ratio (weight ratio) of 1-linoleoylglycerophosphocholine to phospholipid in the blood, serum, or plasma of subjects, are measured, and the measured value is input, if the value is the predetermined threshold or less (threshold or more depending on compound), suspicion of interstitial cystitis is determined and output. In addition, it is also possible to configure a system or a program in which a plurality of values is provided and the values are in a predetermined range, the values are categorized in stages to output a possibility. Specifically, it is possible to employ a configuration in which a plurality of threshold values is provided, and the possibility is determined in stages. For example, in the case of 5 stages, the determination may be categorized from A (high) to E (low).