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EP0901375A1 - Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea) - Google Patents

Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea)

Info

Publication number
EP0901375A1
EP0901375A1 EP97917365A EP97917365A EP0901375A1 EP 0901375 A1 EP0901375 A1 EP 0901375A1 EP 97917365 A EP97917365 A EP 97917365A EP 97917365 A EP97917365 A EP 97917365A EP 0901375 A1 EP0901375 A1 EP 0901375A1
Authority
EP
European Patent Office
Prior art keywords
interieukin
patient
group
treatment
compound
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Withdrawn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
EP97917365A
Other languages
German (de)
English (en)
Inventor
Patrick Thomas Prendergast
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0901375A1 publication Critical patent/EP0901375A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P33/00—Antiparasitic agents
    • 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
    • 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
    • A61P37/02—Immunomodulators

Definitions

  • IL-12 Interieukin 12
  • IL-10 Interieukin 10
  • the present inventor has found that the anti-viral agents (general formula I herein) as disclosed in U S Patent No 4,956,355 (Prendergast) have additional beneficial therapeutic effects when used in a combination therapy with agents that inhibit Interieukin 10 synthesis and/or action Agents which inhibit Interieukin 10 can be identified by identifying those compounds which have the ability to inhibit cyclic AMP activity in addition to agents which demonstrate Interieukin 10 inhibition when employed in the screening protocol (Screening IL-10) as herein described.
  • Interieukin 10 can be inhibited by any of a variety of compounds, including one or a combination of the following compounds: - Canavanine Sulphate, L-Canavanine Sulphate, Herbimycin A (Wako Pure Chemicals Industries, Ltd., Japan), Genistein (Sigma Chemicals Co., St. Lous, Mo , USA), secalonic acid D, isoflavinoids, cytokinins, amphiphilic triterpenoids, or analogues to the above together with polyclonal or monoclonal antiserum to Interieukin 10 or any of its peptide sequences
  • the anti-viral agent is a 17-ketosteroid compound having the general formula (I)
  • R is a hydrogen atom
  • R 1 is a chemical group selected from the group consisting of a hydrogen atom, an SO 2 OM group wherein M is selected from the group consisting of a hydrogen atom, a sodium atom, a sulphatide group
  • each of R 2 and R 3 which may be the same or different, is selected from the group consisting of straight and branched chain alkyl radicals of 1 to 14 carbon atoms, a phosphatide group
  • each of R 2 and R 3 which may be the same or different, is selected from the group consisting of straight and branched chain alkyl radical of 1 to 14 carbon atoms, and a glucuronide group
  • the broken line represents an optical double bond
  • the hydrogen atom at position 5 is present in the ⁇ - or ⁇ - configuration, or the compound comprises a mixture of both configurations
  • the compounds are conjugated compounds
  • a method of enhancing the Th 1 immune protective response when using one or more 17-ketosteroid compound as an anti-viral, anti-bacterial, anti-mycoplasm or anti-intra cellular parasitic agent by combining it with anti-serum either poly or monoclonal to Interieukin 10 (cytokine inhibitory factor) and/or with any compound which can effectively inhibit synthesis or the biological function of this specific cytokine Interieukin 10 and/or an Interieukin 10 (cytokine inhibitory factor) receptor molecule blocking agent.
  • Interieukin 10 cytokine inhibitory factor
  • Th 1 immune protective response is required by patients in need of anti-cancer, anti-viral, anti-metastatic, anti-multi drug resistant cancer cell and/or bacterial, non-resistant bacterial infection therapy.
  • the present invention is also directed to the use of such compounds in the manufacture of a medicament for providing any such treatment
  • the pharmaceutical formulation according to the invention may be administered locally or systemically.
  • systemic administration is meant any mode or route of administration which results in effective levels of active ingredient appearing in the blood or at a site remote from the site of administration of said active ingredient.
  • the pharmaceutical formulation for systemic administration according to the invention may be formulated for enteral, parenteral or topical administration. Indeed, all three types of formulation may be used simultaneously to achieve systemic administration of the active ingredient
  • Suitable formulations for oral administration include hard or soft gelatin capsules, dragees, pills, tablets, including coated tablets, elixirs, suspensions, syrups or inhalations and controlled release forms thereof.
  • Solid dosage forms in addition to those formulated for oral administration include rectal suppositories.
  • Suitable formulations for topical administration include creams, gels, jellies, mucilages, pastes and ointments.
  • the compounds may be also be formulated for transdermal administration, for example, in the form of transdermal patches so as to achieve systemic administration
  • Suitable injectable solutions include intravenous, subcutaneous and intramuscular injectable solutions.
  • the compounds may also be administered in the form of an infusion solution or as a nasal inhalation or spray.
  • the pharmaceutical formulation according to the invention is administered in unit doses comprising from 10 to 1000 mg of active ingredient.
  • each unit dose comprises from 5 to 500 mg of each active ingredient.
  • the pharmaceutical formulation contains at least two active ingredients.
  • the combination therapy is administered at a rate of from 1 unit dose to 10 unit doses per day.
  • Administration of the therapy in accordance with the invention is continued for a period of at least one day and in certain cases may be given for the life of the individual.
  • R and R 1 are each hydrogen.
  • An especially preferred compound is dehydroepiandrosterone (DHEA) wherein R and R 1 are each hydrogen and the double bond is present.
  • DHEA dehydroepiandrosterone
  • the compound is epiandrosterone wherein R and R 1 are each hydrogen and the double bond is absent.
  • This unsaturated 5-position steroid can also be prepared as an anti-viral agent wherein the R position is occupied by any of the following halogens (bromine, chlorine, fluorine, iodine).
  • the compuond is 16 ⁇ - bromoepiandrosterone, wherein R is Br, R 1 is H and the double bond is present.
  • the compound is according to formula I, wherein R is Br, R 1 is H and the double bond is not present (i.e., where the dotted line is shown in formula I, there is a single bond).
  • Other preferred compounds are dehydroepiandrosterone sulphate, wherein R is H, R 1 is SO 2 -OM and M is as hereinbefore defined and the double bond is present, and 5 ⁇ -androstan-3 ⁇ -ol-17-one.
  • the compound is selected from dehydroepiandrosterone sulphatides, phosphatides or glucuronide wherein R is H, and R 1 is a sulphatide, phosphatide, or glucuronide group as hereinabove defined, and the double bond is present.
  • the compounds are DHEA conjugates such as hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoylglycol sulfate, O-dihexadecylglycero sulfate, hexadecane sulfonate, dioctadecanoylglycero phosphate, 0- hexadecylglycero phosphate.
  • DHEA conjugates such as hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoylglycol sulfate, O-dihexadecylglycero sulfate, hexadecane sulfonate, dioctadecanoylglycero phosphate
  • This anti-viral steroid had to be combined with an agent to inhibit or interrupt the synthesis and/or action of Interieukin 10.
  • This combination therapy is the preferred embodiment of using the said anti-viral agents (compounds according to general formula I) wherein the anti-viral agents are allowed to generate a Th 1 response.
  • the component of the combination therapy which counteracts the Th., suppressive Interieukin 10 immune side effect of the anti-viral therapy may be anti-serum either polyclonal or monoclonal in origin to Interieukin 10 and/or compounds to inhibit or interrupt the synthesis or effectiveness of the unwanted Interieukin 10.
  • Representative compounds which inhibit Interieukin 10 are disclosed in U.S. Patent No. 5,292,725 (Prendergast), the entirety of which is hereby incorporated by reference, which may be used in the combination therapy to counteract the Th 1 suppressive immune side effect of the anti-viral monotherapy.
  • RD is a patient under my care. He has Acute Myeloid Leukaemia M3 in remission following allogenic bone marrow transplant His major active problems have been GUT Graft Versus Host Disease and severe lung disease. RD's general health has improved over the last 3 months This has coincided with him taking the therapy and he is now enjoying good health For the first time since his diagnosis he has been able to enjoy full days at school. He no longer needs nasal gastric feeds or suffers with diarrhea His lung function remains at 30% but his exercise tolerance has improved dramatically. He no longer needs a wheelchair and can tolerate light exercise. As he is on no other drug regime and has been taking this medication for nearly 3 months we must consider that this therapy is influencing these beneficial effects on his body.
  • DHEA Another area of potential therapeutic benefit previously ascribed to DHEA is the enhancement of vaccine antigen recognition by the immune system in the elderly
  • Interieukin 10 levels achieved versus the DHEA therapies efficacy as vaccine adjuvant We have identified that the administration of recombinant Interieukin 10 to the elderly in association with or in advance of treatment with an antigen vaccine created an enhanced adjuvant effect, which enhanced the antibody response directly Whereas with DHEA there is a chance of not producing elevated levels of Interieukin 10
  • the effectiveness of DHEA therapy really depends on the metabolism, blood levels achieved and timing of the DHEA administration to the patient with or prior to the vaccine antigen.
  • the co-administration of recombinant Interieukin 10 is a more direct means of achieving enhanced antibody response in the elderly or very young patient and removes the uncertainties of steroid metabolism and cytokine responses associated with DHEA monotherapy This for the first time explains why DHEA has very often produced contradictory responses in the therapy of specific conditions e g , Lupus, MS and HIV because the real therapeutic effect is dependent upon cytokine profiles and immune reactions which are generated upon the administration of the steroid or its analogues Therefore, the therapeutic effectiveness of DHEA is unpredicatable as an immune modulator and dependent upon both the steroids metabolism and the cytokine profile of the patient during and prior to DHEA therapy.
  • Desired immune therapeutic response can only be achieved by utilizing directly the Interieukin 10 cytokine required or by co-administering Interieukin 10 inhibitors and/or specific antisera to same DHEA thus administered in a combination therapy will facilitate Interieukin 12 enhancement without the general negative effects of Interieukin 10 whereas Tl" ⁇ response is desired for therapeutic benefit
  • DHEA and the cytokines profile of patients who respond to DHEA therapy and those who do not respond to DHEA therapy have led to my discovery that elevated Interieukin 10 is the active agent responsible for the therapeutic response observed to alleviate the clinical symptoms of lupus
  • E9C, E9E and E9F were stimulated by the addition of DHEA or IL-12 in the presence of gp120.
  • the stimulation caused by the DHEA in each of these cases was equal to or greater than that caused by the IL-12, although the concentration of DHEA causing the stimulation varied from sample to sample.
  • E9A (HIV-1 negative) as well as E9D and E9G (HIV-1 positive) proliferation in the presence of gp120 was suppressed by the addition of DHEA or IL-12.
  • Human IL-12 is a disulfide-bonded heterodimeric cytokine consisting of a 40- and a 35-kD subunit. The genes for this cytokine have been cloned and purified recombinant protein has been produced. It has recently been demonstrated that in vivo administration of murine Interieukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocytes- activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated.
  • NK cytotoxic natural killer
  • mice treated intraperitoneaUy with IL-12 were markedly reduced in mice treated intraperitoneaUy with IL-12, resulting in an increase in survival time.
  • the therapeutic effectiveness of IL- 12 was dose dependent and treatment of subcutaneous tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity.
  • Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors.
  • IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1 , suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine.
  • IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.
  • Los Angeles Patient Study The involvement of Interieukin 12 with CD8+ cell generated was demonstrated in a HIV+ patient study conducted for this patent. Patients with a CDE8+ cell population showed an 84% increase above baseline values and 11 IV viral load was reduced to zero by the administration of polyclonal antibodies to human Interieukin 10. The removal of Interieukin 10 allowed CD8+ cell increase and allowed for HIV viral clearance by restoring HIV specific cell mediated Immune response.
  • Antibody Class IgG
  • IL-1 a IL-1 B, IL-2, IL-3, IL-4, IL-6, IL-7 IL-8, MIP-1a, TNFa and GM-CSF done by EIA.
  • Protocol Summary Run PBMC from HIV- blood first to see if all reagents are performing as expected before proceeding with HIV+ samples 13 Another HIV- sample should be run after all the HIV+ samples have been completed 14. Compile and analyze data. Protocol Summary
  • DHEA combined with Isopentenyl adenosine 5'-monophosphate herein referred to as Compound (D+l).
  • Study Objectives a. Determine the safety and tolerance of administered Compound (D+l) in persons with advanced HIV diseases. b. Determine the effect of administration of Compound (D+l) on measures of HIV Viral Load. Serum PCR (RNA) levels together with HIV p24 antigen (by acid dissociation method). c. Determine the immune and toxicological effects of administered Compound (D+l). d. Determine the pharmokinetics of administered Compound (D+l). Inclusion Criteria a. Age 18 years or older; b. HIV-1 seropositive; c. A CD4+ -T-lymphocyte count of 50 to 300 cells/mm 3 within one month prior to study entry, measured on two separate occasions 72 hours to 28 days apart; d. The following baseline laboratory values.
  • g. Use of suitable contraception by women of childbearing potential (requires one negative serum pregnancy test, beta-HCG, within one week prior to study entry in women of childbearing potential). h.
  • Measures of viral load will include HIV-p24 antigenemia, and HIV-RNA PCR (cell free, serum) and cell HIV-DNA analysis.
  • Clinical benefit will be assessed by change in total body weight, Karnofsky performance score, and amelioration of signs and symptoms of disease present at baseline.
  • Test Drug Compound (D+l) particle size distribution, 87%: ⁇ 5 ⁇ m, 100%: ⁇ 15 ⁇ m, administration in gelatine capsules of 200 mg per capsule.
  • Each capsule contains: 600 mg of DHEA and 600 mg of Isopentenyl adenosine 5' -monophosphate

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention a trait à des médicaments, à leurs procédés de production ainsi qu'à des nécessaires comprenant, (1), un composé de 17-cétostéroïde et/ou (2), un antisérum, polyclonal ou monoclonal, dirigé contre l'interleukine 10, l'interleukine 2 ou l'interleukine 12, ou en combinaison, soit avec n'importe quel composé en mesure d'inhiber réellement une synthèse ou la fonction biologique de l'interleukine 10, de l'interleukine 12 ou de l'interleukine 2, soit avec un agent bloquant de molécule réceptrice de l'interleukine 10, de l'interleukine 12 ou de l'interleukine 2, soit avec un antisérum, qu'il soit polyclonal ou monoclonal, dirigé contre l'alpha-foetoprotéine. Cette invention se rapporte également à des méthodes thérapeutiques faisant intervenir ces composés ou des combinaisons de ces composés, à des méthodes renforçant notamment une réponse immunitaire de protection de Th1 par l'utilisation du composé de 17-cétostéroïde en tant qu'agent antiviral, antibactérien, anti-mycoplasme ou en tant qu'agent antiparasite intracellulaire. L'invention a, en outre, trait à des traitements concernant divers composés et leurs combinaisons.
EP97917365A 1996-04-17 1997-04-17 Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea) Withdrawn EP0901375A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1569596P 1996-04-17 1996-04-17
US15695P 1996-04-17
PCT/IB1997/000414 WO1997038695A1 (fr) 1996-04-17 1997-04-17 Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea)

Publications (1)

Publication Number Publication Date
EP0901375A1 true EP0901375A1 (fr) 1999-03-17

Family

ID=21773003

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97917365A Withdrawn EP0901375A1 (fr) 1996-04-17 1997-04-17 Therapie associee reposant sur l'utilisation de la dehydroepiandrosterone (dhea)

Country Status (9)

Country Link
EP (1) EP0901375A1 (fr)
JP (1) JP2000508654A (fr)
KR (1) KR20000005539A (fr)
CN (1) CN1216470A (fr)
AU (1) AU734807B2 (fr)
CA (1) CA2251733A1 (fr)
IL (1) IL126623A0 (fr)
NO (1) NO984851L (fr)
WO (1) WO1997038695A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010101074A (ko) * 1998-11-24 2001-11-14 추후제출 17-케토스테로이드 화합물 및 그의 유도체, 대사산물 및전구체의 간염 ｃ 바이러스 및 기타 토가바이러스 치료용용도
KR20010101073A (ko) * 1998-11-24 2001-11-14 추후제출 17-케토스테로이드 화합물 및 그의 유도체, 대사산물 및전구체의 아프리카 및 아메리카 크리파노소마증 치료 및말라리아 치료용 용도
US6667299B1 (en) 2000-03-16 2003-12-23 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
AP2001002167A0 (en) * 1998-11-27 2001-06-30 Hollis Eden Pharmaceuticals Use of 17-ketosteroids for the treatment of toxoplasmosis and crytosporidiosis
EP2983705A2 (fr) * 2013-04-10 2016-02-17 Skau Aps Utilisation de peptides immunosuppresseurs en tant qu'adjuvants

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3815472A1 (de) * 1988-05-06 1989-11-16 Centre Regional De Transfusion Monoklonaler antikoerper und seine verwendung
IE882585L (en) * 1988-08-25 1990-02-25 Prendergast Patrick T Viral treatment system
IL94878A (en) * 1989-06-28 2003-01-12 Schering Corp Cytokine synthesis inhibitory factor, antagonists thereof and methods of using same
US5231012A (en) * 1989-06-28 1993-07-27 Schering Corporation Nucleic acids encoding cytokine synthesis inhibitory factor (interleukin-10)
DE69316921T2 (de) * 1992-08-20 1998-06-04 Schering Corp., Kenilworth, N.J. Neue verwendungen für il-10
US5449688A (en) * 1993-03-30 1995-09-12 The United States Of America As Represented By The Department Of Health And Human Services Method of treating chronic inflammatory diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9738695A1 *

Also Published As

Publication number Publication date
NO984851L (no) 1998-12-17
AU2574197A (en) 1997-11-07
CA2251733A1 (fr) 1997-10-23
KR20000005539A (ko) 2000-01-25
WO1997038695A1 (fr) 1997-10-23
IL126623A0 (en) 1999-08-17
JP2000508654A (ja) 2000-07-11
AU734807B2 (en) 2001-06-21
NO984851D0 (no) 1998-10-16
CN1216470A (zh) 1999-05-12

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