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WO1997048367A2 - Compositions et therapie dirigees contre des infections chroniques - Google Patents

Compositions et therapie dirigees contre des infections chroniques Download PDF

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Publication number
WO1997048367A2
WO1997048367A2 PCT/GB1997/001653 GB9701653W WO9748367A2 WO 1997048367 A2 WO1997048367 A2 WO 1997048367A2 GB 9701653 W GB9701653 W GB 9701653W WO 9748367 A2 WO9748367 A2 WO 9748367A2
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WO
WIPO (PCT)
Prior art keywords
glucocorticoid
derivative
tuberculosis
treatment
analogue
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PCT/GB1997/001653
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English (en)
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WO1997048367A3 (fr
Inventor
Graham Arthur William Rook
Rogelio PANDO HERNANDEZ
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Stanford Rook Limited
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Application filed by Stanford Rook Limited filed Critical Stanford Rook Limited
Priority to AU31030/97A priority Critical patent/AU3103097A/en
Publication of WO1997048367A2 publication Critical patent/WO1997048367A2/fr
Publication of WO1997048367A3 publication Critical patent/WO1997048367A3/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the treatment of chronic infections, particularly those in which the metabolism of steroid hormones is disturbed, and more specifically to the provision of methods and compositions comprising combinations of steroidal compounds for the treatment of such infections .
  • Certain chronic infections such as tuberculosis, HIV 19"21 , are characterised by increased adrenal activity in the early phase of the disease, followed by under- activity in the late stages (adrenal insufficiency) .
  • late stages of certain chronic infections such as tuberculosis, syphilis (Parker CR, et al . Proc. Soc. Exp. Biol. Med. (1991) ; 197: 165-167) and HIV are characterised by a fall in the ratio of DHEA to cortisol (both steroid hormones produced by the adrenal glands) , and an immune response biased away from Thl towards a Th2 pattern of lymphocyte response.
  • the Thl pattern is characterised by lymphocytes that release interleukin 2 and interferon gamma, whereas the Th2 lymphocytes release interleukin 4 and their activity is often accompanied by release of interleukin 10 from lymphocytes and other cell types.
  • the effect of interleukins 10 and 4 is to decrease anti-microbial efficiency of the immune response to the infecting organisms (Rook GAW, et al . Bloom BR. Mechanisms of pathogenesis in tuberculosis. In: Bloom BR, ed. Tuberculosis; pathogenesis, protection and control. Washington DC: ASM Press, 1994: 485-501; Clerici M, et al . Immunol. Today.
  • This biasing may, at least in some cases, be a result of an illness-induced imbalance in the hormones and other signals e.g. cytokines which control the production and function of T cells.
  • cytokines which control the production and function of T cells.
  • tuberculosis some patients have infected adrenal glands, resulting in severe adrenal insufficiency and disrupted production of steroidal hormones .
  • Tuberculous mice show adrenal atrophy in the chronic phase of infection (which parallels the human disease)with reductions in weight of the adrenals of up to 50% (Hernandez-Pando R, et al . FEMS Immunol. Med. Microbiol . (1995) ; 12: 63-72) (Fig. 2) .
  • the steroid hormones secreted by the adrenals may be further modified in peripheral tissues, particularly by a series of dehydrogenase, reductase and hydroxylase enzymes, to yield compounds with decreased, increased or otherwise altered activity.
  • Glucocorticoids may be defined by reference to their binding to the glucocorticoid receptor. Some glucocorticoids also bind the mineralocorticoid receptor. Glucocorticoids modulate the immune response by causing dysfunction of T lymphocytes. Pharmacological (i.e. very high) doses will suppress cytokine secretion by mature lymphocytes whether they are Thl or Th2. On the other hand raised physiological levels of glucocorticoids present during the recruitment of an immune response from naive T lymphocytes favour the development of a Th2 cytokine profile.
  • Th-2-mediated diseases such as asthma and hay fever may work via anti-inflammatory effects, and by reducing cytokine production by mature Th2 cells and yet at the same time encourage perpetuation of the underlying problem by driving newly recruited T cells towards Th2 (Daynes RA, et al . J. Invest. Dermatol. (1995) ; 105: 14S-19S; Rook GAW, et al . Immunol. Today (1993) ; 14: 568-569; Brinkmann V, et al . J. Immunol. (1995) ; 155: 3322-8; Ramirez F, et al . J. Immunol. (1996) ; 156: 2406-2412) .
  • Glucocorticoids also cause direct inactivation of anti-mycobacterial mechanisms within macrophages (Brown DH, et al . Infect. Immun. (1995) ; 63: 2983-2988; Rook GA, et al .Eur. J. Respir. Di ⁇ . (1987) ; 71: 286-291) and death by apoptosis of thymocytes (Vacchio MS, et al . J. exp. Med. (1994) ;
  • glucocorticoids have been used as immunosuppressants, for example in inhibition of transplant rejection. They have also found use in the treatment of T lymphocyte leukaemias and as anti- inflammatory drugs in the treatment of e.g. rheumatoid arthritis, however the immunosuppressive action of glucocorticoids severely limits their anti-inflammatory use in tuberculosis and other infectious disease. Tuberculosis is caused by AfycoJbacterium tuberculosis infection which may take hold in various organs, most commonly the lungs. In tuberculosis meningitis, infection causes inflammation of the membranes (meninges) surrounding the brain.
  • the Thl immune response mechanism which is particularly important in the control of M. tuberculosis and Leishmania Major (Leishmaniasis) infection, is particularly sensitive to suppression by glucocorticoids (Lurie MB. Resistance to tuberculosis; experimental studies in native and acquired defensive mechanisms. Cambridge Massachussetts: Harvard University Press, 1964; McCune RM, et al . J. Exp. Med. (1966) ; 123: 469-486; McCune RM, et al . J. Exp. Med. (1966) ; 123: 445-468; Brown DH, et al . Infect. Immun. (1995); 63: 2983-2988; Brown DH, et al . Infect. Immun.
  • glucocorticoids down-regulate the function of macrophages (Rook GA, et al .Eur. J. Respir. Dis. (1987) ; 71: 286-291) , which are the cells that limit the growth of and, when activated by Thl lymphocytes, perhaps actually kill the M. tuberculosis organism. For this reason, administration in tuberculosis treatment must be combined with very effective anti-bacterial drugs administered in tandem (Kumarvelu S, et al . Tuber. Lung. Dis. (1994) ; 75: 203-207) , to help in reducing the side-effects.
  • DHEA is an inflammatory agent and has been proposed as a stimulant of the Thl T cell response (Daynes RA, et al. J. Invest. Dermatol. (1995) ; 105: 14S-19S) , which is the pattern required for immunity to tuberculosis (Rook GAW, et al . Bloom BR. Mechanisms of pathogenesis in tuberculosis. In: Bloom BR, ed. Tuberculosis; pathogenesis, protection and control. Washington DC: ASM Press, 1994: 485-501) .
  • administration of DHEA in tuberculosis may be dangerous as a certain level of glucocorticoid activity is necessary for life. Administration of DHEA to patients already suffering from depressed adrenal function and therefore glucocorticoid insufficiency can therefore be expected to be detrimental .
  • An anti-glucocorticoid is a molecule, which may be a steroid, which opposes one or more effects of a glucocorticoid. As noted, glucocorticoids bind the glucocorticoid receptor.
  • glucocorticoids may have a therapeutic effect in the treatment of HIV infection (Andrieu JM, et al . J. Infect. Dis. (1995); 171: 523-530) , the conclusions drawn from this small study are not generally accepted. In fact there is evidence that glucocorticoids may enhance susceptibility to and growth of Kaposi's sarcoma, a major complication of HIV infection (Guo WX, et al . Am. J. Pathol . (1995) ; 146: 727-734) . Similarly, following the observation that progression to AIDS correlates with a fall in DHEA levels (Wisniewski TL, et al . Am. J. Med. Sci.
  • the present invention has arisen from the surprising finding that the combined administration of a glucocorticoid steroid and an anti-glucocorticoid steroid has a significantly more beneficial effect than would be expected if the detrimental effects of the two compounds simply cancelled each other out, i.e. the combined preparation exhibits an unexpected synergy.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) a glucocorticoid steroid, preferably cortisol, prednisolone or another synthetic analogue of cortisol and ii) an anti- glucocorticoid steroid, preferably DHEA, AED or an anti- glucocorticoid derivative thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of a chronic infection.
  • the present invention provides the use of an anti-glucocorticoid steroid in the manufacture of a medicament for treating a chronic infection.
  • the present invention provides use of a glucocorticoid steroid in the manufacture of a medicament for treating a chronic infection.
  • the present invention provides use of a glucocorticoid steroid, preferably cortisol or prednisolone, and an anti-glucocorticoid steroid, preferably DHEA, AED or a derivative thereof, in the manufacture of a medicament for the treatment of a chronic infection by simultaneous, separate or sequential administration.
  • a glucocorticoid steroid preferably cortisol or prednisolone
  • an anti-glucocorticoid steroid preferably DHEA, AED or a derivative thereof
  • the present invention provides a method of treating an individual suffering from a chronic infection, comprising administration of a glucocorticoid steroid, preferably cortisol, alternatively prednisolone or another analogue of cortisol, and an anti- glucocorticoid steroid, preferably DHEA, AED or a derivative thereof to the individual, simultaneously, separately or sequentially.
  • a glucocorticoid steroid preferably cortisol, alternatively prednisolone or another analogue of cortisol
  • an anti- glucocorticoid steroid preferably DHEA, AED or a derivative thereof
  • Another aspect of the present invention provides a method of making a combined medicament for treatment of a patient with a chronic infection, the method comprising use of a glucocorticoid steroid, preferably cortisol or prednisolone, and an anti-glucocorticoid steroid, preferably DHEA, AED or a derivative thereof, e.g. by admixing DHEA and cortisol, separately or together, with a pharmaceutically acceptable component or vehicle such as an excipient, carrier, buffer, stabiliser or other material, as discussed below, to produce a pharmaceutical composition suitable for simultaneous, separate or sequential administration.
  • a glucocorticoid steroid preferably cortisol or prednisolone
  • an anti-glucocorticoid steroid preferably DHEA, AED or a derivative thereof, e.g. by admixing DHEA and cortisol, separately or together, with a pharmaceutically acceptable component or vehicle such as an excipient
  • glucocorticoid steroid preferably cortisol
  • hydrocortisone or an analogue thereof such as prednisolone
  • an anti-glucocorticoid steroid preferably DHEA, AED or a derivative thereof
  • a kit or pack containing components A and B, wherein component A includes a glucocorticoid steroid, preferably cortisol or an analogue thereof such as prednisolone, and component B includes an anti-glucocorticoid steroid such as DHEA, AED or a derivative thereof, components A and B being formulated for simultaneous, separate or sequential delivery in the treatment of a chronic infection.
  • the chronic infections with which the present invention is concerned may be characterised by the infected individual having one or more of; disturbed metabolism of steroid hormones; adrenal insufficiency, atrophy or other abnormality of the adrenal glands; low DHEA/cortisol ratio in the blood, preferably reflected by altered levels of steroid metabolites in the urine; and biasing of the immune response away from the Thl response and towards the Th2 response.
  • the chronic infection may be one in which the Thl immune response plays a greater role in control of infection than does the Th2 response.
  • tuberculosis particularly infections to which the methods and compositions of the present invention may be applied include tuberculosis, HIV, leishmaniasis, syphilis and the like.
  • the present inventors have surprisingly found that the combined administration of a glucocorticoid steroid and an anti-glucocorticoid steroid has a strikingly beneficial effect on the progression of tuberculous infection.
  • combined treatment increases the response to M. tuberculosis in skin tests, and increases survival times for tuberculosis infected animals whilst decreasing inflammation.
  • Thl response There is evidence of increased Thl response; the Th2-enhancing effect of the glucocorticoid has been removed, but the Thl enhancing effect of the anti-glucocorticoid has not.
  • DHEA derivatives increase inflammation while glucocorticoids decrease it, the anti- glucocorticoid effect is removed but the glucocorticoid effect remains because the inflammation is decreased.
  • the effect is significantly more beneficial than would be expected if the detrimental effects of the two compounds simply cancelled each other out, i.e. the combined preparation exhibits a synergy which could not have been predicted, and is surprising.
  • compositions provided herein may comprise a glucocorticoid and an anti-glucocorticoid steroid as combined (simultaneous or sequential) actives.
  • compounds may be employed which mimic a given active in improving diagnostic status and/or ameliorating one or more symptoms in a chronic infection (mimetics) .
  • Such compounds and their use are within the scope of the present invention.
  • Mimetics may be identified or obtained by screening of other compounds or by more rational design, and this is discussed further below.
  • derivatives or analogues of DHEA or cortisol which retain the anti-glucocorticoid or glucocorticoid activity, respectively.
  • DHEA DHEA
  • AED 3/3,17/3-androstenediol
  • AET 3/3,7,17 / 3- androstenetriol
  • synthetic glucocorticoids may be used, for example prednisone or prednisolone, or dexamethasone, (all available as tablets) , methylprednisolone, dexamethasone or triamcinolone (all available for injection) .
  • Hydrocortisone sodium succinate or hydrocortisone acetate are also available glucocorticoid injectables and cortisone could also be used since it is rapidly metabolised to active cortisol.
  • the designing of mimetics to a known pharmaceutically active compound is a known approach to the development of pharmaceuticals based on a "lead” compound e.g. DHEA, AED or cortisol.
  • Mimetic design, synthesis and testing is generally used to avoid randomly screening large number of molecules for a target property.
  • the pharmacophore Once the pharmacophore has been found, its structure is modelled according to its physical properties, eg stereochemistry, bonding, size and/or charge, using data from a range of sources, eg spectroscopic techniques, X- ray diffraction data and NMR. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modelling process.
  • a range of sources eg spectroscopic techniques, X- ray diffraction data and NMR.
  • Computational analysis, similarity mapping which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms
  • other techniques can be used in this modelling process.
  • the three-dimensional structure of the ligand and its binding partner are modelled. This can be especially useful where the ligand and/or binding partner change conformation on binding, allowing the model to take account of this the design of the mimetic.
  • a template molecule is then selected onto which chemical groups which mimic the pharmacophore can be grafted.
  • the template molecule and the chemical groups grafted on to it can conveniently be selected so that the mimetic is easy to synthesise, is likely to be pharmacologically acceptable, and does not degrade in vivo, while retaining the biological activity of the lead compound.
  • the mimetic or mimetics found by this approach can then be screened to see whether they have the target property, or to what extent they exhibit it. Further optimisation or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.
  • compositions provided may be administered to individuals. Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated.
  • Dose regimens for the glucocorticoids may be within the range used for the anti-inflammatory treatment of acute rheumatoid arthritis, or TB meningitis.
  • a maximal dose may be lmg/kg or more, although doses of about 40-70mg/kg or 50-60mg/kg, possibly as low as 0.25mg/kg, or even less, may be suitable.
  • DHEA has been given orally to humans in other indications at 50mg/day which corresponds to about 0.8mg/kg which was also the approximate level at which AED was administered to mice in the experimental work discussed below (25 ⁇ g AED three times/week in 25g mice) .
  • About 25-100mg/day may be a suitable dose range, however doses of 200mg every four weeks may be a suitable alternative dosage regime in certain circumstances.
  • compositions according to the present invention may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous. Clearly patients prefer oral drugs, but when people are very sick, injection is preferred (intravenous or intramuscular), because it is more accurate, the drug is not vomited up, etc.
  • one embodiment of the present invention may provide an intravenous injection of hydrocortisone sodium succinate plus dehydroepiandrosterone (DHEA) sulphate or androstenediol (AED) sulphate.
  • DHEA and AED derivatives can all also be given orally, as the free compound e.g. in oil, or as water soluble sulphates.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • Figure 1 Shows the % survival of mice with pulmonary TB after treatment with AED alone, corticosterone alone or AED with corticosterone compared to untreated mice.
  • the % surivival figures are shown at days after intratracheal infection with M. tuberculosis .
  • AED 25 ⁇ g was given by subcutaneous injection dissolved in olive oil, 3 times/week (Mon, Wed, Fri) .
  • Corticosterone was added to drinking water at 3 ⁇ g/ml. (Triangles - AED; squares - corticosterone; closed circles - AED and corticosterone; open circles - controls.)
  • FIG. 2 Shows the effect of M. tuberculosis infection in mice on the weight of the adrenal gland.
  • the weight of the right adrenal (mg) is shown at days after intratracheal infection with 10 6 M. tuberculosis .
  • Figure 3 shows the effect of treatment with corticosterone (3 ⁇ g/ml in the drinking water) and and AED (25 ⁇ g s.c. x3 each week - Mon, Wed and Fri - from day 60 after infection) on delayed hypersensitivity to tuberculin. Foot-pad swelling in microns is shown at days since intratracheal infection with M. tuberculosis .
  • Figure 4 shows the therapeutic effect in murine tuberculosis of corticosterone (3 ⁇ g/ml in drinking water; physiological level) and androstenediol (50 ⁇ g x3/ week, in olive oil, s.c) .
  • Figure 4A shows the % of lung affected by pneumonia at days since intratracheal infection with M. tujbercul osi s .
  • Figure 4B shows area of granuloma of lung ( ⁇ 2 ) at days since intratracheal infection with M. tuberculosis .
  • mice were infected (intra tracheal infection) with 10 (Swartz SL, et al . Drugs. (1978) ; 16: 238-255) M. tuberculosis and the weight of the right adrenal gland was monitored through the progression of the infection. After an early phase of adrenal hypertrophy lasting only 3 weeks (Fig.2) the gland atrophies so that in the chronic phase the glands have reduced to 50% of their normal size (Hernandez-Pando R, et al . FEMS Immunol. Med. Microbiol. (1995) ; 12: 63-72) .
  • mice in this phase of the disease were treated with AED (25 ⁇ g in olive oil, administered by subcutaneous injection 3 times a week) or with corticosterone (3 ⁇ g/ml in drinking water) or with both.
  • AED 25 ⁇ g in olive oil, administered by subcutaneous injection 3 times a week
  • corticosterone 3 ⁇ g/ml in drinking water
  • Fig.l the mice treated with AED alone died more rapidly than did untreated infected animals.
  • This treatment was initiated at day 60 when the adrenals are already atrophied (see Fig. 2) .
  • the AED is detrimental, causing not only accelerated death, but also increased tissue-damaging pathology in the lungs .
  • the same detrimental result would be obtained if AED or DHEA were given to human patients at the stage of disease where adrenal function is reduced.
  • the same dose of AED given to normal mice, or to mice at the start of their tuberculosis when the adrenals are increased in size does not cause any detrimental effect and can delay progress of the disease (
  • mice receiving corticosterone alone from day 60 also died rapidly. It should be noted that the mice were receiving no antibacterial drug therapy so the immune dysfunction caused by the glucocorticoid therapy is very apparent. This is equivalent to giving glucocorticoids to a human patient with multidrugresistant disease.
  • mice given combined therapy were strikingly improved relative to untreated controls .
  • Thl lymphocyte accumulation at the injection site was markedly greater for mice receiving the combined treatment than for those receiving no steroid at all.
  • mice were infected by the intraacheal route with M. tuberculosis , and then treated from day 60 with either placebo (saline) three times/week, or with AED (50 ⁇ g three times/week) and corticosterone (3 ⁇ g/ml) in drinking water.
  • the lungs of representative animals were studied at intervals by microscopy and morphometry.
  • Treatment with the steroids decreased the percentage of the lung affected by pneumonia and increased the area of granuloma. It is known that areas of pneumonia contain equal numbers of Th2 and Thl lymphocytes, and correlate with rapid death. On the other hand areas of granuloma are dominated by Thl lymphocytes, and correlate with control of bacterial replication (Hernandez-Pando, et al .

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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)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation simultanée, séparée ou séquentielle, d'une part d'un glucocorticoïde tel que le cortisol, l'un de ses dérivés ou l'un de ses analogues, et d'autre part d'un anti-glucocorticoïde tel que le déhydroépiandrostérone (DHEA), l'un de ses dérivés ou l'un de ses analogues, pour une thérapie dirigée contre des infections chroniques telles que la tuberculose, l'infection par le VIH, la leishmaniose et la syphilis.
PCT/GB1997/001653 1996-06-20 1997-06-18 Compositions et therapie dirigees contre des infections chroniques WO1997048367A2 (fr)

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AU31030/97A AU3103097A (en) 1996-06-20 1997-06-18 Compositions and methods for the treatment of chronic infections

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GBGB9612990.3A GB9612990D0 (en) 1996-06-20 1996-06-20 Compositions and methods for the treatment of chronic infections
GB9612990.3 1996-06-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006036484A3 (fr) * 2004-09-24 2006-06-01 Rxdino Llc Traitement de dermatite au moyen de combinaisons de deshydroepiandrosterone-glucocorticoide
US7405207B2 (en) 2002-06-17 2008-07-29 Epigenesis Pharmaceuticals, Inc. Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof
EP1955700A2 (fr) 1999-09-30 2008-08-13 Hollis-Eden Pharmaceuticals Inc. Traitement thérapeutique des conditions de commande de récepteur androgène
US7456161B2 (en) 2001-04-24 2008-11-25 Epigenesis Pharmaceuticals, Llc Use of DHEA and DHEA-sulfate for the treatment of chronic obstructive pulmonary disease

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL194728C (nl) * 1987-04-16 2003-01-07 Hollis Eden Pharmaceuticals Farmaceutisch preparaat geschikt voor de profylaxe of therapie van een retrovirale infectie of een complicatie of gevolg daarvan.
US5077284A (en) * 1988-12-30 1991-12-31 Loria Roger M Use of dehydroepiandrosterone to improve immune response
AU652130B2 (en) * 1989-09-25 1994-08-18 University Of Utah Research Foundation Use of steroid hormones in compositions for inducing T cell lymphokine production
US5387583A (en) * 1993-04-20 1995-02-07 Loria; Roger M. Compositions containing corticosteroids or analogues thereof and corticosteroid buffering effective amounts of 5-androstene 3B, 17B or 5-androstene 3B, 7B, 17B triol or analogues thereof
WO1995030418A1 (fr) * 1994-05-09 1995-11-16 The Johns Hopkins University Procede permettant de ralentir la progression de l'infection a vih

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1955700A2 (fr) 1999-09-30 2008-08-13 Hollis-Eden Pharmaceuticals Inc. Traitement thérapeutique des conditions de commande de récepteur androgène
US7456161B2 (en) 2001-04-24 2008-11-25 Epigenesis Pharmaceuticals, Llc Use of DHEA and DHEA-sulfate for the treatment of chronic obstructive pulmonary disease
US7405207B2 (en) 2002-06-17 2008-07-29 Epigenesis Pharmaceuticals, Inc. Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof
WO2006036484A3 (fr) * 2004-09-24 2006-06-01 Rxdino Llc Traitement de dermatite au moyen de combinaisons de deshydroepiandrosterone-glucocorticoide

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WO1997048367A3 (fr) 1998-02-05
GB9612990D0 (en) 1996-08-21

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