WO1994013314A1 - Traitement combine des infections a vih mettant en oeuvre la thymosine, l'interleukine et des inhibiteurs de replication du vih ou de transcriptase reverse - Google Patents

Traitement combine des infections a vih mettant en oeuvre la thymosine, l'interleukine et des inhibiteurs de replication du vih ou de transcriptase reverse Download PDF

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WO1994013314A1
WO1994013314A1 PCT/US1993/012171 US9312171W WO9413314A1 WO 1994013314 A1 WO1994013314 A1 WO 1994013314A1 US 9312171 W US9312171 W US 9312171W WO 9413314 A1 WO9413314 A1 WO 9413314A1
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administered
regimen
thn
peg
hiv
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PCT/US1993/012171
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Thomas C. Merigan
Robin Wood
Allan L. Goldstein
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The Board Of Trustees Of The Leland Stanford Junior University
The George Washington University Medical Center
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Application filed by The Board Of Trustees Of The Leland Stanford Junior University, The George Washington University Medical Center filed Critical The Board Of Trustees Of The Leland Stanford Junior University
Priority to AU58716/94A priority Critical patent/AU5871694A/en
Publication of WO1994013314A1 publication Critical patent/WO1994013314A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2292—Thymosin; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • 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

Definitions

  • This invention relates generally to the treatment of humans having HIV infections, and specifically to combination chemotherapy regimens with cytokines, 0 immune response modifiers and anti-retroviral drugs.
  • HIV infection leads to diminished numbers of T- helper cells (CD4 + cells), impairment of functioning of such cells, and progression to an immune deficient 5 state.
  • Infected individuals, particularly those with advanced HIV infections are also predisposed to a variety of opportunistic infections and/or malignancies. The risk of developing opportunistic infections becomes significant when the count of CD4 + 0 cells falls below 200/mm 3 , and continues to increase as the CD4 + cell count decreases further.
  • HIV was first isolated in 1983 from patients with AIDS and its prodrome AIDS-related complex ("ARC").
  • HIV or "human immunodeficiency virus” 5 means a cytopathic human retrovirus that infects human T-lymphocytes, including HIV-1 and HIV-2.
  • AIDS and related syndromes have been identified primarily among homosexuals, intravenous drug users, recipients of blood products from infected persons, and sexual partners or infants of AIDS patients, HIV- specific antibody tests available since 1983 have identified a large seropositive population at further risk for clinical HIV disease. AIDS is a global problem of enormous dimensions.
  • anti-HIV replication drugs currently approved by the FDA for human use are azidothymidine (AZT, zidovudine (ZDV), Retrovir®, Burroughs Wellcome Co.), dideoxycytidine (ddC, Hivid®, zalcitabine, Bristol-Myers, Co.) and dideoxyinosine (ddl, Videx ® , didanosine, Hoffman-LaRoche) , all inhibitors of retrovirus replication in host cells.
  • AZT zidovudine
  • ZDV zidovudine
  • Retrovir® Burroughs Wellcome Co.
  • dideoxycytidine ddC, Hivid®, zalcitabine, Bristol-Myers, Co.
  • dideoxyinosine didanosine, Hoffman-LaRoche
  • cytokines which are variously referred to as cytokines, lymphokines and biological response modifiers include: (1) interleukins (e.g., IL-1 and IL- 2) , which are cytokines involved with the cellular immune response; (2) interferons (e.g., IFN- , - ⁇ , and ⁇ ) that exhibit both immunoregulatory and antiviral properties; and, (3) thymosins (e.g., thymosin l (THN- ⁇ l), a 28-amino acid polypeptide) produced by epithelial cells of the thymus gland and known to be T-cell maturation factors.
  • interleukins e.g., IL-1 and IL- 2
  • interferons e.g., IFN- , - ⁇ , and ⁇
  • thymosins e.g., thymosin l (THN- ⁇ l), a 28-amino acid polypeptide
  • Thymosins have as a primary effect stimulation of the conversion of pluripotent stem cells to thymocytes and the subsequent maturation of thymocytes to activated T-lymphocytes. Thymosins exhibit additional effects, such as stimulatory effects on the production of high affinity IL-2 receptors, IFN- ⁇ and - 7 , and humoral antibodies.
  • IL-1 stimulates maturation and proliferation of T- cells as well as the production of IL-2 by T-cells. Together, these substances act with signals initiated by antigen and immunoglobulins in a manner such that T- cell activation is achieved.
  • the production of IL-2 by CD4 + cells may be important for the stimulation of B- lymphocytes to proliferate and differentiate into immunoglobulin-secreting cells.
  • IL-2 has been shown to stimulate the production of IFN— ⁇ .in vivo in humans and laboratory animals.
  • IFN- ⁇ has been shown to be active in vitro against HIV replication, and, in. vivo, the polypeptide in combination with zidovudine (ZDV) was reported to be active in HIV patients with Kaposi syndrome.
  • ZDV zidovudine
  • interferons have immunoregulatory functions, such as enhancement of natural killer cell (NK) production and activation, as well as inhibition of cell growth.
  • IFN- ⁇ and - ⁇ are considered to be primarily antiviral, whereas IFN- 7 has mainly an immunoregulatory function.
  • IL-2 per se has limited clinical usefulness because of its short circulatory half life.
  • 5 Treatment with IL-2 in HIV disease has required continuous infusions of relatively large amounts of the polypeptide, and has produced variable immune enhancement, 3 ' 4 Chemical modification of rIL-2 by polyethyleneglycol is known to increase its halflife in animal models by as much as 10 to 20-fold.
  • 5 Garaci et al. have recently described in abstract form preliminary results of a combination therapy using THN- ⁇ l, IFN- ⁇ and ZDV with HIV-infected but asymptomatic patients presenting with CD4 + cell counts of between 100 and 500/mm 3 . After a year of therapy, small increases in CD4 * cell counts were observed in a group of ten patients receiving the three drugs, compared to a group of six patients receiving ZDV plus IFN- ⁇ or to a group of ten patients receiving ZDV alone.
  • Applicants have discovered a combination chemotherapy regimen for the treatment of, or prophylaxis against, HIV infections comprising the concurrent adminstration of an immune system potentiating amount of at least one thymosin or an immunoregulatorily active fragment, analogue or derivative thereof, an immune system potentiating amount of IL-2 or derivative thereof, and at least one HIV-replication or HIV-reverse transcriptase inhibitor compound.
  • One aspect of the invention is a method of treating HIV infections in human patients comprising the concurrent administration of effective amounts of at least one thymosin or fragment, analogue or derivative thereof, at least one IL-2 or active derivative thereof, and at least one HIV replication or reverse transcriptase inhibitor.
  • Another aspect of the invention relates to a mercantile composition
  • a mercantile composition comprising, separately, effective amounts of at least one thymosin or an active fragment, analogue or derivative thereof, at least one IL-2 and/or an active derivative thereof, and at least one HIV replication and/or reverse transcriptase inhibitor compound, in unit dosage form.
  • combination chemotherapy regimen comprising the concurrent (i.e., same regimen) administration to HIV-infected patients of at least one immune system potentiating thymosin or active fragment, analogue or derivative thereof, at least one immune system potentiating IL-2 or active derivative thereof, and at least one HIV replication or reverse transcriptase inhibitor compound, in effective forms and doses, which results in beneficially synergistic clinical effects in such patients.
  • Such combination therapies are more effective in vivo than when each is administered as the sole treatment modality.
  • thymosin as used herein is intended to include any immunopotentiating polypeptide made in the thymus gland. It includes, among other polypeptides and fragments, THN- ⁇ l and any immunoregulatorily effective peptide fragment, analogue or derivative thereof. As used herein henceforth, the term “THN- ⁇ l” should be understood to include thymosin- ⁇ l and any immunoregulatorily effective peptide fragment, derivative and analogue thereof.
  • the thymosin portion of the combination chemotherapy regimen comprises a medicament containing as active ingredient at least one thymosin, either in free form or in the form of a pharmaceutically acceptable salt. This medicament may contain, in addition to the active substances, a conventional pharmaceutically acceptable vehicle appropriate to the selected method of administration (see. Remington's Pharmaceutical Sciences, Mack “ Publishing Co., Easton, PA, which is incorporated herein by reference).
  • Thymosins may be obtained either from commercial sources (e.g., Alpha 1 Biomedicals, Inc., Foster City, CA) , by application of conventional methods of peptide synthesis (e.g., Merrifield-type synthesis) or according to U.S. Patent No. 4,353,821, or U.S. Patent No. 4,612,365, which are incorporated herein by reference.
  • a thymosin may be administered orally or parenterally, the latter either intravenously, subcutaneously or intramuscularly, although subcutaneous (s.c.) adminstration is preferred.
  • THN- ⁇ l is a potent immunopotentiating agent when used in a dosage in the range of about 300 to about 1200 ⁇ g/m 2 body surface area as the free compound or as a pharmaceutically acceptable salt, in a pharmaceutically acceptable vehicle. Lyophilized preparations of a thymosin are dissolved in a pharmaceutically acceptable diluent prior to dispensing.
  • a preferred administration regimen for THN- ⁇ l is a twice- weekly s.c. injection of about 1000 to about 2000 ⁇ g of a thymosin.
  • the required dosage will vary with the particular conditions being treated, the severity of the condition, the duration of the treatment that is required, and the other drugs of the combination of the invention that are being concurrently administered.
  • a preferred dosage unit form for pharmaceutical use is l- 2 mg of lyophilized THN- ⁇ l per vial, and this material is reconstituted prior to use by the addition of a diluent.
  • HIV uses the enzyme reverse transcriptase ("RT") to transcribe, i.e., replicate, its RNA into a DNA that is then incorporated into the genome of the host.
  • RT reverse transcriptase
  • ZDV, ddC and ddl which are approved by the FDA for administration to patients, are pyrimidine nucleoside analogues and act as polynucleotide chain terminators.
  • Nevirapine a dipyridodiazepinone that inhibits HIV-1 RT, has been developed by Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.
  • Other drugs within the class that includes nevirapine include tricyclic pyridobenzoxazepinones and dibenzoxapinones.
  • ZDV and/or other pyrimidine nucleoside analogues in an appropriate pharmaceutical dosage unit formulation (e.g., capsules containing 50-100 mg of the drug plus inert carriers and fillers) , are given orally to human HIV-infected patients at effective retrovirus inhibiting dosages and according to regimens appropriate to the severity of the disease and other clinical factors.
  • a preferred effective starting dose of ZDV in combination chemotherapy is 500 mg p.o. given over twenty-four hours. In a 70 kg patient, this dose corresponds to about 1.8 mg/kg every six hours.
  • a lower daily dosage for such a patient may be devised according to the clinical picture and the tests listed below.
  • Nevirapine and similar drugs are administered at doses that range between 50 and 600 mg/day using appropriate dosage units, e.g., capsules containing about 50-600 mg of the drug plus inert fillers or carriers.
  • appropriate dosage units e.g., capsules containing about 50-600 mg of the drug plus inert fillers or carriers.
  • PEG-IL-2 polyethylene glycol in ester linkage with IL-2
  • conjugation to PEG is known to increase by 10- to 20-fold the half life of IL-2.
  • a pharmaceutically acceptable vehicle e.g., 5% dextrose in distilled sterile water
  • PEG-IL-2 has a prolonged duration of action, it may be given by intermittent peripheral i.v. infusion. It is preferred to administer PEG-IL-2 as a single i.v. infusion over 15 minutes weekly or biweekly (i.e. , every two weeks) , with the schedule being determined by the clinical picture.
  • administration of PEG-IL-2 by the s.c. route is also feasible, depending on the clinical circumstances.
  • Appropriate immune system stimulating dosages for PEG- IL-2 range between about 0.1 to about 50 x 10 6 IU/m 2 body area when the CD4 + cell counts of the patients are below about 400 cells/mm 3 .
  • the lower end of this PEG- IL-2 range e.g., about 1 x 10 6 IU/m 2
  • IL-2 may be administered by peripheral i.v. at a dosage of about
  • Convenient pharmaceutical dosage units contain 2-20 IU of IL-2 and 1-5 IU of PEG- IL-2 as lyophilized powders that are reconstituted with diluent prior to use.
  • a pyrimidine nucleoside analogue ZDV, ddl or ddC
  • PEG-IL-2 a pyrimidine nucleoside analogue
  • THN- ⁇ l is injected subcutaneously twice weekly at a dosage of 1- 2 mg per injection.
  • THN- ⁇ l In order to pick up unexpected toxicity of the combination, one may employ a one-month lead-in period in which 0.4 mg of THN- ⁇ l, together with PEG-IL-2 at about 1-3 x 10 6 IU/m 2 , are used. If no significant toxicity is observed, the dose of THN- ⁇ l may be increased to 1.6 mg per injection, and maintained at this level throughout the treatment period.
  • the drugs used in the combination chemotherapy regimens described herein may be assembled in a mercantile pharmaceutical composition which consists of appropriate pharmaceutical dosage units of each drug in a particular combination.
  • the pharmaceutical composition may contain 100 mg capsules of ZDV, vials containing an amount of PEG-IL-2 sufficient to provide 1-3 x 10° IU/m 2 body surface area (e.g., 1-5 IU) , and vials containing 1-2 mg of THN- ⁇ l.
  • Other dosage units may be incorporated into the pharmaceutical composition as required, for example, vials containing 2-20 IU of
  • Measurements of disease-state indicators may be made periodically in patients. These include: lymphocyte subsets (including numbers of activated T4 (CD4 + ), T8 and NK lymphocytes, and monocytes); HIV- specific cytotoxicity; lymphocyte proliferation in response to lectins (e.g..
  • tetanus toxoid or Candida with standard antigens (e.g., tetanus toxoid or Candida); NK and LAK activities; autoantibodies to Class II MHC and CD4 + ; plasma concentrations of IL-2 or PEG-IL-2, THN- ⁇ l and ZDV; antibodies to THN- ⁇ l, IL-2 and PEG-IL-2; soluble IL-2 receptor in plasma; HIV-specific neutralizing antibody titers; the amount of viral protein p24; and quantitation of HIV provirus by, e.g., the polymerase chain reaction.
  • increases in functional immune responses and decreases in opportunistic infections may be determined periodically.
  • Ophthalmic lesions e.g., vascular tortuosity, venous budding, pigmented epithelial atrophy, microhemorages, microaneurysms, cotton wool spots, and periphlebitis
  • Ophthalmic lesions may also be followed as a check on the efficacy of the combination therapy of the invention. All of these methods and techniques for making measurements are standard in this art.

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Abstract

Méthode de traitement des infections à VIH chez l'être humain qui consiste en une chimiothérapie combinée et concurrente dont les composants mettent en ÷uvre au moins un élément actif de thymosine ou un élément actif immunorégulateur, un analogue ou un dérivé de ceux-ci, une interleukine ou un dérivé actif de celle-ci et au moins un inhibiteur de réplication de VIH ou de transcriptase réverse.
PCT/US1993/012171 1992-12-15 1993-12-15 Traitement combine des infections a vih mettant en oeuvre la thymosine, l'interleukine et des inhibiteurs de replication du vih ou de transcriptase reverse WO1994013314A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58716/94A AU5871694A (en) 1992-12-15 1993-12-15 Combination for treating hiv infections containing thymosine, interleukin and hiv replication or reverse transcriptase inhibitors

Applications Claiming Priority (2)

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US99088792A 1992-12-15 1992-12-15
US07/990,887 1992-12-15

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WO1994013314A1 true WO1994013314A1 (fr) 1994-06-23

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JP (1) JPH07267874A (fr)
CN (1) CN1094310A (fr)
AU (1) AU5871694A (fr)
WO (1) WO1994013314A1 (fr)
ZA (1) ZA939217B (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0787008A1 (fr) * 1994-11-17 1997-08-06 University Of South Florida Methode de traitement de l'immunodeficience secondaire
DE19608280A1 (de) * 1996-02-23 1997-08-28 Strathmann Ag & Co Arzneimittel zur kausalen Therapie von HIV- oder SIV-Infektionen
WO1999047146A1 (fr) * 1998-03-17 1999-09-23 Julianna Lisziwiewicz Combinaison anti-vih constituee d'hydroxyuree, de ddi et d'un inhibiteur de protease
WO2003037272A3 (fr) * 2001-11-01 2003-11-20 Sciclone Pharmaceuticals Inc Conjugues de polymeres/peptides thymosine alpha 1
US7208167B2 (en) 2000-08-07 2007-04-24 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis C with thymosin and peptide combination therapy
US7897567B2 (en) 2002-11-25 2011-03-01 Sciclone Pharmaceuticals, Inc. Methods of protecting against radiation damage using alpha thymosin
US8591956B2 (en) 2007-11-28 2013-11-26 Irx Therapeutics, Inc. Method of increasing immunological effect
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers
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Cited By (22)

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JP2009029830A (ja) * 1994-11-17 2009-02-12 Univ Of South Florida 二次性免疫不全症の治療法
EP0787008A4 (fr) * 1994-11-17 1999-02-10 Univ South Florida Methode de traitement de l'immunodeficience secondaire
EP0787008A1 (fr) * 1994-11-17 1997-08-06 University Of South Florida Methode de traitement de l'immunodeficience secondaire
EP2036569A3 (fr) * 1994-11-17 2009-04-01 University Of South Florida Procédé pour le traitement de l'immunodéficience secondaire
DE19608280A1 (de) * 1996-02-23 1997-08-28 Strathmann Ag & Co Arzneimittel zur kausalen Therapie von HIV- oder SIV-Infektionen
WO1999047146A1 (fr) * 1998-03-17 1999-09-23 Julianna Lisziwiewicz Combinaison anti-vih constituee d'hydroxyuree, de ddi et d'un inhibiteur de protease
US7208167B2 (en) 2000-08-07 2007-04-24 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis C with thymosin and peptide combination therapy
US9492519B2 (en) 2000-10-27 2016-11-15 Irx Therapeutics, Inc. Vaccine immunotherapy
US9789173B2 (en) 2000-10-27 2017-10-17 Irx Therapeutics, Inc. Vaccine immunotherapy for treating cervical cancer in immune suppressed patients
US8784796B2 (en) 2000-10-27 2014-07-22 Irx Therapeutics, Inc. Vaccine immunotherapy for treating hepatocellular cancer in immune suppressed patients
US9789172B2 (en) 2000-10-27 2017-10-17 Irx Therapeutics, Inc. Vaccine immunotherapy for treating lymphoma in immune suppressed patients
US9492517B2 (en) 2000-10-27 2016-11-15 Irx Therapeutics, Inc. Vaccine immunotherapy
EA008703B1 (ru) * 2001-11-01 2007-06-29 Сциклон Фармасьютикалс, Инк. Фармацевтическая композиция, обладающая повышенной иммуностимулирующей активностью, способ ее получения и использования
WO2003037272A3 (fr) * 2001-11-01 2003-11-20 Sciclone Pharmaceuticals Inc Conjugues de polymeres/peptides thymosine alpha 1
US7297676B2 (en) 2001-11-01 2007-11-20 Sciclone Pharmaceuticals, Inc. Thymosin alpha 1 peptide/polymer conjugates
US7897567B2 (en) 2002-11-25 2011-03-01 Sciclone Pharmaceuticals, Inc. Methods of protecting against radiation damage using alpha thymosin
US8591956B2 (en) 2007-11-28 2013-11-26 Irx Therapeutics, Inc. Method of increasing immunological effect
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers
US9539320B2 (en) 2009-05-15 2017-01-10 Irx Therapeutics, Inc. Vaccine immunotherapy
US9566331B2 (en) 2009-05-15 2017-02-14 Irx Therapeutics, Inc. Vaccine immunotherapy
US9333238B2 (en) 2009-12-08 2016-05-10 Irx Therapeutics, Inc. Method of immunotherapy for treament of human papillomavirus infection
US9931378B2 (en) 2009-12-08 2018-04-03 Irx Therapeutics, Inc. Method of immunotherapy for treatment of human papillomavirus infection

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AU5871694A (en) 1994-07-04
JPH07267874A (ja) 1995-10-17
ZA939217B (en) 1994-10-03

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