WO1995010283A1 - Traitement d'affections d'ordre medical associees a la formation de radicaux libres - Google Patents

Traitement d'affections d'ordre medical associees a la formation de radicaux libres Download PDF

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Publication number
WO1995010283A1
WO1995010283A1 PCT/AU1994/000619 AU9400619W WO9510283A1 WO 1995010283 A1 WO1995010283 A1 WO 1995010283A1 AU 9400619 W AU9400619 W AU 9400619W WO 9510283 A1 WO9510283 A1 WO 9510283A1
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Prior art keywords
cholestane
pentahydroxy
patient
scymnol
derivative
Prior art date
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PCT/AU1994/000619
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English (en)
Inventor
Theodore Macrides
Original Assignee
J.W. Broadbent Nominees Pty. Ltd.
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Filing date
Publication date
Application filed by J.W. Broadbent Nominees Pty. Ltd. filed Critical J.W. Broadbent Nominees Pty. Ltd.
Priority to EP94930119A priority Critical patent/EP0804204A4/fr
Priority to AU79340/94A priority patent/AU684845B2/en
Publication of WO1995010283A1 publication Critical patent/WO1995010283A1/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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair

Definitions

  • the present invention relates to the treatment of medical disorders arising from biochemical and cellular damage resulting from the action of free radicals in animals, including humans.
  • a free radical is any species capable of independent existence that contains one or more unpaired electrons. Such species show paramagnetism and may be highly reactive. The formation and reactions of free radicals have been reviewed generally by Halliwell and Gutteridge (1984), while Slater (1984) has provided a discussion of cell injuries that are mediated by free radical intermediates, as well as general concepts relevant to free radical processes and to mechanisms of protection against such types of injury.
  • Some biological processes generate more or less stable intermediates that contain an unpaired electron, which can either be donated, or paired with an additional electron from the surroundings.
  • Such intermediates are called free radicals, and they may be the products of various enzymatic and non-enzymatic reactions, some of which are vital for body functions, e.g. reduction of ribonucleoside diphosphates for DNA synthesis and the generation of prostaglandins in the prostaglandin synthase reaction. The latter is essential for inflammatory response following cell injury, and a number of other functions.
  • Most organisms contain chemical antioxidants such as ⁇ -tocopherol (vitamin E), ascorbic acid and different radical and peroxide-inactivating enzymes, e.g.
  • Lipid peroxidation caused by excess generation of radicals may constitute one significant damaging pathway in the above conditions and diseases.
  • Administration of additional antioxidants, which inhibit radical reactions, e.g. lipid peroxidation, would thus provide a way of preventing or curing the above conditions and diseases.
  • Free radicals cause cellular damage by different mechanisms such as oxidation of thiol groups of proteins, DNA strand breaks and lipid peroxidation.
  • the properties of free radicals include: high reactivity with a consequent extremely short life span, self perpetuating and diverse chemical reactivity, low chemical specificity and the ability to be generated both in vivo and in vitro.
  • Free radicals are cellular, and environmental. Free radical production may also be increased during vascular disease states, e.g. inflammation and during unfavourable metabolic conditions such as hypoxia and tissue ischaemia. Free radicals have also been proposed to cause oxidative damage to biological molecules involved in the development of many severe disorders of humans, including atherosclerosis, cancer and parasitic viral infections.
  • Free radical molecular species include, but are by no means limited to, hydroxyl, peroxyl, hypochlorite, superoxide and alkoxy radicals, and reactive molecules such as hydrogen peroxide. They also include singlet oxygens which are not free radicals but are certainly reactive and capable of causing cellular damage.
  • antioxidants Two types of antioxidants can be identified, namely biological and non-enzymatic biological antioxidants.
  • biological and non-enzymatic biological antioxidants include tocopherols, carotenoids, bilirubin, ascorbic acid, uric acid and metal-binding proteins as typical examples.
  • oxygen radicals are known to be capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, proteins and free amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These compounds may have an impact on such cell activities as membrane function, metabolism, and gene expression. (See Halliwell et al. 1985, 1986.)
  • Clinical conditions in which oxygen radicals are thought to be involved include those concerning multiorgan involvement, including inflammatory-immune injury such as glomerulonephritis (idiopathic, membranous), vasculitis (hepatitis B virus, drugs), autoimmune disease; ischaemia-reflow states; drug and toxin- induced reactions; iron overload such as idiopathic haemochromatosis, dietary iron overload (red wine, beer brewed in iron pots), thalassemia and other chronic anaemias; nutritional deficiencies, such as Kwashiorkor, vitamin E deficiency; alcohol; radiation injury; ageing, such as disorders of "premature ageing", immune deficiency of age; cancer and amyloid diseases.
  • inflammatory-immune injury such as glomerulonephritis (idiopathic, membranous), vasculitis (hepatitis B virus, drugs), autoimmune disease; ischaemia-reflow states; drug and toxin- induced reactions; iron overload such as i
  • Additional conditions in which oxygen radicals are thought to be involved include those concerning primary single organ involvement including erythrocyte related conditions, such as phenylhydrazine, primaquine, lead poisoning, protoporphyrin photo-oxidation, malaria, sickle-cell anaemia, fauvism, Fanconi anaemia; lung related conditions such as cigarette-smoking effects, emphysema, hyperoxia, bronchopulmonary dysplasia, oxidant pollutants, acute respiratory distress syndrome, mineral dust pneumoconiosis, bleomycin toxicity, paraquat toxicity; heart and cardiovascular system related conditions, such as alcohol cardiomyopathy, Keshan disease (selenium deficiency), atherosclerosis, doxorubicin toxicity; kidney related conditions, such as nephrotic antiglomerular basement membrane disease, aminoglycoside nephrotoxicity, heavy metal nephrotoxicity, renal grant rejection; gastrointestinal tract related conditions, such as endotoxin liver injury, carbon te
  • Free radicals are therefore potentially dangerous in living systems, and it is biologically advantageous for cells to control the amount of radicals allowed to accumulate.
  • the chelating effect of iron bound to protein, such as in transferring, renders the iron almost completely inactive in accelerating lipid peroxidation and hydroxyl radical formation.
  • Other protective mechanisms include catalase, which exists to remove H 2 0 2 within cells, converting it to H 2 0.
  • Glutathione peroxidase also reduces H 2 0 2 to H 2 0 through the involvement of glutathione, itself an antioxidant that may quench radicals, as do other molecules such as ascorbate, urate, glucose and metallothioniens (Halliwell et al., 1986).
  • the bile alcohols are a group of polyhydroxylated steroids derived structurally from 5 ⁇ -cholestane or 5 ?-cholestane (also known as coprostane). They include, for example, the compounds known as 5 ?-scymnol (3 ⁇ , la, 12 ⁇ ,
  • Scymnol is an unusual bile alcohol in that the terminal methyl groups, C26 and C27 together with C24, are present as alcohols.
  • the natural bile salt occurs as the 27-sulphate sodium salt and was first isolated by Hammerstein in 1898 from the gall bladders of the shark Scymnus borealis .
  • a method for the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient which comprises administering to the patient an effective amount of a bile alcohol or a derivative thereof.
  • the present invention also extends to a composition for use in the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient, which comprises an effective amount of a bile alcohol or a derivative thereof, together with a pharmaceutically acceptable carrier or diluent.
  • the present invention is principally directed to the treatment of human patients, it is to be understood that in its broadest aspect the invention also extends to the treatment of non-human patients, especially non-human mammals.
  • the medical disorders associated with free radical formation which may be treated in accordance with the present invention include those described above arising from biochemical damage to nucleic acids, proteins and free amino acids, lipids and lipoproteins, carbohydrates and connective tissue macromolecules. They include, in particular, the results of photodamage to the skin following UV irradiation so that in one particular aspect, the present invention includes a method and composition as described above for the treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting from UV irradiation.
  • the present invention includes a method and a composition as described above for the treatment of inflammatory disorders or conditions of the skin of a patient.
  • bile alcohols which may be used in the method or composition of this invention include any of the group of polyhydroxylated steroids derived structurally from 5 ⁇ -cholestane or 5 ?-cholestane (or coprostane).
  • Preferred bile alcohols are compounds in this group which include at least one hydroxyl group, preferably two or three hydroxyl groups, at positions 24, 25, 26 and/or 27 of the cholestane molecule. Most preferred are bile alcohols with hydroxyl groups at positions 26 and 27 of the cholestane molecule.
  • Particularly preferred bile alcohols for use in accordance with the present invention include:
  • the derivatives of bile alcohols which may be used in accordance with the present invention include esters with inorganic acids such as sulphuric acid or organic acids such as acetic acid, propionic acid and butyric acid.
  • Particularly preferred bile alcohol derivatives for use in accordance with the present invention include: 5/?-scymnol sulphate 5 ⁇ -cyprinol sulphate.
  • the bile alcohols or derivatives will normally be administered orally, rectally, dermally or topically, or by injection, in the form of pharmaceutical preparations comprising an effective amount of the active substance in a pharmaceutically acceptable dosage form.
  • Suitable pharmaceutically acceptable dosage forms are well known and are described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA.
  • the dosage form may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
  • Dermal or topical administration would normally utilise 0.1-10% by weight, more specifically 0.5-5% by weight, of the active substance in a suitable dermal or topical carrier or vehicle.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g.
  • the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active substances.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the abovementioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl-cellulose as a thickening agent or other excipients known to the man in the art.
  • Preparations for parenteral applications by injection can be prepared in an aqueous solution or suspension of the active substance, preferably in a concentration of from about 0.5% to about 10% by weight.
  • These preparations may also contain stabilising agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • the active substance of this invention is to be used for the treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting from UV radiation
  • the active substance is preferably formulated so as to be administered topically.
  • an effective amount of the active substance is incorporated into a suitable carrier material as a topical pharmaceutical/cosmetic composition which may be made up in a variety of product types including, for example, lotions, creams, oils, gels, sticks, sprays, ointments, pastes, mousses and cosmetics.
  • topical pharmaceutical/cosmetic carrier materials for such compositions are also well known and are described by way of example in International Patent Application No. PCT/US91/02400.
  • topical pharmaceutical/cosmetic compositions may also include one or more penetration enhancing agent(s), and/or anti-inflammatory agent(s), as well as sunscreen or sunblock agent(s) to enhance protection of the skin against the effects of UV irradiation.
  • the bile alcohols particularly 5/?-scymnol and 5 ⁇ -cyprinol, and their derivatives, particularly 5 ?-scymnol sulphate and 5cr-cyprinol sulphate, are surprisingly effective free radical scavengers, particularly of hydroxyl radicals.
  • TSA thiobarbituric acid
  • Deoxyribose is utilised as the target for hydroxyl radical attack which breaks down to produce a three carbon compound malondialdehyde (MDA) which forms a characteristic chromogenic adduct with two molecules of TBA (Gutteridge, 1981).
  • MDA malondialdehyde
  • the three test compounds used as measures of comparison were the known free radical scavengers, promethazine, mannitol and dimethyl sulphoxide (DMSO).
  • Mannitol has been utilised as a model scavenger widely by Moorhouse et al. (1987) however its scavenging ability is somewhat less than that of promethazine, a known hepatoprotector against carbon tetrachloride free radical attack.
  • Moorhouse et al. , (1987) have also found that dimethyl sulphoxide is a potent free radical scavenger. Through the use of these compounds, a qualitative analysis of the abilities of test compounds
  • free radicals may be generated on the surface of skin by the action of the environment, particularly ultraviolet radiation (UVR).
  • UVR ultraviolet radiation
  • sunscreen In the absence of a sunscreen there is nothing to attenuate the effect of UVR and so the potential for free radical formation must be highest in the outermost layers of the skin.
  • Topical application of antioxidants and free radical scavengers has been shown to provide a wide range of benefits to living skin. In most cases it has not been shown that the protectant molecule has penetrated to the viable tissues, but the half life of a free radical is so short that it is difficult to imagine any other mechanism (notwithstanding that free radicals can set up a chain of reactions). Oxygen free radicals and other reactive oxygen species have been shown to be involved in UVR damage to the skin.
  • UVA UV-sensitive UV receptor
  • UVR UV receptor
  • Peroxidation by UVR of the lipid causes damage to cell membranes at the subcellular level, leading to cell damage.
  • free radical scavengers Free radical scavengers also suppress the formation of erythema, sunburn cells, peroxidation of lipids, increased production of ornithine decarboxylase, promotion and initiation of skin cancer, and premature aging of the skin.
  • a free radical scavenger such as a bile alcohol or a derivative thereof may be effective in much smaller amounts, and so not adversely affect the other hair properties, and may favourably influence the greasiness of skin and hair.
  • Perception of greasiness is a function of the total quantity of sebum and of its viscous properties. The latter are a function of the degree of crystallinity of the sebum and will be influenced by peroxidative processes against which free radical scavengers can protect.
  • Acne is a chronic inflammatory disease of the pilosebaceous units which is most prevalent in teenage years. It is characterised by the formation of both inflammatory and non inflammatory lesions which affect primarily the face, neck and trunk.
  • Four major factors are involved in the pathogenesis: increased sebum production, an abnormality of the microbial flora, comification of the pilosebaceous duct and the production of inflammation.
  • Topical therapy is usually effective for the management of mild to moderate acne, however patients with severe acne usually require oral and topical treatment.
  • Benzoyl peroxide is well established as a topical agent in the treatment of acne as it is an effective keratolytic, comedolytic, antimicrobial and anti-inflammatory agent. It has now been shown that the bile alcohols and derivatives are effective anti-inflammatory agents when applied topically to the skin.
  • Gutteridge (1981) A combination of ascorbic acid (0.1 mM), ferrous ammonium sulphate (0.22 mM) and EDTA (0.23 mM), added in this order, produced a hydroxyl radical generating system which after being sparged in nitrogen was added to a solution of deoxyribose (1.0 mM) in phosphate buffer (20 mM, pH 7.4).
  • Ascorbate is almost invariably contaminated with iron salts and is able to initiate the reaction alone, hence its inclusion in the iron salt solution avoided premature initiation of the reaction during preincubation.
  • all glassware used in the procedure was washed with concentrated hydrochloric acid and rinsed twice with milli Q water. All solutions were also made up with milli Q water.
  • Table 1 shows that 5/?-scymnol gave very high levels of protection against deoxyribose damage as did 5 ⁇ -cyprinol.
  • the sulphated bile salts were not as protective, giving levels of protection similar to promethazine and DMSO.
  • Figure 1 shows the combined inhibition studies from 3 experiments for the scavengers.
  • Rate constants for 5 ?-scymnol and 5 ?-scymnol sulphate were determined from their respective slopes from Lineweaver-Burk plots and calculated to be 0.267 M “1 S "1 and 0.195 M “1 S “1 respectively.
  • the rate constant for mannitol was determined in the same manner as the bile salts and calculated to be 0.49 M "1 S '1 .
  • the hydroxyl radicals were generated via the Fenton reaction with deoxyribose used as the target for radical attack. The reaction was run for 30 minutes at 37°C. Results are expressed as the average of three experiments ⁇ S.E.M.
  • the apparent radical scavenging ability for hydroxyl radicals shown by 5 ⁇ - scymnol may be attributed to the hydroxy methyl groups at C26 and C27.
  • the precursor, cholic acid which does not possess the unique 1 ,3 diol structure was assayed for comparison.
  • Cholic acid has a terminal carboxylic acid at C24, therefore it can be suggested that the effectiveness of 5/?-scymnol as a scavenger is due to the C26 and C27 hydroxy methyl groups, since the remainder of the molecule has an identical 5 ?-steroid structure to that of cholic acid.
  • Trolox [6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid] is a hydrophilic analogue of ⁇ -tocopherol with antioxidant activity more active than BHA, BHT, nordihydroguaiaretic acid (NDGA) and propyl gallate (PG).
  • ROS ROS
  • ROS TEST SYSTEM A Superoxide radical Hypoxanthine/xanthine oxidase production of urate. Comparison with Trolox and vitamin C.
  • Microsomal lipid peroxidation Microsomes were isolated from rat livers and their peroxidation in the presence of iron ions and ascorbic acid was measured by thiobarbituric acid (TBA).
  • Peroxyl radical scavenging The ability of the compounds to scavenge alkylperoxyl radicals generated in the aqueous - 19 - phase by the controlled thermolysis of 2,2'-azo- bis-(2-amidinopropane)dihydrochloride(ABAP).
  • Mild to moderate acne was defined as primarily open and closed comedones and some superficial inflamed lesions (papules not pustules).
  • 44 male and 26 female were included according to certain criteria, i.e. they were older than 12 years, free from intercurrent disease, and not taking systemic antibiotics, corticosteroids, retinoids, anticonvulsants or androgens in the 30 days prior to starting the trial.
  • No topical acne therapy was allowed in the two weeks before the trial.
  • Isolutrol 5 ?-scymnol sulphate (Isolutrol) was supplied as a solution with a concentration of 0.15gm/100ml (purified by McFarlane Marketing (Aust.) Pty.Ltd.).
  • the benzoyi peroxide was a commercially available 5% water-based solution. All treatments were pre-packed in identical numbered packages.
  • the trial was designed as a double blind study and the patients were instructed not to describe to the investigator any characteristics of the product such as colour, smell or consistency.
  • An initial baseline assessment was carried out and patients were reassessed at two, four, eight and twelve weeks.
  • the severity of each patient's acne was determined using the "counting technique" described by Burke and Cunliffe (1984). All patient assessments were carried out by the same investigator.
  • the parameters used to assess the relative efficacy of each treatment were changes in the number of superficial inflamed lesions, as well as non- inflamed lesions (open and closed comedones) over the duration of the trial.
  • An assessment of skin tolerance was also conducted at each review with respect to burning and stinging, erythema, scaling, pruritus and dryness. These were graded from 0-nil, 1-mild, 2-moderate to 3-severe, and the patient was asked to comment on any adverse effects experienced.
  • the mean age of patients was 18.6 years (range 13-35 years). There was no significant difference between the two study groups with respect to age, sex, duration of acne, or baseline assessment of facial erythema, pruritus, burning and stinging, dryness, and scaling.
  • Clinical assessment for skin dryness, erythema, pruritus and scaling showed a significant difference between the isolutrol group and the benzoyi peroxide groups at two weeks (p ⁇ 0.05) and four weeks (p ⁇ 0.05), eight weeks (p ⁇ 0.05) and 12 weeks (p ⁇ 0.05), the benzoyi peroxide showed increased dryness, erythema, pruritus and scaling.
  • Clinical assessment for skin burning showed a significant difference between the isolutrol group and the benzoyi peroxide group at two weeks (p ⁇ 0.05), the benzoyi peroxide showing increased skin burning. There was no significant difference between the treatment groups for the clinical assessment of skin burning at four, eight or 12 weeks. Overall, 94% of benzoyi peroxide treated patients reported unwanted effects during the trial, whereas only 34% of isolutrol treated patients reported such problems (see Table 3).
  • Isolutrol is an effective treatment for the reduction in the severity of acne.
  • Isolutrol is as effective as benzoyi peroxide in reducing the numbers of inflamed lesions however, unlike benzoyi peroxide, Isolutrol is not capable of significantly reducing the numbers of non-inflamed lesions. It is possible that this difference may be due to the different modes of action and the particular efficacy of Isolutrol in reducing the number of inflamed lesions indicates that Isolutrol has anti-inflammatory properties in addition to reducing hyperseborrhoea. Clinical assessment of side-effects showed that Isolutrol was more acceptable than benzoyi peroxide in the first month of treatment.
  • Isolutrol may prove to be a useful adjunct to the treatment regime of patients unable to tolerate benzoyi peroxide.

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Abstract

Un procédé de traitement de lésions biochimiques ou d'une affection d'ordre médical asociées à la formation de radicaux libres chez un patient consiste à administrer à ce dernier une dose efficace d'un alcool biliaire ou d'un dérivé de ce dernier, en particulier le 5β-scymnol, du sulfate de 5β-scymnol, du 5α-cyprinol ou sulfate de 5α-cyprinol. L'invention se rapporte également au traitement de lésions dermatologiques et/ou capillaires produites par la lumière, et associées à la formation de radicaux libres provoquée par un rayonnement ultraviolet, ainsi qu'au traitement de troubles de ou d'états inflammatoires de la peau. Des compositions sont également décrites, y compris des compositions topiques.
PCT/AU1994/000619 1993-10-12 1994-10-12 Traitement d'affections d'ordre medical associees a la formation de radicaux libres WO1995010283A1 (fr)

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EP94930119A EP0804204A4 (fr) 1993-10-12 1994-10-12 Traitement d'affections d'ordre medical associees a la formation de radicaux libres
AU79340/94A AU684845B2 (en) 1993-10-12 1994-10-12 Treatment of medical disorders associated with free radical formation

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AUPM1752 1993-10-12
AUPM175293 1993-10-12

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FR2760362A1 (fr) * 1997-03-10 1998-09-11 Vitasterol Utilisation cosmetique ou dermatologique de steroides 7-hydroxyles
EP1633337A2 (fr) * 2003-05-29 2006-03-15 Mitos Pharmaceuticals, Inc Methodes d'utilisation de nitroxydes conjointement avec des photosensibilisants et des sonosensibilisants
WO2008078096A2 (fr) * 2006-12-23 2008-07-03 Renovo Limited Médicaments et méthodes pour favoriser la contraction d'une plaie
WO2013090986A1 (fr) * 2011-12-20 2013-06-27 Mcfarlane Marketing (Aust.) Pty. Ltd. Traitement de la séborrhée
US9090652B2 (en) 2006-06-27 2015-07-28 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions

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AU3186189A (en) * 1988-02-19 1989-09-06 J.W. Broadbent Nominees Pty. Ltd. Isolation of 24-R scymnol
AU8079891A (en) * 1990-06-30 1992-01-23 Tsumura & Co., Ltd. Bile alcohol and drug containing the same as active ingredient

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JP3555762B2 (ja) * 1991-10-16 2004-08-18 リチャードソン、ビックス、インコーポレーテッド 非イオン性ポリアクリルアミド誘導体を含有した低ｐＨ水性化粧品ゲル
AU675211B2 (en) * 1991-10-16 1997-01-30 Richardson-Vicks Inc. Enhanced skin penetration system for improved topical delivery of drugs
EG20380A (en) * 1991-10-16 1999-02-28 Richardson Vicks Inc Enhanced skin penetration system for improved topical delivery of drugs

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WO1998040074A1 (fr) * 1997-03-10 1998-09-17 Vitasterol (S.A.R.L.) Utilisation cosmetique ou dermatologique de steroides 7-hydroxyles
US6407084B2 (en) 1997-03-10 2002-06-18 Vitasterol Sarl Cosmetic or dermatological use of 7-hydroxylated steroids
US6620803B2 (en) 1997-03-10 2003-09-16 Vitasterol Sarl Cosmetic or dermatological use of 7-hydroxylated steroids
FR2760362A1 (fr) * 1997-03-10 1998-09-11 Vitasterol Utilisation cosmetique ou dermatologique de steroides 7-hydroxyles
EP1633337A2 (fr) * 2003-05-29 2006-03-15 Mitos Pharmaceuticals, Inc Methodes d'utilisation de nitroxydes conjointement avec des photosensibilisants et des sonosensibilisants
EP1633337A4 (fr) * 2003-05-29 2007-09-05 Mitos Pharmaceuticals Inc Methodes d'utilisation de nitroxydes conjointement avec des photosensibilisants et des sonosensibilisants
US9090652B2 (en) 2006-06-27 2015-07-28 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US9763964B2 (en) 2006-06-27 2017-09-19 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
WO2008078096A2 (fr) * 2006-12-23 2008-07-03 Renovo Limited Médicaments et méthodes pour favoriser la contraction d'une plaie
WO2008078096A3 (fr) * 2006-12-23 2008-08-28 Renovo Ltd Médicaments et méthodes pour favoriser la contraction d'une plaie
AU2012321108B2 (en) * 2011-12-20 2015-07-09 Mcfarlane Marketing (Aust.) Pty. Ltd. Treatment of seborrhoea
WO2013090986A1 (fr) * 2011-12-20 2013-06-27 Mcfarlane Marketing (Aust.) Pty. Ltd. Traitement de la séborrhée
RU2624238C2 (ru) * 2011-12-20 2017-07-03 Макфарлейн Маркетинг (Ауст.) Питиуай Лтд. Лечение себореи

Also Published As

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EP0804204A4 (fr) 1998-04-22
CA2170591A1 (fr) 1995-04-20
ZA947912B (en) 1995-05-24
EP0804204A1 (fr) 1997-11-05

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