DE102011089558A1 - Use of a cosmetic topical composition comprising trimethylglycine (betaine) and a urea derivative in a carrier for increasing mechanical stability of the epidermis and/or for improving the barrier properties of the epidermis - Google Patents

Abstract

Use of a cosmetic topical composition comprising trimethylglycine (betaine) and at least one urea derivative of (I) in a carrier for increasing the mechanical stability of the epidermis and/or for improving the barrier properties of the epidermis, is claimed. Use of a cosmetic topical composition comprising trimethylglycine (betaine) and at least one urea derivative of formula (R1-N(R2)-C(=O)-N(R4)-R3) (I) in a carrier for increasing the mechanical stability of the epidermis and/or for improving the barrier properties of the epidermis, is claimed. R1-R4 : H, 1-4C alkyl, 2-6C alkenyl or 2-6C hydroxyalkyl with at least one OH, where at least one of R1-R4 is 2-6C hydroxyalkyl with at least one OH.

Description

The present application relates to novel uses of cosmetic compositions containing trimethylglycine and at least one selected urea derivative.

In the course of aging, the texture of the uppermost skin layer, the epidermis, changes.

It gets thinner and the connections between the cells relax. As a result, the aging skin is particularly susceptible to external influences, such as mechanical stress or climate effects. The skin is slightly vulnerable, sensitive to external stimuli and dries up faster. Consumers are looking for facial care products that visibly and tangibly improve the texture of the skin over a longer period of time, in addition to having an immediate effect. In particular, consumers with more mature skin often complain of dry skin, which can be easily injured by mechanical influences and more itching or burning due to irritation.

Cosmetic compositions containing trimethylglycine (betaine) and N, N'-bis (2-hydroxyethyl) urea are already known in the art as skin moisturizing agents, see WO 2006/018198 and EP 2275078.

The object of the present application was to provide a method for improving the barrier properties of the epidermis, in particular the epidermis of more mature skin, that is, of individuals who are at least 40 years old.

Surprisingly, the combination of betaine (trimethylglycine) and at least one selected urea derivative resulted in increased activity of the tight junction protein-1 (TJP-1) gene and protein production of claudin-1, another important cell-cell junction protein in the epidermis, and thus to increased mechanical strength and better barrier properties of the epidermis.

Both active substances are known as fountain solutions. New and completely surprising, both substances promote the cohesion of the epidermis via the expression of tight junction proteins, because claudin-1 strengthens the epidermal cell structure.

An improved cell structure protects especially mature skin from mechanical injury.

Furthermore, exogenous pollutants, such as chemicals or microbes, can more easily penetrate the skin through a solidified cell structure and lead to negative effects.

worin
die Reste R1, R2, R3 und R4 unabhängig voneinander für ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, eine C₂-C₆-Alkenylgruppe oder eine C₂-C₆-Hydroxyalkylgruppe mit mindestens einer Hydroxygruppe stehen,
mit der Maßgabe, dass mindestens einer der besagten Reste eine C₂-C₆Hydroxyalkylgruppe mit mindestens einer Hydroxygruppe bedeutet,
zur Steigerung der mechanischen Festigkeit der Epidermis und/oder zur Verbesserung der Barriereeigenschaften der Epidermis. The present application therefore relates to the non-therapeutic, cosmetic use of a cosmetic topical composition which contains trimethylglycine (betaine) and at least one urea derivative of the formula (UREA-I) in a cosmetically acceptable carrier,

wherein
R _1, R _2, R 3 and R ₄ independently of one another represent a hydrogen atom, a C ₁ -C ₄ -alkyl group, a C ₂ -C ₆ -alkenyl group or a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group,
with the proviso that at least one of said radicals is a C ₂ -C ₆ hydroxyalkyl group having at least one hydroxy group,
to increase the mechanical strength of the epidermis and / or to improve the barrier properties of the epidermis.

The use according to the invention preferably serves for the protection of the epidermis from mechanical injuries and / or from exogenous noxae.

Uses preferred according to the invention are characterized in that the cell-cell compounds in the epidermis are improved.

Further preferred uses according to the invention are characterized in that the activity of the tight junction protein-1 gene (TJP-1) and / or the protein production gene of claudin-1 is increased.

Particularly preferred urea derivatives of the formula (UREA-I) are those which contain at least one C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group which consists of at least one member selected from the group of 2-hydroxyethyl, 2-hydroxy-2-methylpropyl 2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 1,3-dihydroxyprop-2-yl, tris (hydroxymethyl) methyl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 2, 3-dihydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxy-2-methylprop-2-yl, 2,3,4,5,6-pentahydroxyhexyl and 1,3,4,5,6- Pentahydroxyhex-2-yl is selected.

It is preferred to use at least one urea derivative of the formula (UREA-I) which satisfies the preferred proviso of the formula (UREA-I) in that at least one of the radicals R 1 to R 4 is a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxy group means. With particular preference, in each case two radicals of R _1, R _2, R _{3 and} R _{4 represent} a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group. Particularly preferably, the two radicals of R _1, R _2, R _{3 and} R _{4 are} a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group, these two radicals being positioned at different nitrogen atoms of the urea (N, N 'position). Examples of C ₁ -C ₄ -alkyl groups which can be used in compounds of the formula (UREA-I) are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

Examples of C ₂ -C ₆ -alkenyl groups which can be used in compounds of the formula (UREA-I) are vinyl, 2-propen-1-yl (allyl) or 3-buten-1-yl.

Particular preference is given to at least one compound from the group comprising the representatives N- (2-hydroxyethyl) urea, N, N-bis (2-hydroxyethyl) urea, N, N'-bis (2-hydroxyethyl) urea, N- (3-hydroxypropyl) urea, N, N-bis (3-hydroxypropyl) urea, N, N'-bis (3-hydroxypropyl) urea, N- (2-hydroxypropyl) urea, N, N-bis ( 2-hydroxypropyl) urea, N, N'-bis (2-hydroxypropyl) urea, N- (2-hydroxy-2-methyl-prop-2-yl) urea, N, N-bis (2-hydroxy) 2-methyl-prop-2-yl) urea, N, N'-bis (2-hydroxy-2-methyl-prop-2-yl) urea, N- (1,3-dihydroxy-2-methyl-prop Urea, N, N-bis (1,3-dihydroxy-2-methyl-prop-2-yl) urea, N, N'-bis (1,3-dihydroxy-2-methyl) prop-2-yl) urea, N- (1,3-dihydroxy-2-hydroxymethyl-prop-2-yl) urea, N, N-bis (1,3-dihydroxy-2-hydroxymethyl-prop-2-yl) yl) urea and N, N'-bis (1,3-dihydroxy-2-hydroxymethylprop-2-yl) urea. Very particularly preferably, N- (2-hydroxyethyl) urea and N, N'-bis (2-hydroxyethyl) urea, for example, available as a commercial product Hydro Vance ^® by the company Akzo Nobel.

Cosmetic compositions used according to the invention contain at least one urea derivative of the aforementioned formula (UREA-I), preferably in a total amount of 0.1 to 4.5 wt .-%, more preferably from 0.5 to 4 wt .-%, especially preferably from 0.8 to 3.5% by weight and in particular from 1.0 to 1.5% by weight, the amounts being based on the total weight of the topical composition.

Further cosmetic compositions used according to the invention comprise N, N'-bis (2-hydroxyethyl) urea, preferably in a total amount of from 0.1 to 4.5% by weight, more preferably from 0.5 to 4% by weight, particularly preferably from 0.8 to 3.5% by weight and in particular from 1.0 to 1.5% by weight, the quantities being based on the total weight of the topical composition.

Further preferably used according to the invention cosmetic compositions contain betaine (trimethylglycine) in a total amount of 0.1 to 6 wt .-%, more preferably from 0.5 to 5 wt .-%, particularly preferably from 1 to 4 wt .-% and in particular from 2.0 to 3% by weight, the amounts being based on the total weight of the topical composition.

Uses preferred according to the invention are characterized in that N, N'-bis (2-hydroxyethyl) urea in a total amount of 0.1 to 4.5 wt .-%, more preferably from 0.5 to 4 wt .-%, especially preferably from 0.8 to 3.5% by weight and in particular from 1.0 to 1.5% by weight, and (trimethylglycine) in a total amount of from 0.1 to 6% by weight, more preferably from 0 , 5 to 5 wt .-%, particularly preferably from 1 to 4 wt .-% and in particular from 2.0 to 3 wt .-%, wherein the amounts are based on the total weight of the topical composition.

Further uses preferred according to the invention are characterized in that the epidermis is human epidermis of individuals who are at least 40 years old.

worin
die Reste R1, R2, R3 und R4 unabhängig voneinander für ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, eine C₂-C₆-Alkenylgruppe oder eine C₂-C₆-Hydroxyalkylgruppe mit mindestens einer Hydroxygruppe stehen,
mit der Maßgabe, dass mindestens einer der besagten Reste eine C₂-C₆Hydroxyalkylgruppe mit mindestens einer Hydroxygruppe bedeutet,
und das bevorzugt ausgewählt ist aus N,N’-Bis(2-hydroxyethyl)harnstoff,
zur Herstellung einer prophylaktischen oder therapeutischen topischen Zusammensetzung zum Schutz der Epidermis vor mechanischen Verletzungen und/oder vor exogenen Noxen. A further subject of the present application is the use of trimethylglycine (betaine) and at least one urea derivative of the formula (UREA-I)

wherein
R _1, R _2, R 3 and R ₄ independently of one another represent a hydrogen atom, a C ₁ -C ₄ -alkyl group, a C ₂ -C ₆ -alkenyl group or a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group,
with the proviso that at least one of said radicals is a C ₂ -C ₆ hydroxyalkyl group having at least one hydroxy group,
and which is preferably selected from N, N'-bis (2-hydroxyethyl) urea,
for the preparation of a prophylactic or therapeutic topical composition for the protection of the epidermis from mechanical injury and / or from exogenous noxae.

Compositions used according to the invention may be present as pastes, ointments, lotions or creams. Fixed funds can be present, for example, as a pencil.

Advantageously, the skin treatment agents used in the invention are in the form of a liquid, flowable or solid oil-in-water emulsion, water-in-oil emulsion, multiple emulsion, in particular an oil-in-water-in-oil or water-in Oil-in-water emulsion, macroemulsion, miniemulsion, microemulsion, PIT emulsion, nanoemulsion, Pickering emulsion, hydrodispersion, a hydrogel, a lipogel, a mono- or multiphase solution, a foam, or a mixture with at least one as medical adhesive suitable polymer. The agents may also be presented in anhydrous form, such as an oil or a balm. Here, the carrier may be a vegetable or animal oil, a mineral oil, a synthetic oil or a mixture of such oils.

Particularly preferred compositions according to the invention are in the form of a flowable emulsion and preferably contain at least one further skin-conditioning active ingredient and at least one emulsifier.

Suitable conditioning active substances are preferably those substances which are absorbed on keratinic materials, in particular on the skin, and improve the physical and sensory properties of both the skin and of the product as such.

Conditioners smooth the top layer of the skin and make it soft and supple. Through the choice of conditioning agents (greasy - less greasy, fast or slow spreading, quickly or slowly absorbed into the skin and so on), the skin feel of the entire product can be adjusted. Preferred conditioning agents may be selected from fatty substances, especially vegetable oils, such as sunflower oil, olive oil, soybean oil, rapeseed oil, almond oil, jojoba oil, orange oil, wheat germ oil, peach kernel oil and the liquid portions of coconut oil, lanolin and its derivatives, liquid paraffin oils, isoparaffin oils and synthetic hydrocarbons , Di-n-alkyl ethers having a total of 12 to 36 carbon atoms, z. B. di-n-octyl ether and n-hexyl n-octyl ether, fatty acids, especially linear and / or branched, saturated and / or unsaturated C _8-30 fatty acids, fatty alcohols, particularly saturated, mono- or polyunsaturated, branched or unbranched fatty alcohols having 4-30 carbon atoms, which may be ethoxylated with 1-75, preferably 5-20 ethylene oxide units and / or propoxylated with 3-30, preferably 9-14 propylene oxide units, ester oils, ie esters of C _{6 30-} fatty acids with C _2-30 fatty alcohols, hydroxycarboxylic acid alkyl esters, dicarboxylic acid esters such as di-n-butyl adipate and diol esters such as ethylene glycol diol or propylene glycol di (2-ethylhexanoate), symmetrical, asymmetrical or cyclic esters of carbonic acid with fatty alcohols, eg. B. glycerol carbonate or dicaprylyl carbonate (Cetiol ^® CC), mono, - di- and tri fatty acid esters of saturated and / or unsaturated linear and / or branched fatty acids with glycerol, which, preferably 7-9 ethylene oxide units may be ethoxylated with 1-10, z. B. PEG-7 glyceryl cocoate, waxes, especially insect waxes, plant waxes, fruit waxes, ozokerite, microwaxes, ceresin, paraffin waxes, triglycerides gesaettigter and optionally hydroxylated C _16-30 fatty acids, eg. Hardened triglyceride fats, phospholipids, for example, soybean lecithin, egg lecithin and cephalins, shea butter, silicone compounds selected from decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, and silicone polymers, which may, if desired, be cross-linked, e.g. B. polydialkylsiloxanes, polyalkylarylsiloxanes, ethoxylated and / or propoxylated polydialkylsiloxanes with the earlier INCI name Dimethicone Copolyol, as well as polydialkylsiloxanes containing amine and / or hydroxyl groups, preferably substances with the INCI names Dimethiconol, Amodimethicone or Trimethylsilylamodimethicone. The amount of fatty substances used in the compositions used according to the invention is preferably 0.1-99% by weight, more preferably 2-50% by weight and most preferably 5-20% by weight, based in each case on the total composition.

Suitable surface-active substances and / or emulsifiers are, for example, addition products of 4 to 30 mol of ethylene oxide and / or 0 to 5 mol of propylene oxide onto linear C ₈ -C ₂₂ -fatty alcohols, on C ₁₂ -C ₂₂ fatty acids and on C ₈ -C ₁₅ - Alkylphenols, C ₁₂ -C ₂₂ fatty acid mono- and diesters of addition products of 1 to 30 moles of ethylene oxide onto C ₃ -C ₆ polyols, in particular glycerol, ethylene oxide and polyglycerol addition products of methyl glucoside fatty acid esters, fatty acid alkanolamides and fatty acid glucamides, C ₈ -C ₂₂ alkyl mono- and oligoglycosides and their ethoxylated analogues, with degrees of oligomerization of 1.1 to 5, in particular 1.2 to 2.0, and glucose are preferred as the sugar component, mixtures of alkyl (oligo) glucosides and Fatty alcohols, eg. Example, the commercially available product Montanov ^® 68, addition products of 5 to 60 moles of ethylene oxide with castor oil and hydrogenated castor oil, partial esters of polyols having 3-6 carbon atoms with saturated C ₈ -C ₂₂ fatty acids, sterols (sterols), in particular cholesterol, lanosterol, beta-sitosterol, stigmasterol, campesterol and ergosterol, as well as mycosterols, phospholipids, especially glucose phospholipids, fatty acid ester of sugars and sugar alcohols such as sorbitol, polyglycerols and polyglycerol, preferably Polyglyceryl-2-dipolyhydroxystearate (commercial product Dehymuls ^® PGPH) and Polyglyceryl-3 -diisostearat (commercial product Lameform ^® TGI) as well as linear and branched C ₈ -C ₃₀ fatty acids and their Na, K, ammonium, Ca, Mg and Zn salts.

The agents used according to the invention may contain the emulsifiers preferably in amounts of from 0.1 to 25% by weight, particularly preferably 0.5-15% by weight, based on the total agent.

Other suitable additives of the emulsions are thickeners, eg. As anionic polymers of acrylic acid, methacrylic acid, crotonic acid, maleic anhydride and 2-acrylamido-2-methylpropansulfonsaeure, wherein the acidic groups may be wholly or partially present as sodium, potassium, ammonium, mono- or triethanolammonium salt and at least one may be included nonionic monomer. Preferred nonionic monomers are acrylamide, methacrylamide, acrylic esters, methacrylic esters, vinylpyrrolidone, vinyl ethers and vinyl esters. Preferred anionic copolymers are acrylic acid-acrylamide copolymers and in particular polyacrylamide copolymers with sulfonic acid-containing monomers. These copolymers can also be present in crosslinked form. Suitable commercial products are NS Sepigel ^® 305, Simulgel ^® 600, Simulgel ^® and Simulgel EPG ^® of the company SEPPIC. Further particularly preferred anionic homopolymers and copolymers are uncrosslinked and crosslinked polyacrylic acids.

Such compounds are for example the commercial products Carbopol ^®. A particularly preferred anionic copolymer contains as monomer 80-98% of an unsaturated, optionally substituted C _3-6 carboxylic acid or its anhydride and 2-20% of optionally substituted acrylic acid esters of saturated C _10-30 carboxylic acids, the copolymer having the can be crosslinked aforementioned crosslinking agents. Corresponding commercial products are Pemulen ^® and Carbopol ^® grades 954, 980, 1342 and ETD 2020 (ex BF Goodrich).

• – Parfumöle,
• – Substanzen zur Einstellung des pH-Wertes,
• – Komplexbildner wie EDTA, NTA, β-Alanindiessigsaeure und Phosphonsaeuren,
• – Treibmittel wie Propan-Butan-Gemische, Pentan, Isopentan, Isobutan, N₂O, Dimethylether, CO₂ und Luft,
• – Wirkstoffe wie Hyaluronsäure und/oder Glycyrrhizinsäure bzw. deren physiologisch verträglich Salze und/oder Derivate,
• – Pigmente und/oder
• – Abrasivstoffe.

Further suitable additives are, for example:

• - perfume oils,
• - substances for adjusting the pH,
• Complexing agents such as EDTA, NTA, β-alaninediacetic acid and phosphonic acid,
• Propellants such as propane-butane mixtures, pentane, isopentane, isobutane, N ₂ O, dimethyl ether, CO ₂ and air,
• Active ingredients such as hyaluronic acid and / or glycyrrhizic acid or their physiologically tolerable salts and / or derivatives,
• - pigments and / or
• - Abrasives.

Experimental Section - Gene expression analysis of TJP-1

Epidermal skin models were treated topically with different cosmetic formulations. 24 hours after application, the models were isolated and the gene activities by polymerase chain reaction for the activity of the tight junction protein-1 (TJP-1) gene determined. As a result, it has surprisingly been found that the formula containing only hydroxyethyl urea as active leads to a 160-fold expression of this important zona occludens gene compared to untreated models of epidermis. If the cosmetic formula is further supplemented with betaine, the increase in gene activity can be demonstrated to be 200% compared to the untreated control. Untreated control Formula + hydroxyethyl urea Formula + hydroxyethyl urea + betaine TJP-1 gene activity 100% 160% 200%

Immunohistological detection of claudin-1

Epidermal skin models were treated topically with different cosmetic formulations. 24 h after application, the models were isolated and the protein amount and distribution in the skin cross-section using immunohistological methods, the protein levels of another important tight junctions protein, the claudin-1, demonstrated. In this case, an increase in the amount of claudin-1 protein after application of a formula containing hydroxethyl urea in comparison to the untreated control could be qualitatively demonstrated. In addition, a further significant increase could be achieved by the combination of hydroxethyl urea with betaine.

These results are congruent with the analysis of gene activity.

Formulation example used according to the invention (oil-in-water emulsion) (amounts in% by weight) 1,6-Hexanediol 6 Dibutyl adipate 5 glycerin 4.3 safflower oil 3 C14-22 Alcohols 2.4 Betaine 2 Caprylic / Capric Triglycerides 2 Cyclomethicone 1.5 Aluminum Starch Octenylsuccinate 1.0 N, N'-bis (2-hydroxyethyl) urea 1.5 Cetearyl Alcohol 1.5 Glyceryl stearate 0.8 C12-20 alkyl glucosides 0.8 urea 0,075 Polyisobutene 0,275 Hydrolyzed soy protein 0.03375 Sodium carbomer 0.2 Sodium Acrylate / Sodium Acryloyl Dimethyl Taurate Copolymer 0.15 tocopherol 0.1 Caprylyl / caprylic glucosides 0,008 Sorbitan Oleate 0.01 Ammonium lactates 0.03 Perfume 0.4 phenoxyethanol 0.5 Ethylparaben 0.2 methylparaben 0.2 Aqua ad 100

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2006/018198 [0004]
• EP 2275078 [0004]

Claims (10)

Non-therapeutic, cosmetic use of a cosmetic topical composition containing in a cosmetically acceptable vehicle trimethylglycine (betaine) and at least one urea derivative of the formula (UREA-I),

wherein the radicals R1, R2, R3 and R4 independently of one another represent a hydrogen atom, a C ₁ -C ₄ -alkyl group, a C ₂ -C ₆ -alkenyl group or a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group, with In that at least one of said radicals is a C ₂ -C ₆ hydroxyalkyl group having at least one hydroxyl group, for increasing the mechanical strength of the epidermis and / or for improving the barrier properties of the epidermis. Use according to claim 1 for the protection of the epidermis from mechanical injuries and / or from exogenous noxae. Use according to claim 1 or 2, characterized in that the cell-cell compounds in the epidermis are improved. Use according to claim 1, 2 or 3, characterized in that the activity of the tight junction protein-1 gene (TJP-1) and / or the protein production gene of claudin-1 is increased. Use according to claim 1, 2, 3 or 4, characterized in that the urea derivative of the formula (UREA-I) is N, N'-bis (2-hydroxyethyl) urea. Use according to claim 1, 2, 3, 4 or 5, characterized in that at least one urea derivative of the formula (UREA-I) in a total amount of 0.1 to 4.5 wt .-%, more preferably from 0.5 to 4 wt .-%, particularly preferably from 0.8 to 3.5 wt .-% and in particular from 1.0 to 1.5 wt .-%, wherein the amounts are based on the total weight of the topical composition. Use according to claim 1, 2, 3, 4, 5 or 6, characterized in that betaine (trimethylglycine) is present in a total amount of from 0.1 to 6% by weight, more preferably from 0.5 to 5% by weight, more preferably from 1 to 4% by weight and in particular from 2.0 to 3% by weight, the amounts being based on the total weight of the topical composition. Use according to claim 1, 2, 3, 4, 5, 6 or 7, characterized in that N, N'-bis (2-hydroxyethyl) urea in a total amount of 0.1 to 4.5 wt .-%, more preferably from 0.5 to 4 wt .-%, particularly preferably from 0.8 to 3.5 wt .-% and in particular from 1.0 to 1.5 wt .-%, and (trimethylglycine) in a total amount of 0 , 1 to 6 wt .-%, more preferably from 0.5 to 5 wt .-%, particularly preferably from 1 to 4 wt .-% and in particular from 2.0 to 3 wt .-%, are included the amounts refer to the total weight of the topical composition. Use according to claim 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that the epidermis is human epidermis of individuals at least 40 years old. Use of trimethylglycine (betaine) and at least one urea derivative of the formula (UREA-I)

wherein the radicals R _1, R _2, R 3 and R ₄ independently of one another represent a hydrogen atom, a C ₁ -C ₄ -alkyl group, a C ₂ -C ₆ -alkenyl group or a C ₂ -C ₆ -hydroxyalkyl group having at least one hydroxyl group, with the proviso in that at least one of said radicals is a C ₂ -C ₆ hydroxyalkyl group having at least one hydroxy group, and which is preferably selected from N, N'-bis (2-hydroxyethyl) urea, for the preparation of a prophylactic or therapeutic topical composition for the protection of Epidermis from mechanical injury and / or from exogenous noxae.