EP1146882A2 - Therapie combinee pour le traitement des infections dues au vif - Google Patents

Therapie combinee pour le traitement des infections dues au vif

Info

Publication number
EP1146882A2
EP1146882A2 EP99926027A EP99926027A EP1146882A2 EP 1146882 A2 EP1146882 A2 EP 1146882A2 EP 99926027 A EP99926027 A EP 99926027A EP 99926027 A EP99926027 A EP 99926027A EP 1146882 A2 EP1146882 A2 EP 1146882A2
Authority
EP
European Patent Office
Prior art keywords
fiv
azt
cats
combination
treatment
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99926027A
Other languages
German (de)
English (en)
Inventor
Ben M. Dunn
Janet K. Yamamoto
Maki Arai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ARAI, MAKI
DUNN, BEN M.
YAMAMOTO, JANET K.
Original Assignee
University of Florida
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 University of Florida filed Critical University of Florida
Publication of EP1146882A2 publication Critical patent/EP1146882A2/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the subject invention was made with government support under a research project supported by NIH Grant AI30904. The government has certain rights in this invention.
  • Feline immunodeficiency virus is a lentivirus which causes immunodeficiency syndrome in domestic cats (Pedersen et al, 1987; Siebelink et al, 1990). FIV closely resembles human immunodeficiency virus (HIV) in genomic, biochemical, and morphologic characteristics as well as clinical and hematological manifestations (Johnson et al., 1994; Pedersen et al, 1987; Yamamoto, Sparger et al,
  • FIV infection of domestic cats is considered to be an excellent small animal model for testing prophylactic and therapeutic strategies against AIDS Viruses (Gardner, 1991; Johnson et al, 1994).
  • HIV protease inhibitors e.g., Sequinavir (SQV), Indinavir (IDV), Ritonavir, Nelfinavir
  • SQV Sequinavir
  • IDV Indinavir
  • Ritonavir e.g., Nelfinavir
  • 3TC rapidly induces mutations which can phenotypically reverse the mutations caused by AZT, enabling the antiviral activity of AZT to persist in the host (Boucher et al, 1993; Larder, 1995; Tisdale et al, 1993).
  • This unique feature of 3TC makes it a prime candidate for use in combination with AZT.
  • the combination AZT/3TC therapy had synergistic or additive effects at decreasing plasma virus load and increasing CD4 cell counts and function (Katlama et al, 1994; Lange, 1995; Paul et al, 1995; Staszewski, 1995).
  • the addition of an HIV protease inhibitor to this combination further decreased the viral load and improved the CD4 cell count (Deeks et al, 1997; Torres et al, 1997).
  • the subject invention concerns methods for therapeutic and prophylactic treatment of feline animals against infection by FIV.
  • Methods of the present invention utilize a combination of antiretroviral compounds.
  • an effective amount of a composition comprising AZT and another nucleoside such as 3TC .
  • cats are given an effective dose(s) of a composition comprising AZT, a nucleoside analog such as 3TC and a retroviral protease inhibitor.
  • the protease inhibitor is HBY-793 (Hoescht-Bayer).
  • Figure 1 shows anti-FIV activities of AZT, 3TC, FIV-PI, and HIV-PI (IDV and
  • RT data are presented as % control, whereby % control represents RT mean of triplicate treated cultures divided by RT mean of triplicate untreated cultures and multiplied by 100.
  • Figure 2 shows anti-FIV activities of AZT, 3TC, FIV-PI, and FIV-PI in primary PBMC infected with FIV Bang .
  • the RT data are presented as % control and the results from treated culture sets which are statistically different from the values of the untreated controls are indicated by either p ⁇ 0.05 (P) or p ⁇ 0.005 (P*) based on Student T test.
  • the Harvest Day 16 result for AZT/3TC culture set was statistically different (p ⁇ 0.03) from the results of AZT culture set and 3TC culture set from the same time point, as indicated by (Y) above AZT/3TC bar (panel A).
  • the Day 9 and 12 harvest results for AZT/3TC/FIV-PI culture set were statistically different (p ⁇ 0.05) from the results of AZT/3TC culture set and FIV-PI culture set from the same time points, as indicated by (Z) above AZT/3TC/FIV-PI bars (panel B).
  • Figure 3 shows anti-FIV activities of AZT, 3TC, FIV-PI, and HIV-PI in primary PBMC infected with F1V UK . 8 (subtype A strain).
  • Nucleoside analogue and PI doses were 0.1 ⁇ M and 0.01-0.5 ⁇ M, respectively, in Experiment 1 (panel A) and 0.05 ⁇ M and 0.01-0.5 ⁇ M respectively, in Experiment 2 (panel B).
  • the RT data are presented as % control and the results from treated culture sets which are statistically different from the values of the untreated controls are indicated by either p ⁇ 0.05 (P) or p ⁇ 0.005 (P*).
  • Figure 4 shows the chemical structure of the protease inhibitor designated herein as HBY-793.
  • the subject invention concerns methods for therapeutic and prophylactic treatment of cats against infection by FIV.
  • Methods of the present invention utilize a combination of antiretroviral compounds.
  • cats can be administered an effective amount of a composition comprising AZT and another nucleoside analog.
  • the nucleoside analog is 3TC.
  • cats are given an effective dose(s) of a composition comprising AZT, another nucleoside analog and a retroviral protease inhibitor.
  • the nucleoside analog is 3TC.
  • the protease inhibitor is HBY-793.
  • the structure of HYB-793 is shown in Figure 4.
  • Other retroviral protease inhibitors that can inhibit FIV proteases are contemplated within the scope of this invention.
  • FIV-infected cats treated according to the methods of the present invention can also be given bone marrow transplantation after total body irradiation in conjunction with the antiretroviral drug combination therapy.
  • the bone marrow transplanted can be either allogeneic or autologous.
  • compositions of the subject invention can be administered using standard procedures known in the art.
  • the compositions can be administered as oral or nasal formulations.
  • the compositions can also be administered by parenteral injection, i.e., intravenous, intramuscular, or subcutaneous injection.
  • parenteral injection i.e., intravenous, intramuscular, or subcutaneous injection.
  • the amounts and dosage regimens for administration can readily be determined by the ordinarily skilled clinician.
  • Cats that are not infected with FIV can be treated according to the methods of the present invention to provide effective prophylactic treatment against FIV infection.
  • FIN- infected cats can be treated according to the subject methods to provide effective therapy for controlling, inhibiting or eliminating FIV infection in that cat.
  • kits comprising in one or more containers
  • AZT another nucleoside analog and an inhibitor of a retroviral protease.
  • the nucleoside analog is 3TC.
  • the retroviral protease inhibitor is HBY-793.
  • Example I In vitro Efficacy of AZT. 3TC. and PI
  • feline T-cell lines chronically infected with FIV Pet (FL-4 cells) or FIV Bang (FIV Bang /FeT-J cells) at 2xl0 5 cells/ml were treated for 3 weeks with a single drug or various combinations of AZT, 3TC, an FIV protease inhibitor (FIV-PI; Hoescht-Bayer HBY-793), and HIV protease inhibitors (HIV-PI) (Fig. 1A and IB).
  • Saquinavir (SQV) and Indinavir (IDV) were used as the HIV-PIs.
  • Culture supernatants were harvested and the cells were resuspended in fresh culture media containing appropriate drug(s) at 34 day intervals.
  • Viral replication was determined by measuring the levels of reverse transcriptase (RT) activity in the culture supernatants (Rey et al, 1984). Drug toxicity in these cultures were monitored by viability and absolute cell count analyses using trypan blue exclusion method (Mishell et al, 1980).
  • RT reverse transcriptase
  • AZT and 3TC exert their antiretroviral activity by preventing the reverse transcription of viral RNA into viral DNA, whereas FIV-PI prevents the production of a whole virion by inhibiting the FIV protease from cleaving viral gag-pro-- pol precursor into their individual components. Therefore, cell lines which have proviral integration will not be affected by nucleoside analogues. Based on semi-quantitative PCR analysis, FIV Bang /FeT-J cells and FL-4 cells used in current study had proviral integration of 50-80% and >95%, respectively (data not shown).
  • the minor anti-FIV activity of AZT and 3TC observed in FIV Ban arriving/FeT-J cells may be due to the antiviral effect of the nucleoside analogues on the 20-50% of the cells which were still free of FIV proviral integration.
  • potent anti-FIV activity was observed with FIV-PI in both proviral integrated cell lines.
  • PBMC peripheral blood mononuclear cells
  • SPF pathogen free
  • the anti-FIV activities of AZT, 3TC, and FIV-PI are not restricted to specific FIV strain or subtype, although some strains appear to be more sensitive to one drug over another.
  • single-drug treatments with FIV-PI but not HIV-PIs SQV and IDV
  • SQV and IDV inhibited FIV replication in PBMC cultures.
  • addition of SQV or IDV to the AZT/3TC combination did not enhance the antiviral activity of the AZT/3TC combination.
  • Example 2 Prophylactic Efficacy of AZT/3TC in Cats Based on the findings from in vitro studies, the prophylactic use of AZT/3TC combination was next tested in experimental cats.
  • This treatment dose was based on the in vivo research, in which six SPF cats (2 cats per treatment group) treated (BID) with either AZT or 3TC at 100 mg/kg or AZT/3TC combination at 50 mg/kg each had no hematological or clinical abnormalities after two weeks of treatment.
  • the cats were monitored daily for clinical signs and twice a month for hematological changes, FIV load in PBMC and plasma, anti-FIV antibody titers, and CD4/CD8 ratio and absolute counts (Diehi et al, 1995; Green et al, 1993; Okada et al, 1994; Tellier et al, 1997; Yamamoto et al, 1991).
  • Example 3 Therapeutic Efficacy of AZT/3TC in Chronically FIV-infected Cats
  • Allogeneic bone marrow transplantation (BMT) in combination with total body irradiation (TBI) and anti-FIV drug therapy was evaluated as an immune reconstitution therapy for FIV-infected cats.
  • TBI total body irradiation
  • anti-FIV drug therapy can block the infection of engrafted donor cells in the BMT recipients.
  • BMT with donor BM cells from uninfected cats will reconstitute normal hematopoietic system.
  • the TBI/BMT combination alone was unable to decrease the virus load due to rapid infection of engrafted donor cells.
  • Prophylactic therapy with AZT/3TC combination protected 100% of the cats from F ⁇ V UK _ 8 challenge infection. Moreover, the only FIV-infected cat to survive allogeneic BMT also received concurrent AZT/3TC therapy. This cat had complete hematopoietic engraftment including normal CD8 counts. However, its CD4 counts were only slightly higher than the levels observed before BMT. Furthermore, only slight decrease in plasma virus load was observed during high-dose AZT/3TC therapy. Nonetheless, its anti-FIV antibody titers were 100-fold lower than those before BMT. This cat was still healthy at one year post-BMT and is still responsive to AZT/3TC therapy.
  • Antiviral compounds of the invention can be formulated according to known methods for preparing pharmaceutically useful compositions. Remington's Pharmaceutical Science by E.W. Martin describes formulations which can be used in connection with the subject invention. In general, the compositions of the subject invention will be formulated such that an effective amount of the antiviral compounds are is combined with a suitable carrier in order to facilitate effective administration of the composition. It should, of course, be understood that the compositions and methods of this invention may be used in combination with other therapies. The compositions used in these therapies may also be in a variety of forms.
  • compositions of the invention include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, suppositories, injectable, and infusible solutions.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions also preferably include conventional pharmaceutically acceptable carriers and adjuvants which are known to those of skill in the art.
  • the compositions of the invention are in the form of a unit dose.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained.
  • the AZT/3TC treatment was started 3 days before FIV inoculation (-0.4 post-infection) at a dose of 75 mgkg each and decreased to 34 mg/kg at 4 wk post-infection (pi) and then to 10 mg/kg at 5 wk pi.
  • the AZT/3TC treatment was withdrawn at 6 wk pi and resumed at a low dose of 5 mg/kg at 7 wk pi.
  • the changes in doses if each drug, including the amount (mg/kg) and time (wk pi) are shown, b Samples before drug or placebo treatment (Pre) and those at various weeks post-infection (wk) were tested for FIV levels, FIV antibodies, and CD4/CD8 rations.
  • FIV levels were determined by virus isolation (VI), PCR for FIV provirus in PBMC, and RT-PCR for plasma viral RNA (vRNA). FIV antibodies were determined by immunoblot analysis. In general, RT-PCR for plasma viral RNA was less sensitive than PCR of FIV provirus in PBMC after amplification of infected cells by cocultu ⁇ ng. c Inverted CD4/CD8 ratios are bolded.
  • each drug was decreased from 20 mg/kg to 10 mg/kg at 3 weeks treatment. Treatment was withdrawn in one cat (#144) at 6 weeks of treatment and resumed one week later at 5 mg/kg. The changes in doses of each drug, including amount (mg/kg) and time (wk after initial treatment), are shown, b Samples before drug or placebo treatments (0 wk) and those at various weeks after initial treatment (wk) were tested for FIV levels, FIV antibodies, and CD4/CD8 ratios. FIV loads were determined by the number of PBMC (50 to 5xl0 6 PBMC cocultured with 5xl0 6 feeder PBMC) needed for positive virus isolation.
  • Virus isolation results are presented as 50 (+4-++), 5xl0 2 (+++), 5x10' (++), and 5xl0 4 (4-) PBMC from treated and untreated cats needed to isolate FIV from a culture containing 5xl0 6 uninfected feeder PBMC.
  • FIV antibody titer is defined as the minimal dilution (in og, 0 ) at which antibodies to FIV major core protein (p26) could be detected.
  • Serial log dilutions of serum (10 4 to 10" 7 dilution) were incubated with immunoblot strip for 2 hrs and processed using the immunoblot method. End point titrations of FIV antibodies are presented as 10 5 (+) and 10 6 (+-*-).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des procédés de traitements thérapeutiques et prophylactiques des infections des chats par le VIF recourant à une combinaison de composés antirétroviraux. Dans une exécution le procédé consiste à administrer à un animal une dose efficace d'AZT et d'un autre analogue de glucoside tel que par exemple du 3TC; dans une autre exécution on administre aux chats une ou des doses efficaces d'AZT, de 3TC et d'un inhibiteur de protéase rétrovirale.
EP99926027A 1998-05-29 1999-05-28 Therapie combinee pour le traitement des infections dues au vif Withdrawn EP1146882A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8728198P 1998-05-29 1998-05-29
US87281P 1998-05-29
PCT/US1999/011940 WO1999060988A2 (fr) 1998-05-29 1999-05-28 Therapie combinee pour le traitement des infections dues au vif

Publications (1)

Publication Number Publication Date
EP1146882A2 true EP1146882A2 (fr) 2001-10-24

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EP99926027A Withdrawn EP1146882A2 (fr) 1998-05-29 1999-05-28 Therapie combinee pour le traitement des infections dues au vif

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EP (1) EP1146882A2 (fr)
AU (1) AU4219799A (fr)
CA (1) CA2374198A1 (fr)
WO (1) WO1999060988A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067984A2 (fr) 2001-02-22 2002-09-06 University Of Florida Materiaux et methodes permettant de detecter, de prevenir et de traiter une infection retrovirale a vih ou a vif
RU2331420C2 (ru) * 2005-12-08 2008-08-20 Роберт Шалвович Бибилашвили Противовирусное средство (варианты) и способ лечения на его основе
WO2013006905A1 (fr) * 2011-07-13 2013-01-17 White Cell Rx Holdings Pty Ltd Système de gestion de médicaments

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US6689761B1 (en) * 1995-02-01 2004-02-10 Merck & Co., Inc. Combination therapy for HIV infection
MY115461A (en) * 1995-03-30 2003-06-30 Wellcome Found Synergistic combinations of zidovudine, 1592u89 and 3tc
AU6676796A (en) * 1995-07-13 1997-02-10 Sloan-Kettering Institute For Cancer Research Compounds, compositions, and methods for inhibiting replication of retroviruses and for inhibiting tumor promoter initiated transcription
JP2000515852A (ja) * 1996-06-25 2000-11-28 グラクソ、グループ、リミテッド Ｈｉｖの治療に使用するためのｖｘ４７８、ジドブジン、ｆｔｃおよび／または３ｔｃを含んでなる組合わせ
DE19703131A1 (de) * 1997-01-29 1998-07-30 Bayer Ag Verwendung von Chinoxalin in Dreier-Kombination mit Protease-Inhibitoren und Reverse Transkriptaseinhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen
GB9809213D0 (en) * 1998-04-29 1998-07-01 Glaxo Group Ltd Pharmaceutical compositions
BR9911457A (pt) * 1998-06-24 2001-12-11 Univ Emory Uso de 3'-azida-2', 3'-dideoxiuridina em combinaçãocom drogas anti-hiv adicionais para a manufaturade um medicamento para o tratamento de hiv

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9960988A2 *

Also Published As

Publication number Publication date
CA2374198A1 (fr) 1999-12-02
AU4219799A (en) 1999-12-13
WO1999060988A3 (fr) 2000-12-07
WO1999060988A9 (fr) 2000-02-24
WO1999060988A2 (fr) 1999-12-02

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