WO1998005339A1 - Use of ursodeoxycholic acid in hiv infection - Google Patents
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- WO1998005339A1 WO1998005339A1 PCT/EP1997/004325 EP9704325W WO9805339A1 WO 1998005339 A1 WO1998005339 A1 WO 1998005339A1 EP 9704325 W EP9704325 W EP 9704325W WO 9805339 A1 WO9805339 A1 WO 9805339A1
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- ursodeoxycholic acid
- cyclodextrin
- udca
- hiv
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- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title claims abstract description 48
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 14
- 208000031886 HIV Infections Diseases 0.000 title claims abstract description 10
- 208000037357 HIV infectious disease Diseases 0.000 title claims description 9
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 title claims description 9
- 210000000987 immune system Anatomy 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 24
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 claims description 19
- 238000002560 therapeutic procedure Methods 0.000 claims description 17
- 210000004698 lymphocyte Anatomy 0.000 claims description 16
- 210000004027 cell Anatomy 0.000 claims description 13
- 229920000858 Cyclodextrin Polymers 0.000 claims description 11
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 9
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 6
- 229960002656 didanosine Drugs 0.000 claims description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 6
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 5
- 229940124411 anti-hiv antiviral agent Drugs 0.000 claims description 5
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 4
- 229960002555 zidovudine Drugs 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 10
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 9
- 238000011282 treatment Methods 0.000 description 7
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 6
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 6
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 5
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 4
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 description 2
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- 229940064914 retrovir Drugs 0.000 description 2
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- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- GHCZAUBVMUEKKP-NHIHLBCISA-N 2-[[(4R)-4-[(3R,5S,7S,10S,13R,17R)-3,7-Dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]acetic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)C1C2C2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)CC1 GHCZAUBVMUEKKP-NHIHLBCISA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 208000015163 Biliary Tract disease Diseases 0.000 description 1
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 1
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 1
- 108010041397 CD4 Antigens Proteins 0.000 description 1
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
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- 210000001772 blood platelet Anatomy 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- 239000008845 cholagoga Substances 0.000 description 1
- 229940124571 cholagogue Drugs 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
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- 239000007938 effervescent tablet Substances 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- RUDATBOHQWOJDD-DNMBCGTGSA-N isoursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-DNMBCGTGSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000016332 liver symptom Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- GHCZAUBVMUEKKP-UHFFFAOYSA-N ursodeoxycholic acid glycine-conjugate Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)CC2 GHCZAUBVMUEKKP-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
Definitions
- the present invention relates to a new use of 3 ⁇ -7ß-dihydroxy-5ß-cholan-24-acid (ursodeoxycholic acid, UDCA) or derivatives thereof for improving the immune system in patients with HIV infection and in particular for prophylaxis, for the therapy of an HIV infection .
- UDCA ursodeoxycholic acid
- the infection process of the human immunodeficiency virus is initiated by an interaction of the outer coat protein gpl20 with the CD4 molecule expressed on lymphocytes, monocytes and macrophages.
- the outer coat protein gpl20 with the CD4 molecule expressed on lymphocytes, monocytes and macrophages.
- CD4-positive cells bind HIV, but are not necessarily infected. It has therefore been postulated that further host cell-specific factors are required which interact with the HIV coat protein in order to activate the fusion domain of the viral gp41 (Werner, A. AIDS Research (AIFO) 9th year, October 1994, volume 10).
- CD26 dipeptidyl peptidase IV
- the surface marker CD26 which is particularly expressed on T lymphocytes, is a dipeptidyl peptidase IV expressed on activated lymphocytes, which acts as a marker for interleukin-2-producing CD4 lymphocytes (Scholz W. (1986) "Association of IL-2 production with the expression of dipeptidyl-peptidase IV (DPIV) on human T lymphocytes "in Leukocyte Typing II (Reinherz, EL et al. eds.) Vol. 1: Human T lymphocytes, p. 489, Springer Verlag, New York).
- Ursodeoxycholic acid a natural bile acid that also occurs in human bile in a low concentration and acts as a cholagogue, is today the treatment of choice for primary biliary cirrhosis (PBC), because in many studies UDCA led to a reduction in symptoms and in almost everyone to a significant drop in laboratory parameters (Leuschner U. (1994), Internist, 35, 1147-1155).
- UDCA showed in initial studies a positive effect on liver symptoms and the associated pain in the upper abdominal area in AIDS-associated diseases of the biliary tract (cholangiopathies) (Chan, MF et al. , Gastrointest. Endoscopy., 40 (2, Pt. 2), 1994).
- the present invention relates to the use of ursodeoxycholic acid or derivatives thereof for the manufacture of a medicament for improving the immune system in patients with HIV infection and in particular for prophylaxis for the therapy of HIV infection.
- the values of CD26-positive cells, the absolute lymphocyte number and / or CD4-positive peripheral blood lymphocytes increase, and above all the values of CD26-positive cells and absolute lymphocyte number.
- Derivatives of ursodeoxycholic acid are, for example, iso-ursodeoxycholic acid and ursodeoxycholic acid conjugates such as tauro-ursodeoxycholic acid and glyco-ursodeoxycholic acid.
- the drug is preferably given orally.
- the daily doses are primarily around 5-20 mg / kg, preferably around 10 mg / kg body weight.
- suitable pharmaceuticals are UDCA capsules with 250 mg UDCA, UDCA tablets with 500 mg UDCA, UDCA suspensions with 500 mg UDCA / 5 ml, UDCA-cyclodextrin complex effervescent tablets with 500 mg UDCA and a tauro-ursodeoxycholic acid solution with 100 mg ' UDCA / 5 ml for intravenous use.
- UDCA can be administered together with cyclodextrin, in particular with a water-soluble cyclodextrin, especially with 2-hydroxypropyl- ⁇ -cyclodextrin (Vandelli et al. (1995) Int. J. Pharm., 118, 77 -83).
- a mixture of UDCA and cyclodextrin which results in a complex of UDCA and cyclodextrin.
- the molar ratio is in particular 1: 1.
- UDCA preferably as UDCA-cyclodextrin mixture
- one or more anti-HIV agents preferably azidothymidine (Retrovir 3) and / or dideoxyinosine (Videx ®) to administer.
- the present invention therefore also relates to a pharmaceutical composition which, in a separate or mixed unit dosage form UDCA, optionally together with cyclodextrin, preferably 2-hydroxypropyl- ⁇ -cyclodextrin as component A and one or more anti-HIV agents, preferably azidothymidine and / or dideoxyinosine , contains as component B.
- UDCA showed no side effects in the treatment of primary biliary cirrhosis over the course of 12 years (Leuschner U. (1994) J. Hepatol., 21, 624-633).
- ASAT alanine aminotransferase
- ALAT aspartate aminotransferase
- GGT Gammmaglutamyltranspeptidase
- the CD4-positive lymphocytes which ranged between 162 and 400 cells per ⁇ l in the preliminary examinations, were also determined.
- the expression of CD26 in peripheral blood lymphocytes was determined before, during and after therapy with UDCA.
- peripheral blood lymphocytes were isolated from whole blood by means of density gradient centrifugation and the CD26-positive cells were then determined by the method of Lojda ((Lojda, Z: (1977) Histoehernistry, 54, 299-309).
- Lojda Lojda, Z: (1977) Histoehernistry, 54, 299-309
- cytofluorimetric determinations on CD3, CD4, CD8, CD16, CD19, CD25 and CD26 were performed and the number of lymphocytes was determined, and the ongoing tests were carried out at monthly intervals.
- the determinations showed that the CD26 values of the patient PG (Table 1) during the four-month therapy with UDCA from 3 to 10%, the patient RH (Table 2) from 3 to 13% and the patient CJ (Table 3) of 2 rose to 16% and the patient's FR (Table 4) from 8 to 16%.
- the absolute lymphocyte count (Ly) also increased during therapy with UDCA in the patient PG (Table 1) from 0.5 * 10 6 to 3.6-10 6 , in the patient RH (Table 2) from 1.0 * 10 6 to 4.0 * 10 6 , in the patient CJ (Table 3) from 2.0'10 6 to 4.0 * 10 6 and in the patient FR (Table 4) from 0.8'10 6 to 2, 3- 10 6 .
- CD4-positive peripheral blood lymphocytes showed fluctuations, but after 4 months of therapy with UDCA they reached the highest values in all patients like never before (Table 1-4). After the therapy was discontinued, CD4-positive peripheral blood lymphocytes remained high in two patients (Tables 2 and 3) and dropped to the baseline values before therapy in two patients (Tables 1 and 4).
- peripheral blood lymphocytes increased 2-14-fold after therapy with UDCA. At the same time, the number of lymphocytes rose 2-4 times. The number of CD4-positive cells has increased slightly.
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
A new use is disclosed of 3α-7β-dihydroxy-5β-cholic-24 acid (ursodeoxycholic acid, UDCA) or its derivatives to improve the immune system of HIV-infected patients, as well as in particular for preventing and treating HIV infections.
Description
Verwendung von Ursodeoxycholsäure bei HIV-Infektion Use of ursodeoxycholic acid in HIV infection
Die vorliegende Erfindung betrifft eine neue Verwendung von 3α-7ß-Dihydroxy-5ß-cholan-24-säure (Ursodeoxycholsäure, UDCA) oder Derivaten davon zur Verbesserung des Immunsystems bei Patienten mit HIV-Infektion sowie insbesondere zur Prophylaxe, zur Therapie einer HIV-Infektion.The present invention relates to a new use of 3α-7ß-dihydroxy-5ß-cholan-24-acid (ursodeoxycholic acid, UDCA) or derivatives thereof for improving the immune system in patients with HIV infection and in particular for prophylaxis, for the therapy of an HIV infection .
Der Infektionsvorgang des Humanen Immundefizienzvirus (HIV) wird durch eine Interaktion des äußeren Hüllproteins gpl20 mit dem auf Lymphozyten, Monozyten und Makrophagen exprimierten CD4-Molekül eingeleitet. Allerdings ist diese Interaktion für eine erfolgreiche Infektion nicht ausreichend, da CD4-positive Zellen HIV binden, aber nicht zwangsläufig infiziert werden. Es wurde daher postuliert, daß weitere wirtszellspezifische Faktoren notwendig sind, die mit dem HIV-Hüllprotein interagieren, um die Fusionsdomäne des viralen gp41 zu aktivieren (Werner, A. AIDS-Forschung (AIFO) 9. Jahrgang, Oktober 1994, Heft 10).The infection process of the human immunodeficiency virus (HIV) is initiated by an interaction of the outer coat protein gpl20 with the CD4 molecule expressed on lymphocytes, monocytes and macrophages. However, this interaction is not sufficient for a successful infection, since CD4-positive cells bind HIV, but are not necessarily infected. It has therefore been postulated that further host cell-specific factors are required which interact with the HIV coat protein in order to activate the fusion domain of the viral gp41 (Werner, A. AIDS Research (AIFO) 9th year, October 1994, volume 10).
In einer weiteren Veröffentlichung wird diskutiert, daß die auf aktivierten Lymphozyten exprimierte Dipeptidylpeptidase IV (CD26) dieses seit langem gesuchte Molekül sein könnte (Callebaut, C. et al. (1993) Science, 262, 2045-2050). Interessanterweise wurde auch bei HlV-Infizierten eine verminderte Expression von CD26 festgestellt (Blazquez, M. V. et al. (1992) J. Im unol., 149(9), 3073-3077; Vanham, G. et al. (1993) J. of Acguired Immune Deficiency Syndromes, 6(7), 749-757). Nach Chal ers et al. (Chalmers, A. H. et al., (1990) Immunol. Cell Biol., 68, 81-85) kann CD26 als
Monitoring der klinischen Progression der HIV-Infektion verwendet werden.Another publication discusses that the dipeptidyl peptidase IV (CD26) expressed on activated lymphocytes could be this long-sought molecule (Callebaut, C. et al. (1993) Science, 262, 2045-2050). Interestingly, a reduced expression of CD26 was also found in HIV-infected people (Blazquez, MV et al. (1992) J. Im unol., 149 (9), 3073-3077; Vanham, G. et al. (1993) J. of Acguired Immune Deficiency Syndromes, 6 (7), 749-757). According to Chal ers et al. (Chalmers, AH et al., (1990) Immunol. Cell Biol., 68, 81-85) can CD26 as Monitoring the clinical progression of HIV infection can be used.
Der Oberflächeninarker CD26, der insbesondere auf T- Lymphocyten expri iert wird, ist eine auf aktivierten Lymphozyten expri ierte Dipeptidylpeptidase IV, die als ein Marker für Interleukin-2-produzierende CD4 Lymphozyten fungiert(Scholz W.(1986) "Assoziation of IL-2 production with the expression of dipeptidyl-peptidase IV (DPIV) on human T lymphocytes" in Leukocyte Typing II (Reinherz, E. L. et al. eds.) Vol. 1: Human T lymphocytes, S. 489, Springer Verlag, New York) .The surface marker CD26, which is particularly expressed on T lymphocytes, is a dipeptidyl peptidase IV expressed on activated lymphocytes, which acts as a marker for interleukin-2-producing CD4 lymphocytes (Scholz W. (1986) "Association of IL-2 production with the expression of dipeptidyl-peptidase IV (DPIV) on human T lymphocytes "in Leukocyte Typing II (Reinherz, EL et al. eds.) Vol. 1: Human T lymphocytes, p. 489, Springer Verlag, New York).
Unerwarteterweise wurde nun gefunden, daß bei Gabe von UDCA vor allem die Werte von CD26-positiven Zellen und absoluter Lymphozytenzahl wieder anstiegen und sich der Immunstatus von HlV-Infizierten insgesamt verbesserte.It has now been found, unexpectedly, that when UDCA was administered, the values of CD26-positive cells and the absolute number of lymphocytes in particular rose again and the immune status of HIV-infected persons improved overall.
Ursodeoxycholsäure, eine natürliche auch in der menschlichen Galle in geringer Konzentration vorkommende und als Cholagogum wirkende Gallensäure, gilt heute bei der primär bilären Leberzirrhose (PBC) als das Mittel der Wahl, denn in vielen Studien führte UDCA zu einem Nachlassen der Symptome und bei fast allen zu einem deutlichen Abfall der Laborpararaeter (Leuschner U.(1994), Internist, 35, 1147- 1155).Ursodeoxycholic acid, a natural bile acid that also occurs in human bile in a low concentration and acts as a cholagogue, is today the treatment of choice for primary biliary cirrhosis (PBC), because in many studies UDCA led to a reduction in symptoms and in almost everyone to a significant drop in laboratory parameters (Leuschner U. (1994), Internist, 35, 1147-1155).
Darüber hinaus fanden Kürktschiev et al. (1993) bei Patienten mit PBC, daß sich das Verhältnis CD4+ : CD8+ Zellen innerhalb der ersten 4 Wochen nach Beginn der UDCA-Therapie zugunsten der CD8-Suppressorzellen verschob. Da die CD26/Dipeptidylpeptidase IV-positiven primären Blutlymphozyten sowohl CD4+ als auch CD8+ T-Lymphozyten- Populationen angehören können, kann die Normalisierung einer verminderten inhibitorischen Funktion des Immunsystems bei der Therapie der primär biliären Zirrhose mit UDCA möglicherweise für einen günstigen therapeutischen Effekt mitverantwortlich sein (Kürktschiev, D. et al. (1993), Z.
Gastroenterol (Suppl. 2), 31, 104-105), obwohl die Relevanz dieser Befunde bisher ungeklärt ist.In addition, Kürktschiev et al. (1993) in patients with PBC that the CD4 +: CD8 + cell ratio shifted in favor of the CD8 suppressor cells within the first 4 weeks after the start of UDCA therapy. Since CD26 / dipeptidyl peptidase IV-positive primary blood lymphocytes can belong to both CD4 + and CD8 + T lymphocyte populations, the normalization of a reduced inhibitory function of the immune system in the treatment of primary biliary cirrhosis with UDCA may possibly be responsible for a favorable therapeutic effect ( Kürktschiev, D. et al. (1993), Z. Gastroenterol (Suppl. 2), 31, 104-105), although the relevance of these findings has not yet been clarified.
Ähnlich wie bei der PBC und anderen Lebererkrankungen mit cholestatischen Sy ptomen/Gallenflußstörungen zeigte UDCA in ersten Untersuchungen eine positive Wirkung auf die Lebersymptomatik und der damit verbundenen Schmerzzustände im oberen Abdominalbereich bei AIDS-assoziierten Erkrankungen der Gallenwege (Cholangiopathien) (Chan, M. F. et al., Gastrointest. Endoscopy. , 40 (2, Pt. 2), 1994).Similar to PBC and other liver diseases with cholestatic symptoms / bile flow disorders, UDCA showed in initial studies a positive effect on liver symptoms and the associated pain in the upper abdominal area in AIDS-associated diseases of the biliary tract (cholangiopathies) (Chan, MF et al. , Gastrointest. Endoscopy., 40 (2, Pt. 2), 1994).
Gegenstand der vorliegenden Erfindung ist die Verwendung von Ursodeoxycholsäure oder Derivaten davon zur Herstellung eines Arzneimittels zur Verbesserung des Immunsystems bei Patienten mit HIV-Infektion sowie insbesondere zur Prophylaxe zur Therapie einer HIV-Infektion. Insbesondere steigen die Werte von CD26-positiven Zellen, der absoluten Lymphozytenzahl und/oder CD4-positiven peripheren Blutlymphozyten, vor allem steigen die Werte von CD26-positiven Zellen und absoluter Lymphozytenzahl. Derivate der Ursodeoxycholsäure sind beispielsweise die Iso-Ursodeoxycholsäure und Ursodeoxycholsäure-Konjugate wie die Tauro-Ursodeoxycholsäure und die Glyko-Ursodeoxycholsäure.The present invention relates to the use of ursodeoxycholic acid or derivatives thereof for the manufacture of a medicament for improving the immune system in patients with HIV infection and in particular for prophylaxis for the therapy of HIV infection. In particular, the values of CD26-positive cells, the absolute lymphocyte number and / or CD4-positive peripheral blood lymphocytes increase, and above all the values of CD26-positive cells and absolute lymphocyte number. Derivatives of ursodeoxycholic acid are, for example, iso-ursodeoxycholic acid and ursodeoxycholic acid conjugates such as tauro-ursodeoxycholic acid and glyco-ursodeoxycholic acid.
Das Arzneimittel wird vorzugsweise oral gegeben. Die Tagesdosen liegen vor allem bei ca. 5-20 mg/kg, vorzugsweise bei ca. 10 mg/kg Körpergewicht. Als Arzneimittel eignen sich beispielsweise UDCA-Kapseln mit 250 mg UDCA, UDCA-Tabletten mit 500 mg UDCA, UDCA-Suspensionen mit 500 mg UDCA/5 ml, UDCA-Cyclodextrin-Komplex-Brausetabletten mit 500 mg UDCA und eine Tauro-Ursodeoxycholsäure-Lösung mit 100 mg'UDCA/5 ml zur intravenösen Anwendung.The drug is preferably given orally. The daily doses are primarily around 5-20 mg / kg, preferably around 10 mg / kg body weight. Examples of suitable pharmaceuticals are UDCA capsules with 250 mg UDCA, UDCA tablets with 500 mg UDCA, UDCA suspensions with 500 mg UDCA / 5 ml, UDCA-cyclodextrin complex effervescent tablets with 500 mg UDCA and a tauro-ursodeoxycholic acid solution with 100 mg ' UDCA / 5 ml for intravenous use.
Um die Bioverfügbarkeit von UDCA zu verbessern, kann man UDCA zusammen mit Cyclodextrin, insbesondere mit einem wasserlöslichen Cyclodextrin, vor allem mit 2-Hydroxypropyl- ß-cyclodextrin verabreichen (Vandelli et al. (1995) Int. J. Pharm., 118, 77-83). Vorzugsweise wird eine Mischung aus UDCA
und Cyclodextrin verabreicht, die zu einem Komplex aus UDCA und Cyclodextrin führt. Das molare Verhältnis liegt hierbei insbesondere bei 1:1.In order to improve the bioavailability of UDCA, UDCA can be administered together with cyclodextrin, in particular with a water-soluble cyclodextrin, especially with 2-hydroxypropyl-β-cyclodextrin (Vandelli et al. (1995) Int. J. Pharm., 118, 77 -83). Preferably a mixture of UDCA and cyclodextrin, which results in a complex of UDCA and cyclodextrin. The molar ratio is in particular 1: 1.
Bei der Behandlung von HIV-Patienten ist es auch vorteilhaft, UDCA, vorzugsweise als UDCA-Cyclodextrin-Mischung, getrennt oder gemischt mit einem oder mehreren Anti-HIV-Mitteln, vorzugsweise Azidothymidin (Retrovir3) und/oder Dideoxyinosin (Videx®) zu verabreichen. Die vorliegende Erfindung betrifft daher auch eine pharmazeutische Zusammensetzung, die in einer getrennten oder gemischten Einheitsdosierungsform UDCA gegebenenfalls zusammen mit Cyclodextrin, vorzugsweise 2- Hydroxypropyl-ß-cyclodextrin als Komponente A und ein oder mehrere Anti-HIV-Mittel, vorzugsweise Azidothymidin und/oder Dideoxyinosin, als Komponente B enthält.In the treatment of HIV patients, it is also advantageous to UDCA, preferably as UDCA-cyclodextrin mixture, separately or mixed with one or more anti-HIV agents, preferably azidothymidine (Retrovir 3) and / or dideoxyinosine (Videx ®) to administer. The present invention therefore also relates to a pharmaceutical composition which, in a separate or mixed unit dosage form UDCA, optionally together with cyclodextrin, preferably 2-hydroxypropyl-β-cyclodextrin as component A and one or more anti-HIV agents, preferably azidothymidine and / or dideoxyinosine , contains as component B.
Die Behandlung von HlV-Infizierten mit UDCA ist auch deshalb besonders vorteilhaft, weil UDCA bei der Behandlung von primärer biliärer Zirrhose im Laufe von 12 Jahren keine Nebenwirkungen zeigte (Leuschner U. (1994) J. Hepatol., 21, 624-633).The treatment of HIV-infected people with UDCA is also particularly advantageous because UDCA showed no side effects in the treatment of primary biliary cirrhosis over the course of 12 years (Leuschner U. (1994) J. Hepatol., 21, 624-633).
Die folgenden Beispiele sollen die Erfindung näher erläutern:The following examples are intended to illustrate the invention:
BeispieleExamples
Methoden:Methods:
In einer ersten Pilotstudie wurden vier junge, männliche Patienten aus der HIV-Ambulanz untersucht und nach Aufklärung und Einverständniserklärung mit UDCA behandelt. Die Dosis betrug 750 mg/Tag über eine Dauer von 4 Monaten. Die Patienten befanden sich in einer stabilen Krankheitsphase, wobei zwei Patienten z. Z. ohne medikamentöse Behandlung und zwei seit eineinhalb Jahren konstant Retrovir® und Videx® erhielten.In a first pilot study, four young, male patients from the HIV outpatient clinic were examined and treated with UDCA after being informed and giving their consent. The dose was 750 mg / day over a period of 4 months. The patients were in a stable phase of the disease, with two patients e.g. Currently without drug treatment and two have been receiving Retrovir ® and Videx ® consistently for one and a half years.
Laufend bestimmt wurden die Standardwerte zu Hämoglobin, Leukozyten, Thrombozyten, die Leberenzyrae ASAT (Alaninaminotransferase) , ALAT (Aspartataminotransferase) ,
GGT (Gammmaglutamyltranspeptidase) sowie die Cholestase- Parameter alkalische Phosphatase und Gesamt-Bilirubin. Ferner wurden die CD4-positiven Lymphozyten bestimmt, die sich bei den Voruntersuchungen zwischen 162 und 400 Zellen pro μl bewegten. Zudem wurde die Expression von CD26 bei den peripheren Blutlymphozyten vor, während und nach der Therapie mit UDCA bestimmt. Hierzu wurden die peripheren Blutlymphozyten mittels Dichtegradientenzentrifugation aus Vollblut isoliert und anschließend die CD26-positiven Zellen nach der Methode von Lojda ((Lojda, Z: (1977) Histoehernistry, 54, 299-309) bestimmt. Parallel dazu wurden auch zytofluorimetrische Bestimmungen zu CD3, CD4, CD8, CD16, CD19, CD25 und CD26 durchgeführt und die Lymphozytenzahl bestimmt. Die laufenden Untersuchungen wurden in monatlichen Intervallen durchgeführt.The standard values for hemoglobin, leukocytes, thrombocytes, the liver enzymes ASAT (alanine aminotransferase), ALAT (aspartate aminotransferase), GGT (Gammmaglutamyltranspeptidase) as well as the cholestase parameters alkaline phosphatase and total bilirubin. The CD4-positive lymphocytes, which ranged between 162 and 400 cells per μl in the preliminary examinations, were also determined. In addition, the expression of CD26 in peripheral blood lymphocytes was determined before, during and after therapy with UDCA. For this purpose, the peripheral blood lymphocytes were isolated from whole blood by means of density gradient centrifugation and the CD26-positive cells were then determined by the method of Lojda ((Lojda, Z: (1977) Histoehernistry, 54, 299-309). At the same time, cytofluorimetric determinations on CD3, CD4, CD8, CD16, CD19, CD25 and CD26 were performed and the number of lymphocytes was determined, and the ongoing tests were carried out at monthly intervals.
Ergebnisse:Results:
Die Bestimmungen zeigten, daß die CD26-Werte des Patienten P. G. (Tabelle 1) während der viermonatigen Therapie mit UDCA von 3 auf 10%, des Patienten R. H. (Tabelle 2) von 3 auf 13%, des Patienten C. J. (Tabelle 3) von 2 auf 16% und des Patienten F. R. (Tabelle 4) von 8 auf 16% anstiegen. Auch die absolute Lymphozytenzahl (Ly) stieg während der Therapie mit UDCA bei dem Patienten P. G. (Tabelle 1) von 0,5 *106 auf 3,6-106, bei dem Patienten R. H. (Tabelle 2) von 1,0*106 auf 4,0*106, bei dem Patienten C. J. (Tabelle 3) von 2,0'106 auf 4,0* 106 und bei dem Patienten F. R. (Tabelle 4) von 0,8'106 auf 2,3- 106.The determinations showed that the CD26 values of the patient PG (Table 1) during the four-month therapy with UDCA from 3 to 10%, the patient RH (Table 2) from 3 to 13% and the patient CJ (Table 3) of 2 rose to 16% and the patient's FR (Table 4) from 8 to 16%. The absolute lymphocyte count (Ly) also increased during therapy with UDCA in the patient PG (Table 1) from 0.5 * 10 6 to 3.6-10 6 , in the patient RH (Table 2) from 1.0 * 10 6 to 4.0 * 10 6 , in the patient CJ (Table 3) from 2.0'10 6 to 4.0 * 10 6 and in the patient FR (Table 4) from 0.8'10 6 to 2, 3- 10 6 .
Im Vergleich mit gesunden Probanten, bei denen die CD26 Expression bei 18-28% und die absolute Lymphozytenzahl bei 4,0-106 lag, war also bei den vier Patienten sowohl die CD26- Expression wie auch die absolute Lymphozytenzahl vor der UDCA-Behandlung deutlich abgesenkt. Während der Therapie mit UDCA stieg, wie oben bereits ausgeführt, der Anteil der CD26- positiven peripheren Blutlymphozyten an und lag nach 4 Monaten bei 10-16%. Die absolute Lymphozytenzahl hat sich in diesem Zeitraum bis zum Normbereich erhöht. Subjektiv haben
sich alle Patienten gut gefühlt. 6 Monate nach dem Therapieschluß war die CD26-Expression bei drei Patienten (Tabellen 1, 3 und 4) unverändert erhöht geblieben und bei einem Patienten (Tabelle 2) ist sie leicht abgefallen.In comparison with healthy test subjects, in which the CD26 expression was 18-28% and the absolute lymphocyte number 4.0-10 6 , the CD26 expression and the absolute lymphocyte number were before the UDCA treatment in the four patients significantly lowered. As already explained above, the proportion of CD26-positive peripheral blood lymphocytes increased during therapy with UDCA and was 10-16% after 4 months. The absolute number of lymphocytes has increased to the normal range during this period. Have subjective all patients felt good. 6 months after the end of therapy, CD26 expression remained unchanged in three patients (Tables 1, 3 and 4) and decreased slightly in one patient (Table 2).
Die CD4-positiven peripheren Blutlymphozyten zeigten Schwankungen, haben jedoch nach 4 Monaten Therapie mit UDCA bei allen Patienten die höchsten Werte erreicht wie nie zuvor (Tabelle 1-4). Nach dem Abbruch der Therapie sind die CD4- positiven peripheren Blutlymphozyten bei zwei Patienten hoch geblieben (Tabelle 2 und 3) und bei zwei Patienten bis auf die Ausgangswerte vor der Therapie abgefallen (Tabelle 1 und 4).The CD4-positive peripheral blood lymphocytes showed fluctuations, but after 4 months of therapy with UDCA they reached the highest values in all patients like never before (Table 1-4). After the therapy was discontinued, CD4-positive peripheral blood lymphocytes remained high in two patients (Tables 2 and 3) and dropped to the baseline values before therapy in two patients (Tables 1 and 4).
Die übrigen Laborparameter haben keine besonderen Abweichungen gezeigt.The other laboratory parameters showed no special deviations.
ZusammenfassungSummary
Die anfangs niedrige CD26-Expression der peripheren Blutlymphozyten steigerte sich nach Therapie mit UDCA um das 2-14fache. Gleichzeitig stiegen die Lymphozytenzahlen um das 2-4fache. Die Zahl der CD4-positiven Zellen hat sich leicht erhöht.
The initially low CD26 expression of peripheral blood lymphocytes increased 2-14-fold after therapy with UDCA. At the same time, the number of lymphocytes rose 2-4 times. The number of CD4-positive cells has increased slightly.
TABELLE 1 (Patient P.G.]TABLE 1 (patient P.G.]
TABELLE 2 (Patient R.H.)
- a -TABLE 2 (patient RH) - a -
4-4-
UDCA UDCA Therapiebeginn TherapieendeUDCA UDCA Start of therapy End of therapy
TABELLE 3 (Patient C.J.)TABLE 3 (patient C.J.)
TABELLE 4 (Patient F.R.)
TABLE 4 (patient F.R.)
Claims
1. Verwendung von 3α-7ß-Dihydroxy-5ß-cholan-24-säure (Ursodeoxycholsäure) oder Derivaten davon zur Herstellung eines Arzneimittels zur Verbesserung des Immunsystems bei Patienten mit HIV-Infektion sowie insbesondere zur Prophylaxe , zur Therapie einer HIV- Infektion.1. Use of 3α-7ß-dihydroxy-5ß-cholan-24-acid (ursodeoxycholic acid) or derivatives thereof for the manufacture of a medicament for improving the immune system in patients with HIV infection and in particular for prophylaxis, for the therapy of an HIV infection.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß bei der Verbesserung des Immunsystems die Werte von CD26-positiven Zellen, absoluter Lymphozytenzahl und/oder CD4-positiven peripheren Blutlymphozyten ansteigen.2. Use according to claim 1, characterized in that in the improvement of the immune system the values of CD26-positive cells, absolute lymphocyte count and / or CD4-positive peripheral blood lymphocytes increase.
3. Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß bei der Verbesserung des Immunsystems die Werte von CD26-positiven Zellen und absoluter Lymphozytenzahl ansteigen.3. Use according to claim 1 or 2, characterized in that in the improvement of the immune system, the values of CD26-positive cells and the absolute number of lymphocytes increase.
4. Verwendung nach einem der Ansprüche 1-3, dadurch gekennzeichnet, daß das Arzneimittel oral gegeben wird.4. Use according to any one of claims 1-3, characterized in that the medicament is given orally.
5. Verwendung nach einem der Ansprüche 1-4, dadurch gekennzeichnet, daß ca. 5-20 mg/kg/Tag an Ursodeoxycholsäure gegeben wird.5. Use according to any one of claims 1-4, characterized in that about 5-20 mg / kg / day is given to ursodeoxycholic acid.
6. Verwendung nach einem der Ansprüche 1-5, dadurch gekennzeichnet, daß die Ursodeoxycholsäure zusammen mit Cyclodextrin verabreicht wird.6. Use according to any one of claims 1-5, characterized in that the ursodeoxycholic acid is administered together with cyclodextrin.
7. Verwendung nach einem der Ansprüche 1-6, dadurch gekennzeichnet, daß die Ursodeoxycholsäure zusammen mit wasserlöslichem Cyclodextrin verabreicht wird. 7. Use according to any one of claims 1-6, characterized in that the ursodeoxycholic acid is administered together with water-soluble cyclodextrin.
8. Verwendung nach einem der Ansprüche 1-7, dadurch gekennzeichnet, daß die Ursodeoxycholsäure zusammen mit 2-Hydroxypropyl-ß-cyclodextrin verabreicht wird.8. Use according to any one of claims 1-7, characterized in that the ursodeoxycholic acid is administered together with 2-hydroxypropyl-ß-cyclodextrin.
9. Verwendung nach einem der Ansprüche 6-8, dadurch gekennzeichnet, daß eine Mischung von Ursodeoxycholsäure und Cyclodextrin verabreicht wird.9. Use according to any one of claims 6-8, characterized in that a mixture of ursodeoxycholic acid and cyclodextrin is administered.
10. Verwendung nach einem der Ansprüche 1-9, dadurch gekennzeichnet, daß das genannte Arzneimittel getrennt oder zusammen mit einem oder mehreren Anti-HIV-Mitteln gegeben wird.10. Use according to any one of claims 1-9, characterized in that said medicament is given separately or together with one or more anti-HIV agents.
11. Verwendung nach Anspruch 10, dadurch gekennzeichnet, daß die Anti-HIV-Mittel Azidothymidin und/oder Dideoxyinosin sind.11. Use according to claim 10, characterized in that the anti-HIV agents are azidothymidine and / or dideoxyinosine.
12. Pharmazeutische Zusammensetzung enthaltend in einer getrennten oder gemischten Einheitsdosierungsform Ursodeoxycholsäure gegebenenfalls zusammen mit Cyclodextrin, vorzugsweise 2-Hydroxypropyl-ß- cyclodextrin als Komponente A und ein oder mehrere Anti-HIV-Mittel, vorzugsweise Azidothymidin und/oder Dideoxyinosin, als Komponente B. 12. Pharmaceutical composition containing ursodeoxycholic acid in a separate or mixed unit dosage form, optionally together with cyclodextrin, preferably 2-hydroxypropyl-β-cyclodextrin as component A and one or more anti-HIV agents, preferably azidothymidine and / or dideoxyinosine, as component B.
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Non-Patent Citations (10)
Title |
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B.STROHMAIER: "5.Münchner AIDS-Tage: neue Hintergründe", PHARMAZEUTISCHE ZEITUNG, vol. 141, no. 14, April 1996 (1996-04-01), pages 69 - 71, XP002046176 * |
D. ADLER ET AL.: "Untersuchungen der Dipeptyl-Peptidase IV peripherer Blutlymphozyten bei Patienten mit primärer biliärer Zirrhose", Z.GASTROENTEROL., vol. 32, no. 2, February 1993 (1993-02-01), pages 135 - 139, XP002046175 * |
D.KÜRKTSCHIEV ET AL.: "Dipepridyl-Peptidase IV humaner Lymphozyten bei Patienten mit orimärer biliärer Zirrhose unter UDCA-Therapie", Z. GASTROENTEROL., vol. 31, no. suppl. 2, February 1993 (1993-02-01), pages 104 - 105, XP002046181 * |
D.KÜRKTSCHIEV ET AL.: "Immunomodulating effect of ursodeoxycholic acid therapy in patients with primary biliary cirrhosis", J.HEPATOL., vol. 18, no. 3, July 1993 (1993-07-01), pages 373 - 377, XP002046177 * |
H.BOUCHE ET AL.: "AIDS-related cholangitis: Diagnostic features and course in 15 patients", J.HEPATOL., vol. 17, no. 1, January 1993 (1993-01-01), pages 34 - 39, XP002046178 * |
I.SCOTINIOTIS ET AL.: "Hepatitis C: Diagnosis and Treatment", JOURNAL OF GENERAL INTERNAL MEDICINE, vol. 10, no. 5, May 1995 (1995-05-01), pages 273 - 282, XP002046183 * |
J.A.NASH ET AL.: "GALLBLADDER AND BILIARY TRACT DISEASE IN AIDS", GASTROENTEROLOGY CLINICS OF NORTH AMERICA, vol. 26, no. 2, June 1997 (1997-06-01), pages 323 - 335, XP002046180 * |
L. QUÉRÉ ET AL.: "Triterpenes as Potential Dimerization Inhibitors of HIV-1 Protease", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 227, no. 2, 14 October 1996 (1996-10-14), pages 484 - 488, XP002046174 * |
M.BABA ET AL.: "Selective Activity of Several Cholic Acid Derivatives Against Human Immunodeficiency Virus Replication In Vitro", J.ACQUIRED IMMUNE DEFIC. SYNDR., vol. 2, no. 3, June 1989 (1989-06-01), pages 264 - 271, XP002046179 * |
M.YOSHIKAWA ET AL.: "Effects of ursodeoxycholic acid on target apoptosis induced by an antigen-specific CD4+-T cell line", INTERNATIONAL HEPATOLOGY COMMUNICATIONS, vol. 4, no. 5, February 1996 (1996-02-01), pages 268 - 276, XP002046182 * |
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