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WO1998005339A1 - Utilisation de l'acide ursodesoxycholique en cas d'infection par vih - Google Patents

Utilisation de l'acide ursodesoxycholique en cas d'infection par vih Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
use according
ursodeoxycholic acid
cyclodextrin
udca
hiv
Prior art date
Application number
PCT/EP1997/004325
Other languages
German (de)
English (en)
Inventor
Klaus-Ulrich Schentke
Dimo KÜRKTSCHIEV
Original Assignee
Dr. Falk Pharma Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Falk Pharma Gmbh filed Critical Dr. Falk Pharma Gmbh
Publication of WO1998005339A1 publication Critical patent/WO1998005339A1/fr

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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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une utilisation nouvelle de l'acide 3α-7β-dihydroxy-5β-cholique-24 (acide ursodésoxycholique, UDCA) ou de ses dérivés pour renforcer le système immunitaire de patients infectés par le VIH, ainsi que notamment pour prévenir et pour traiter des infections par le VIH.
PCT/EP1997/004325 1996-08-01 1997-07-29 Utilisation de l'acide ursodesoxycholique en cas d'infection par vih WO1998005339A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19631122.5 1996-08-01
DE1996131122 DE19631122A1 (de) 1996-08-01 1996-08-01 Verwendung von Ursodeoxycholsäure bei HIV-Infektion

Publications (1)

Publication Number Publication Date
WO1998005339A1 true WO1998005339A1 (fr) 1998-02-12

Family

ID=7801520

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004325 WO1998005339A1 (fr) 1996-08-01 1997-07-29 Utilisation de l'acide ursodesoxycholique en cas d'infection par vih

Country Status (2)

Country Link
DE (1) DE19631122A1 (fr)
WO (1) WO1998005339A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8706313D0 (en) * 1987-03-17 1987-04-23 Health Lab Service Board Treatment & prevention of viral infections
US5221669A (en) * 1991-04-19 1993-06-22 The United States Of America As Represented By The Department Of Health And Human Services Antiviral compositions containing α-cyclodextrin sulfates alone and in combination with other known antiviral agents and glucocorticoids and methods of treating viral infections

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
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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Publication number Publication date
DE19631122A1 (de) 1998-02-05

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