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WO1998005339A1 - Use of ursodeoxycholic acid in hiv infection - Google Patents

Use of ursodeoxycholic acid in hiv infection Download PDF

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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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use according
ursodeoxycholic acid
cyclodextrin
udca
hiv
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PCT/EP1997/004325
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German (de)
French (fr)
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Klaus-Ulrich Schentke
Dimo KÜRKTSCHIEV
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Dr. Falk Pharma Gmbh
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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
    • A61K31/56—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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  • Pharmacology & Pharmacy (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.
Figure imgf000009_0001
Figure imgf000009_0001
TABELLE 1 (Patient P.G.]TABLE 1 (patient P.G.]
Figure imgf000009_0002
Figure imgf000009_0002
Figure imgf000009_0003
Figure imgf000009_0003
TABELLE 2 (Patient R.H.) - a -TABLE 2 (patient RH) - a -
Figure imgf000010_0001
Figure imgf000010_0001
4-4-
UDCA UDCA Therapiebeginn TherapieendeUDCA UDCA Start of therapy End of therapy
TABELLE 3 (Patient C.J.)TABLE 3 (patient C.J.)
Figure imgf000010_0002
Therapiebeginn Therapieende
Figure imgf000010_0002
Start of therapy End of therapy
TABELLE 4 (Patient F.R.) TABLE 4 (patient F.R.)

Claims

Patentansprüche 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.
PCT/EP1997/004325 1996-08-01 1997-07-29 Use of ursodeoxycholic acid in hiv infection WO1998005339A1 (en)

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