Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones

Definitions

• the invention relates to uses of inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase.
• HMGCoA reductase 3-Hydroxyl-3-methylglutaryl coenzyme A reductase catalyzes the conversion of 3-hydroxyl-3-methylglutaryl coenzyme A to mevalonate and is the key enzyme in cholesterol synthesis, i.e. the synthesis of mevalonate is the pacemaker reaction of this synthetic route. Accordingly, inhibitors of this enzyme are used in the treatment or prevention of diseases which are associated with or are associated with an elevated cholesterol level, in order thereby to lower the concentration of the cholesterol.
• Angiogenic diseases of the skin have recently increased significantly and can have multiple causes; For example, they can be caused by mechanical influences, chemical substances, physical factors, infections by microorganisms and by stimuli from the body such as uremia, cell disintegration, etc.
• angiogenic skin diseases are usually treated by excision, radiation and / or administration of therapeutic agents. These show a clear effectiveness, but have numerous undesirable side effects, especially with long-term use.
• the object of the present invention is therefore to provide an alternative treatment option for angiogenic skin diseases which avoids the above-mentioned side effects.
• Another object of the invention is a treatment option to provide for such diseases that are associated with angiogenic processes of the skin, in particular non-inflammatory skin aging processes, autoimmune reactions of the skin, autoimmune disorders of the skin, rejection reactions and neuropathies.
• interleukin 8 acts.
• “Induction of hiterleukins in the skin” is understood to mean any process in which an increase in the concentration of interleukins in the skin is observed.
• induction of interleukins means the expression of interleukins.
• induction of Interleukins in the skin are understood to mean an increased transport of interleukins into the skin or a slow rate of breakdown of interleukins in the skin.
• the objects of the invention are also achieved through the use of inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase for the treatment and / or prophylaxis of hyperproliferative diseases of the skin.
• the diseases are selected from the group comprising:
• eczematous dermatitis such as atopic and seborrheic dermatitis, allergic dermatitis, photoallergic and phototoxic dermatitis, phyto-photodermatitis, radiation dermatitis,
• the objects of the invention are also achieved by using inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase for the treatment and / or prophylaxis of aging processes of the skin, by using inhibitors of 3-hydroxyl-3- methylglutaryl-coenzyme A reductase for the treatment and / or prophylaxis of skin neuropathies and by using inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase for the treatment and / or prophylaxis of autoimmune reactions of the skin, with preference is that the autoimmune reactions are selected from the group consisting of blistering, infiltrates and sclerodization of the connective tissue.
• the objects of the invention are also achieved by using inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase for the treatment and / or prophylaxis of autoimmune diseases of the skin, it being preferred that the autoimmune diseases of the skin are selected from the Group that includes scleroderma, lupus erythematosus, pemphigus, pemphigoid and vitiligo.
• the objects of the invention are also achieved by using inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme-reductase for the treatment and / or prophylaxis of rejection reactions, it being preferred that the rejection reactions manifest on the skin.
• the treatment is topical and / or systemic.
• the inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase are selected from the group comprising lovastatin, mevastatin, simvastatin, provastatin, fuvastatin, cerivastatin, atorvastatin and related substances.
• the inhibitors are administered in the form of tablets, dragées, pills, suppositories, injections, ointments, creams, individually or in any combination thereof.
• 1 to 1000 mg of inhibitor are administered per kg of body weight and day, it being preferred that the administration be carried out in 1 to 10 individual doses per day.
• the invention is based on the surprising finding that inhibitors of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase, in addition to their inhibitory effect on the synthesis of mevalonate and pro-inflammatory cytokines, also have an inhibitory effect on the induction of pro-angiogenic cytokines, in particular Has interleukin 8 in skin cells. Since the interleukins act as intercellular messenger proteins in angiogenic processes in the skin, targeted regulation of their concentration level has a diverse influence on numerous metabolic processes in the skin in the human (and animal) organism. It shows that the administration of HMGCoA reductase inhibitors z. B.
• “Induction of interleukins” is understood to mean all processes in which an increase in the concentration of interleukins is observed. This can be done, for example, by an increased expression of interleukins.
• the increase in concentration can be intracellular or intercellular.
• Skin here means the organ covering the body of an organism.
• the term can refer to animal or human skin.
• skin means the subcutis (subcutis) or the skin (cutis) or the epidermis ( Epidermis) or sweat glands or sebaceous glands or hair bags with hair or any combination or the entirety of the components just mentioned.
• the skin can be healthy or ill-shaped.
• the term “in the skin” encompasses the possibility of intercellular localization and / or intracellular localization.
• 3-hydroxyl-3-methylglutaryl-coenzyme A reductase (EC 1JJ.34) is understood to mean an enzyme which is responsible for the conversion catalyzed by 3-hydroxyl-3-methylglutaryl-coenzyme-A to mevalonate.
• the term includes isoenzymes, truncated proteins, covalently modified proteins, mutated proteins and point mutated proteins.
• a standard assay can be carried out in which radioactively labeled substrate is offered (Gebhardt R., Inhibition of cholesterol biosynthesis ba water-soluble garlic extract in primary cultures of rat hepatocytes, Arzneistoffforschung 1991, 41: 800 - 4 ).
• Non-inflammatory aging processes of the skin are understood to mean those processes which are more likely to lead to changes in the skin with regard to their structure or metabolism.
• Neuroopathies of the skin are understood to mean all clinical pictures which are pain, stinging, burning or itchy skin.
• Everyone under “skin autoimmune reactions” Understand autoimmune reactions of the body that are visible on the skin but not necessarily directed against it.
• Autoimmune diseases of the skin are understood to mean all diseases in which the body's immune system is directed against the body's own skin.
• Rejection reactions are understood to mean all the body's own reactions which are aimed at the destruction of a transplant, in particular as a result of an immune response by the recipient.
• the process of “manifesting on the skin” is understood to mean a process that is visible on the skin and that either a) occurs on / in or on the skin, or b) at a different location than the skin in the body. Specifically means in case a) a reaction on the body's own skin as a result of a process that takes place or has expired on the skin, for example a skin transplant In case b) this means a reaction on the body's skin, for example as a result of a rejection of a kidney transplant.
• FIG. 1 shows the percentage of interleukin 6 (IL-6) in cell culture supernatants after irradiation with UVB under the action of the HMGCoA reductase inhibitors lovastatin (FIG. 1A) and mevastatin (FIG. 1B) according to the prior art , and
• FIG. 2 shows the percentage of interleukin 8 (IL-8) in cell culture supernatants after irradiation with UVB under the action of the HMGCoA reductase inhibitors lovastatin (FIG. 2A) and mevastatin (FIG. 2B).
• IL-8 interleukin 8
• Figure 3 shows that lovastatin reduces the amount of interleukin-8 transcript after UVB irradiation.
• the detection and quantification of the transcript amounts was carried out as described (Kippenberger et al. 1998; Loitsch et al. 1999).
• Geometric dilutions (1: 3) of the internal standard (IST) were co-amplified with the associated wild-type cDNA (WT).
• This representative agarose gel shows the regulation of interleukin-8 mRNA as a function of lovastatin (10 ⁇ M), UVB light irradiation, and the combination of UVB light irradiation in the presence of lovastatin.
• the expression of interleukin 6 and interleukin 8 was first induced in an in vitro model.
• human keratinocytes from the HaCaT cell line were sown in culture vessels (2 ⁇ 10 6 cells / 9.6 cm 2 ) and incubated for 24 h. 4 h before the start of the experiment, the culture medium was replaced by new culture medium which was supplemented with 1 and 10 ⁇ M lovastatin and mevastatin, respectively. Immediately before irradiation with 150 mJ / cm 2 UVB light, the medium was drawn off and replaced by phosphate buffer, also supplemented with the HMGCoA reductase inhibitors. This step avoids the creation of toxic photo products.
• interleukin 6 (FIG. 1) and interleukin 8 (FIG. 2) caused by UVB radiation can be inhibited by the addition of HMGCoA reductase inhibitors depending on the concentration.
• the basic titer of interleukin 8 is already approximately halved by adding HMGCoA reductase inhibitors (lovastatin FIG. 2A, mevastatin FIG. 2B) (see FIG. 2).
• HMGCoA reductase inhibitors (lovastatin FIG. 2A, mevastatin FIG. 2B) (see FIG. 2).
• FIG. 1 shows the concentration-dependent inhibition of IL-6 expression by the inhibitors lovastatin (FIG. 1A) and mevastatin (FIG. 1B) according to the prior art. It is shown in FIG. 1A that the increased concentration of IL-6 induced by UV radiation, which is increased seven-fold in the control mixture compared to a non-irradiated sample, can be reduced by the administration of lovastatin. While the titer of IL-6 in the absence of lovastatin due to UV radiation could be increased to 700% of the value determined in the absence of UV radiation, this increase was only approximately 5.5 for 1 ⁇ M lovastatin and 10 ⁇ M lovastatin -fold or approximately 4-fold.
• Fig. 2 shows the dependence of the IL-8 titer on the concentration of the inhibitor administered.
• this ratio (determined value under UV irradiation: determined value without UV irradiation) is approximately 2.9 and 3.5, respectively.
• mevastatin (0 ⁇ M, 1 ⁇ M, 10 ⁇ M
• the values are approximately 1.7, 3.7 and 3.8, respectively.
• RNA information is now available.
• the transcripts for IL-8 were then semi-quantitative to an unregulated gene (glyceraldehyde dehydrogenase) as described, presented and evaluated (Kippenberger et al. 1998; Loitsch et al. 1999) (see FIG. 3).
• HMG-CoA reductase inhibitors not only inhibit the release of preformed IL-8, but also intervene to regulate the level of the mRNA.
• the reduced values for the IL-8 mRNA content can be due to a reduced gene transcription or a shortening of the mRNA half-life.
• the New data confirm the previous data and clearly show that the suppression of IL-8 is not based on a general cytotoxic effect.

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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)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2000
  • 2000-11-21 DE DE2000157648 patent/DE10057648A1/de not_active Withdrawn
• 2001
  • 2001-11-21 AU AU2002221882A patent/AU2002221882A1/en not_active Abandoned
  • 2001-11-21 WO PCT/EP2001/013569 patent/WO2002041916A2/fr not_active Ceased

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