WO2008078099A1 - Antagonistes du lxr pour la prévention, la réduction ou l'inhibition de la formation de cicatrices - Google Patents

Antagonistes du lxr pour la prévention, la réduction ou l'inhibition de la formation de cicatrices Download PDF

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Publication number
WO2008078099A1
WO2008078099A1 PCT/GB2007/004958 GB2007004958W WO2008078099A1 WO 2008078099 A1 WO2008078099 A1 WO 2008078099A1 GB 2007004958 W GB2007004958 W GB 2007004958W WO 2008078099 A1 WO2008078099 A1 WO 2008078099A1
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Prior art keywords
scarring
wound
scar
antagonist
inhibition
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PCT/GB2007/004958
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English (en)
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Mark William James Ferguson
Nicholas Occleston
Sharon O'kane
Nick Goldspink
Kerry Nield
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Renovo Limited
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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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to medicaments for the prevention, reduction or inhibition of scarring.
  • the invention also provides methods for the prevention, reduction or inhibition of scarring.
  • a scar may be defined as "fibrous connective tissue that forms at the site of injury or disease in any tissue of the body" (the scarring response is common throughout all adult mammals). Scarring may result from healing of a wound, or through the deposition of scar tissue associated with fibrotic disorders. The scarring response is conserved between the majority of tissue types and in each case leads to the same result, formation of fibrotic tissue termed "a scar”. Many different processes are at work during the scarring response, and much research has been conducted into discovering what mediates these processes, and how they interact with each other to produce the final outcome.
  • the scarring response has arisen as the evolutionary solution to the biological imperative to prevent the death of a wounded animal.
  • the body reacts rapidly to repair the damaged area, rather than attempt to regenerate the damaged tissue.
  • the scar may be defined as the structure produced as a result of the reparative response. Since the injured tissue is not regenerated to attain the same tissue architecture present before wounding a scar may be identified by virtue of its abnormal morphology as compared to unwounded tissue. Such scars are composed of connective tissue deposited during the healing process.
  • a scar may comprise connective tissue that has an abnormal organisation (as seen in scars of the skin) and/or connective tissue that is present in an abnormally increased amount. Most scars consist of both abnormally organised and excess connective tissue.
  • Extracellular matrix (ECM) molecules comprise the major structural component of both "normal” (unwounded) and scarred skin. In normal skin these molecules form fibres that have a characteristic random arrangement that is commonly referred to as "basket-weave". In general the fibres observed within normal skin are of larger diameter than those seen in scars. Fibres in scars also exhibit a marked degree of alignment with each other as compared to the random arrangement of fibres in normal skin. Both the size and arrangement of ECM may contribute to the scars altered mechanical properties, most notably increased stiffness, when compared with normal skin.
  • scars may be depressed below the surface of the surrounding tissue, or elevated above the surface of the undamaged skin.
  • Scars may be relatively darker coloured than the normal skin (hyperpigmentation) or may have a paler colour (hypopigmentation) than their surroundings.
  • Either hyperpigmented or hypopigmented scars constitute a readily apparent cosmetic defect. It is also known that scars may be redder than unwounded skin, causing them to be noticeable and cosmetically unacceptable. It has been shown that the cosmetic appearance of a scar is one of the major factors contributing to the psychological impact of scars upon the sufferer, and that these effects can remain long after the cause of the scar, be it either a wound or a fibrotic disorder, has passed.
  • Scars may also have deleterious physical effects upon the sufferer. These effects typically arise as a result of the mechanical differences between scars and normal skin.
  • the abnormal structure and composition of scars mean that they are typically less flexible than normal skin.
  • scars may be responsible for impairment of normal function (such as in the case of scars covering joints which may restrict the possible range of movement) and may retard normal growth if present from an early age.
  • Scarring may also occur at many other body sites, and the effects of scarring at these sites may also be deleterious to the sufferer. For example, scarring in the eye (whether as a result of accidental injury, surgical intervention, or a fibrotic disorder) can impair vision and even lead to blindness. Scarring of the internal organs may lead to the formation of strictures and adhesions that significantly or totally impair function of the organ in question. Scarring of tendons and ligaments may cause lasting damage to these organs, and thereby reduce the motility or function of associated joints. Scarring associated with blood vessels, and particularly the valves of the heart, may occur after injury or surgery.
  • Scarring of blood vessels may lead to restenosis, which causes a narrowing of the blood vessel and thus reduces the flow of blood through the scarred area.
  • Scarring in the peripheral nervous system may prevent transmission along the nerve and may prevent or reduce reconnection of damaged nerve tissue, and/or functional neuronal transmission.
  • pathological scarring One way in which the scarring response may be altered is through the production of abnormal excessive scarring (commonly referred to as pathological scarring).
  • Hypertrophic scars are a common form of pathological scarring, and have marked adverse effects on the sufferer. Hypertrophic scars are elevated above the normal surface of the skin and contain excessive collagen arranged in an abnormal pattern. As a result, such scars are often associated with a marked loss of normal mechanical function. This may be exacerbated by the tendency of hypertrophic scars to undergo contraction after their formation, an activity normally ascribed to their abnormal expression of muscle-related proteins (particularly smooth-muscle actin). Children suffer from an increased likelihood of hypertrophic scar formation, particularly as a result of burn injuries.
  • Keloids are another common form of pathological scarring. Keloid scars are not only elevated above the surface of the skin but also extend beyond the boundaries of the original injury. Keloids contain excessive connective tissue that is organised in an abnormal fashion, normally manifested as whorls of collagenous tissue. The causes of keloid formation are open to conjecture, but it is generally recognised that some individuals have a genetic predisposition to their formation. Both hypertrophic scars and keloids are particularly common in those of the African Continental Ancestry Group or Asian Continental Ancestry Group.
  • a further common form of pathological scarring is pterygium in which a wedge-shaped fibrotic outgrowth of subconjunctival tissue may grow to the border of the cornea or beyond. Pterygium is more frequent among those frequently exposed to strong sunlight or dusty conditions.
  • Connective tissue contractures are a further common form of pathological scarring, in which normally elastic connective tissues are replaced by inelastic fibrous tissue. Hypertrophic scarring of connective tissue is observed in Dupuytren's Contracture, in which a thick "scar like" band forms along the palm of the hand due to hyperplasia of the palmar fascia.
  • scarring may be defined as the production of the structure that remains on healing of a wound
  • similar disturbances of the extracellular matrix may also give rise to scarring associated with a number of medical conditions known as fibrotic disorders.
  • fibrotic disorders In these disorders excessive fibrosis leads to pathological derangement and malfunctioning of tissue.
  • Scars associated with fibrotic disorders are characterised by the accumulation of fibrous tissue (predominately collagens, as described above) in an abnormal fashion within the damaged tissue. Accumulation of such fibrous tissues may result from a variety of disease processes, all of which lead to the same end result.
  • Fibrotic disorders are usually chronic. Examples of fibrotic disorders include cirrhosis of the liver, liver fibrosis, glomerulonephritis, pulmonary fibrosis, chronic obstructive pulmonary disease, scleroderma, myocardial fibrosis, fibrosis following myocardial infarction, proliferative vitreoretinopathy (PVR), arthritis and adhesions e.g. in the digestive tract, abdomen, pelvis, spine.
  • PVR proliferative vitreoretinopathy
  • Liver X Receptors are nuclear oxysterol receptors that regulate multiple target genes involved in cholesterol homeostasis.
  • Two Liver X Receptors are known to exist, Liver X Receptor Alpha (LXR ⁇ , also known as NRl H3) and Liver X Receptor Beta (LXR ⁇ , also known as NR1H2).
  • LXR ⁇ Liver X Receptor Alpha
  • LXR ⁇ Liver X Receptor Beta
  • the amino acid sequence of LXR ⁇ is shown in Sequence ID Nos. 1 and 2
  • the amino acid sequence of LXR ⁇ is shown in Sequence ID No. 3
  • the amino acid sequence of LXR ⁇ is shown in Sequence ID No. 4
  • the sequence of DNA encoding this polypeptide is shown in Sequence ID No. 5.
  • LXRs liver X receptors
  • oxysterols metabolites of cholesterol
  • LXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer) and binds to hormone response elements on DNA which elicits expression or transrepression of gene products.
  • LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types.
  • the two LXRs, LXRa and LXR ⁇ , are activated by physiological concentrations of oxidized derivatives of cholesterol, such as 22(/?)-hydroxycholesterol, 27-hydroxycholesterol and 24(5),25-epoxycholesterol.
  • LXRs stimulate transcription by forming a heterodimer with the retinoid X receptor (RXR) and binding to the consensus responsive sequence DR4 in the promoter regions of several target genes, including those of cholesterol 7 ⁇ -hydroxylase (CYP7A1), cholesterol ester-transfer protein (CETP), ATP -binding cassette proteins (ABC), apolipoprotein E (ApoE), lipoprotein lipase (LPL), and sterol response element-binding protein Ic (SREBP-Ic).
  • RXR retinoid X receptor
  • LXR ⁇ decreases circulating LDL and tissue cholesterol by 1) facilitating cholesterol excretion in the gallbladder and catabolism through bile acid formation in the liver, 2) reducing cholesterol absorption in the intestine, and 3) promoting cholesterol efflux from cells in peripheral tissues such as resident macrophages.
  • LXRa and LXR ⁇ share considerable sequence homology (77% identity in DNA- and ligand-binding domains), and appear to respond to the same endogenous ligands. Crystal structures of the ligand-binding domains of LXRa and LXR ⁇ indicate that their binding pockets are virtually identical. LXRa is expressed at high levels in liver, intestine, adipose tissue and macrophages, whereas LXR ⁇ is expressed ubiquitously. LXR ⁇ is also expressed at low levels in the skin.
  • LXR may be involved in glucose metabolism and inflammation by regulating critical molecules involved in these pathophysiological processes.
  • LXRs have also been found to modulate immune and inflammatory responses in macrophages.
  • LXR activation represses a set of inflammatory genes after bacterial, LPS, TNF-a, or IL- IB stimulation. Examples of such genes include those involved in generation of bioactive molecules such as iNOS and COX2, IL-6 and IL- l ⁇ , the chemokines monocyte chemoattractant protein- 1 (MCP-I) and MCP-3, and MMP9; both LXR isoforms possess anti-inflammatory activity.
  • MCP-I monocyte chemoattractant protein- 1
  • MCP-3 MCP-3
  • MMP9 both LXR isoforms possess anti-inflammatory activity.
  • medicaments and/or methods of the invention may constitute alternatives to those provided by the prior art. However, it is preferred that medicaments and/or methods of treatment provided by the invention may constitute improvements over the prior art.
  • a medicament manufactured in accordance with this aspect of the invention should be one that provides a therapeutically effective amount of the selected antagonist of LXR activity.
  • This first aspect of the invention also provides an antagonist of LXR activity for use as a medicament for the prevention, reduction or inhibition of scarring.
  • a method of preventing, reducing or inhibiting scarring comprising administering a therapeutically effective amount of an antagonist of LXR activity, to a patient in need of such prevention, reduction or inhibition.
  • the scarring, prevention, reduction or inhibition of which is to be achieved by the medicaments or methods of the invention may be scarring that results from healing of a wound, or, additionally or alternatively, may be scarring associated with a fibrotic disorder. It may be preferred that the scarring is scarring that results from the healing of a wound. Scarring of the skin represents a preferred site of scarring that may be prevented, reduced or inhibited utilising the medicaments or methods of the invention. Thus it will be appreciated that scarring resulting from the healing of skin wounds represents a form of scarring that may particularly benefit from prevention, reduction or treatment in accordance with the present invention, and with the medicaments or methods of the present invention.
  • the present invention is based on the inventors' new and surprising finding that antagonists of LXR activity may be used in the prevention, reduction or inhibition of scarring. There are no previous reports that would lead the skilled person to believe that antagonists of LXR activity may be used to effectively prevent, reduce or inhibit scarring.
  • an "antagonist of LXR activity" is to be understood to encompass any substance that is capable of reducing the activity of LXR to a therapeutically effective extent.
  • Suitable antagonists may include competitive antagonists (which bind to the same receptor binding site as the agonist) and/or noncompetitive antagonists (which bind to a different receptor binding site than that bound by the agonist).
  • competitive and non-competitive antagonists it will be appreciated that other substances may be used to reduce LXR activity therapeutically, and thereby inhibit scarring, and that these substances will also constitute suitable antagonists of LXR activity within the context of the present invention.
  • antagonists of this sort include substances capable of reducing the expression of LXR, and thereby therapeutically reducing LXR activity.
  • Suitable antagonists capable of reducing the expression of LXR include RNA interference (RNAi) agents, antisense nucleic acids, ribozymes, and agents such as aptamers that are capable of binding to nucleic acids encoding LXR to prevent their transcription or translation (it will be appreciated that some such agents, particularly aptamers, may also be used to reduce the activity of LXR even after expression of this protein).
  • RNA interference is initiated by the conversion of double stranded RNA into 21-23 nucleotide fragments, termed small interfering RNAs (siRNAs) that direct the degradation of the target RNAs.
  • siRNA selection is based on the selection of three to four, 21 nucleotide sequences in the target mRNA that begin with an AA dinucleotide.
  • These 21 nucleotide sequences should ideally have a 30 to 50% content of nucleotides G or C (since these are found to be more active than those with a higher GIC content), and not contain stretches of more than 4 T's or A's in the target sequence, since a 4-6 nucleotide poly(T) tract acts as a termination signal for the enzyme RNA pol III.
  • RNA pol III There are several methods for preparing siRNAs, once they have been designed, including chemical synthesis, in vitro transcription, siRNA expression vectors, and PCR expression cassettes.
  • RNAi has been shown in vivo to prevent ocular scarring by targeting the TGF- ⁇ pathway using siRNAs derived from the coding sequence of the human TGF-beta receptor II (T ⁇ RII )gene (Nakamura, et al 2004).
  • T ⁇ RII human TGF-beta receptor II
  • the use of these strategies to antagonise the activity of LXR represents a preferred embodiment of the medicaments or methods of the invention.
  • Antisense oligonucleotides target specific mRNA molecules that are complementary to the sequence of the oligonucleotide.
  • the mRNA:oligonucleotide hybrid molecules are recognized by RNase H, which subsequently degrades the mRNA.
  • the most efficient antisense oligonucleotides are between 15 and 25 nucleotides in length and are complementary to sequence surrounding the initiator AUG site of the mRNA.
  • Other sequence motifs that can be targeted to reduce mRNA levels are regions of the mRNA that interact with proteins, ribosomes, spliceosomes and other large entities. Although theoretically chosen, antisense oligonucleotide sequences may be predicted to bind efficiently to target mRNA.
  • PNA peptide nucleic acid
  • Oligonucleotides designed and generated in accordance with the considerations outlined above represent preferred antagonists of LXR activity for use in the medicaments or methods of the invention.
  • Ribozymes have the ability to catalyse both RNA splicing and cleavage.
  • RNA-cleaving ribozymes gain their target specificity from Watson-Crick base-pairing between the ribozyme's binding-arm sequences and sequences that flank the cleavage site of the target RNA. Once bound, their mechanism of cleavage involves attack of the 2'-OH that is 5' to the scissile bond in the target, thus destabilizing the target RNAs phosphate backbone.
  • the resultant products dissociate from the ribozyme complex and the ribozyme is released and may bind and cleave other targets again.
  • the cleavage event renders the mRNA untranslatable and leads to further degradation of the target by cellular ribonucleases.
  • the mRNA target site for ribozymes is about 15 nucleotides in length, but since these ribozymes bind their cognate RNA using two independent binding arms 6-7 nucleotides in length (interrupted by the nucleotide being cleaved), ribozyme binding to the target is weaker than it would be to a contiguous sequence of 13-15 nucleotides. This weak binding leads to better sequence specificity, since it makes the ribozyme more sensitive to the effects of mismatches.
  • ribozymes To protect against degradation by host nucleases, ribozymes have been developed that contain stabilizing chemical modifications, primarily at the 2'-OH position of the sugar residue in each nucleotide. The inventors believe that ribozymes may constitute suitable antagonists of LXR activity for use in the medicaments or methods of the invention.
  • Aptamers are nucleic acid molecules that assume a specific, sequence-dependent shape and bind to specific target ligands based on a lock-and-key fit between the aptamer and ligand.
  • aptamers may comprise either single- or double-stranded DNA molecules (ssDNA or dsDNA) or single-stranded RNA molecules (ssRNA).
  • Aptamers may be used to bind both nucleic acid and non-nucleic acid targets.
  • Preferably aptamers may be used to bind to gene expression products having a molecular weight of between 100 and 10,000 Da.
  • ssDNA aptamers may be preferred when it is wished to bind, and thus neutralise, gene expression products comprising DNA.
  • Suitable aptamers may be selected from random sequence pools, from which specific aptamers may be identified which bind to the selected target molecules with high affinity.
  • Methods for the production and selection of aptamers having desired specificity are well known to those skilled in the art, and include the SELEX (systematic evolution of ligands by exponential enrichment) process. Briefly, large libraries of oligonucleotides are produced, allowing the isolation of large amounts of functional nucleic acids by an iterative process of in vitro selection and subsequent amplification through polymerase chain reaction.
  • aptamers for the reduction of LXR expression may be advantageous, since aptamers have relatively stable shelf lives.
  • Aptamers suitable for use in the methods of the invention may preferably be stabilized by chemical modifications (for example 2'- NH 2 and 2'-F modifications).
  • Aptamers designed and generated in accordance with these considerations may constitute preferred antagonists of LXR activity suitable for use in the medicaments and methods of the invention.
  • the skilled person will appreciate that a mixture of two, or more, different antagonists of LXR activity may be used in the medicaments or methods of the invention to inhibit scarring, and such use may represent a preferred embodiment of the invention.
  • a person skilled in the art may well be able to identify whether or not a substance of interest is an antagonist of LXR activity by reference to known texts, tables or other publications.
  • the ability of a substance of interest to antagonise LXR activity may readily be determined with reference to well known assays, examples of which are discussed in greater detail elsewhere in the specification. Such assays may be used as the basis for high throughput screening designed to identify suitable antagonists for use in accordance with the invention.
  • HEK293 cells are co-transfected with either, lOOng of pGL3B EIb 3XLXRE luciferase plasmid, lOOng of pCMV6 LXR ⁇ and 50ng of CMV ⁇ -galactosidase, or alternatively with a Gal4- responsive luciferase plasmid (pGSluc), an LXR ⁇ -LBD/GAL4 DNA-binding domain expression plasmid and CMV ⁇ -galactosidase.
  • pGSluc Gal4- responsive luciferase plasmid
  • T0901317 an LXR agonist
  • fibrate esters LXR antagonists
  • a combination of T0901317 and a dose range of fibrate esters Following 24 hours of treatment, cells are lysed, and firefly luciferase activity measured. In this assay antagonistic activity of the fibrate esters is demonstrated by a reduction in luciferase activity when compared to stimulation with T0901317.
  • Fenofibrate ester represents a preferred example of an antagonist of LXR activity suitable for use in the medicaments or methods of the present invention.
  • the systemic name of fenofibrate ester is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester.
  • the empirical formula of fenofibrate is C 20 H 21 O 4 Cl 1 , and its structure is shown in Structure I.
  • Fenofibrate has a molecular weight of 360.83, and at room temperature is a solid with limited solubility in water. Methods by which fenofibrate ester may be sufficiently dissolved to provide a therapeutically effective solution suitable for use in the medicaments or methods of the invention are considered elsewhere in the specification.
  • Fenofibrate belongs to the fibrate family of molecules. Other members of this chemical family include bezafibrate, clofibrate and gemfibrozil.
  • ester forms of the other fibrate family members listed above will be similarly active with regards to scar inhibition and that they are thus suitable for use in the medicaments or methods of the invention.
  • LXR antagonistic activity of fenofibrate ester is derived from the carboxylate ester structural feature.
  • the binding pocket of the family of receptors to which LXR is a member has a conserved hydrogen bond interaction which, in the case of LXR antagonists, appears to be blocked by the key carboxylate ester functional group.
  • carboxylate group is in the acid form, these compounds have been known to possess agonist activity towards other targets, as evidenced by Thomas et al. (J. Biol. Chem., 2003, 278, 2403-2410). Therefore, the inventors believe that it is the ester that is the key structural feature that makes fenofibrate ester (and related structures) LXR antagonists suitable for use in the medicaments or methods of the invention.
  • ester forms of the fibrate family act as specific antagonists of LXR activity (whereas in their acid forms they may selectively interact with other receptors, such as PPAR, as opposed to LXR).
  • a suitable antagonist of LXR activity for use in the medicaments and methods of the invention may be selected from the group consisting of fenofibrate ester; bezafibrate ester; clofibrate ester and gemfibrozil ester.
  • Fenofibrate is used in the treatment of hyperlipidemia, where it lowers cholesterol and triglyceride levels in the blood.
  • fenofibrate ester has any effect on scarring (either on scarring that results from the healing of a wound, or on scarring that is associated with a fibrotic disorder).
  • Fenofibrate ester is available commercially in a range of forms suitable for administration by various different means, as considered elsewhere in the specification.
  • fenofibrate ester suitable for use in the medicaments and methods of the present example may be obtained from Sigma Aldrich (with the Catalogue Number #F6020). Fenofibrate ester from this source may be used to produce an intradermally injectable medicament, as described elsewhere in the specification.
  • fenofibrate ester or other related compounds sharing the structural features of fenofibrate ester that impart LXR antagonist activity, represent preferred antagonists of LXR activity that may be used in the medicaments and methods of the invention, it will be appreciated that any compound that is able to therapeutically effectively antagonise LXR activity may be used in the medicaments and methods described.
  • LXR activity other than f ⁇ brate esters
  • suitable antagonists of LXR activity include geranylgeranyl pyrophosphate, 7-ketocholesterol-3-sulfate, and 5a, 6a-epoxycholesterol-3-sulfate.
  • Geranylgeranyl pyrophosphate is a non-sterol mevalonate metabolite that was recently demonstrated to inhibit ABCAl expression through antagonism of LXR. It is commercially available from sources such as Sigma- Aldrich. 7-ketocholesterol-3- sulfate, and 5a, 6a-epoxycholesterol-3-sulfate are members of a class of auto-oxidised cholesterol-sulfates that are discussed further below.
  • Riccardin F the structure of which is shown below, is reported to be a dual LXR ⁇ /LXR ⁇ antagonist. Riccardin F thus represents an antagonist of LXR activity that may be used in the medicaments or methods of the invention.
  • Wy-14643 which, in the ester form, is an LXR ⁇ antagonist.
  • the structure of this compound is shown below, and it represents an example of antagonist of LXR that may be used in the medicaments or methods of the invention.
  • Medicaments and methods of the invention utilising antagonists of LXR activity may be used in the prevention, reduction or inhibition of scarring that may otherwise result from the healing of a wound.
  • medicaments and methods of the invention utilising antagonists of LXR activity may be used in the prevention, reduction or inhibition of scarring that may otherwise be associated with a fibrotic disorder. It is particularly preferred that medicaments or methods of the invention be used to prevent, reduce or inhibit scarring of the skin, whether such scarring arises as a result of healing of a skin wound, or in association with a fibrotic disorder afflicting the skin.
  • An antagonist of LXR activity may preferably be administered to a site that may be associated with scarring (for the present purposes a site where scarring has already occurred, or may be expected to occur).
  • an antagonist of LXR activity may be administered to a patient's wound that would otherwise be likely to give rise to a scar.
  • An antagonist of LXR activity may be administered to an existing scar to prevent the further progression of scarring.
  • Administration of antagonists of LXR activity to an existing scar may also reduce the level of scarring associated with the existing scar. It will thus be appreciated that an antagonist of LXR activity may be administered to a site of a fibrotic disorder in order to prevent further scarring, and/or to reduce scarring that has already occurred associated with the fibrotic disorder.
  • Preferred routes of administration that may be used in accordance with all of the embodiments considered above include topical administration, and particularly topical injection of suitable antagonists.
  • Examples of specific contexts in which the prevention, reduction or inhibition of scarring that may otherwise arise from the healing of a wound may be achieved using the medicaments and methods of the invention include, but are not limited to, those selected from the group consisting of: use in the skin; use in the eye (including the prevention, reduction or inhibition of scarring resulting from eye surgery such as LASIK surgery, PRK surgery, or cataract surgery - in which the lens capsule may be subject to scarring); use in capsular contraction (which is common surrounding breast implants); use in blood vessels; use in the peripheral nervous system (where prevention, reduction or inhibition of scarring may enhance neuronal reconnection); use in tendons, ligaments or muscle; use in the oral cavity, including the lips and palate (such as in preventing, reducing or inhibiting scarring resulting from treatment of cleft lip or palate); use in the internal organs such as the liver, heart, brain, digestive tissues and reproductive tissues; and use in body cavities such as the abdominal cavity, pelvic cavity and thoracic cavity (where prevention, reduction or inhibition of scarring may reduce the
  • the medicaments and methods of the invention may be used to prevent, reduce or inhibit adhesions, such as those occurring in the abdomen, pelvis or spine. It is particularly preferred that the medicaments and methods of the invention be used to prevent, reduce or inhibit scarring of the skin (dermal scarring).
  • Scarring associated with fibrotic disorders may include scarring associated with fibrotic disorders selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative disorders such multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.
  • fibrotic disorders selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibros
  • Medicaments of the invention will generally comprise a pharmaceutically acceptable excipient, diluent or carrier in addition to the antagonist of LXR activity.
  • Medicaments of the invention may preferably be in the form of an injectable solution comprising an antagonist of LXR activity. Solutions suitable for localised injection (such as intradermal injection) constitute particularly preferred forms of the medicaments of the invention. -,
  • a "therapeutically effective antagonist of LXR activity” is considered to be any antagonist of LXR activity that is capable of preventing, reducing or inhibiting scarring.
  • a therapeutically effective antagonist of LXR activity suitable for use in accordance with the present invention may be one that is capable of preventing, reducing or inhibiting scarring that may otherwise result from a wound to which the antagonist is added.
  • a therapeutically effective antagonist of LXR activity suitable for use in accordance with the present invention may be one capable of preventing, reducing or inhibiting scarring associated with a fibrotic disorder at a site where the antagonist is added.
  • a "therapeutically effective amount" of an antagonist of LXR activity is considered to be an amount of such an antagonist that is able to bring about a required prevention, reduction or inhibition of scarring.
  • the scarring that is to be prevented, reduced or inhibited may be scarring that results from healing of a wound, and/or scarring associated with a fibrotic disorder.
  • a therapeutically effective amount of an antagonist of LXR activity may be an amount that is effective to reduce scarring by at least 10% compared to scarring that would otherwise be expected to occur without administration of the antagonist.
  • a therapeutically effective amount may be capable of achieving at least a 20% reduction in scarring, more preferably at least 50%, even more preferably at least 75% and most preferably at least a 90% reduction in scarring compared to scarring that would otherwise be expected to occur without administration of the antagonist.
  • a therapeutically effective amount of an antagonist of LXR activity may be an amount that is effective to reduce scarring of a treated wound by at least 10% compared to scarring produced on healing of a comparable untreated wound.
  • a therapeutically effective amount may be capable of achieving at least a 20% reduction in scarring, more preferably at least 50%, even more preferably at least 75% and most preferably at least a 90% reduction in scarring compared to scarring produced on healing of an untreated wound.
  • a therapeutically effective amount of an antagonist of LXR activity may be an amount that is effective to reduce scarring of a treated site of fibrosis by at least 10% compared to the amount scarring that would otherwise be present at a comparable untreated site of fibrosis.
  • a "treated site of fibrosis" and "untreated site of fibrosis" are defined further elsewhere in the specification.
  • a therapeutically effective amount may be capable of achieving at least a 20% reduction in scarring, more preferably at least 50%, even more preferably at least 75% and most preferably at least a 90% reduction in scarring compared to scarring present at a comparable untreated site of fibrosis.
  • a therapeutically effective amount of an antagonist of LXR activity may preferably be an amount able to therapeutically alter the abundance and/or orientation of ECM components (such as collagen) in a treated scar.
  • a medicament of the invention should provide a therapeutically effective amount of an antagonist of LXR activity.
  • a medicament of the invention may be provided in the form of one or more dosage units, each dosage unit comprising a therapeutically effective amount of an antagonist of LXR activity.
  • the inventors have surprisingly found that the scar-inhibiting efficacy of antagonists of LXR activity shows a "bell shaped" profile when plotted against the concentration of the antagonist provided.
  • the ability of antagonists of LXR activity to inhibit scarring initially increases as the concentration of the antagonist provided increases.
  • This increasing scar-inhibitory activity then reaches a maximum, which is brought about by an optimised amount of the antagonist of LXR activity in question. After this maximum the addition of greater quantities of the antagonist of LXR activity does not give rise to greater inhibition of scarring, and, in fact, the inhibition of scarring observed may decrease as increasing quantities of the antagonist are administered.
  • an amount of an antagonist of LXR activity that does not improve scarring, or an amount that actually serves to worsen scarring, will not constitute a therapeutically effective amount for the purposes of the present invention.
  • a therapeutically effective amount of the antagonist of LXR activity, fenofibrate ester should be less than 2nmoles per linear cm (or cm ) of a wound, or per cm of a fibrotic disorder, the scarring of which it is wished to inhibit.
  • a therapeutically effective amount should not exceed 1.3 nmoles per linear cm (or cm 2 ) of a wound or fibrotic disorder.
  • a therapeutically effective amount of fenofibrate ester should be less than 250ng per linear cm of wound, or cm 2 of a wound or fibrotic disorder, over a 24 hour period, and even more preferably less than lOOng fenofibrate ester per linear cm of wound, or cm 2 of a wound or fibrotic disorder, over a 24 hour period, and still more preferably less than 20ng fenofibrate ester per linear cm of wound, or cm 2 of a wound or fibrotic disorder, over a 24 hour period.
  • Provision of approximately IOng of fenofibrate ester per linear cm of wound, or cm 2 of a wound or fibrotic disorder constitutes a preferred therapeutically effective amount for use in the medicaments or methods of the invention.
  • Preferred therapeutically effective amounts of antagonists of LXR activity may be investigated using in vitro and in vivo models, and suitable assessments of efficacy made with reference to various parameters for the measurement of scarring, as described elsewhere in the specification.
  • a suitable animal model in which the therapeutic effectiveness of an antagonist of LXR activity may be assessed, and in which a therapeutically effective amount of an antagonist of LXR activity may be determined may involve providing the antagonist to incisional or excisional wounds of experimental animals (such as mice, rats or pigs), and assessing the scarring that results on healing of the wound.
  • incisional or excisional wounds of experimental animals such as mice, rats or pigs
  • the commonality of the biological mechanisms underlying scarring means that this scarring may also be investigated using incisional or excisional wound healing models of the type outlined above.
  • bleomycin to experimental animals allows the generation of an experimental model of fibrosis of the lung that may be used to assess effectiveness of antagonists of LXR in the context of inhibiting scarring associated with lung fibrosis.
  • administration of CCl 4 to experimental animals allows the generation of an experimental model of fibrosis of the liver that may be used to assess effectiveness of antagonists of LXR in the context of inhibiting scarring associated with liver fibrosis.
  • ah experimental model of glomerulonephritis may be established either by injection of suitable serum proteins into an experimental animal or injection of nephrotoxic serum, and either of these animal models may be useful in assessment of antagonists of LXR activity in the inhibition of scarring associated with kidney fibrosis.
  • the invention also provides, in a third aspect, the use of an antagonist of LXR activity in the preparation of a medicament for administering between approximately 13pmoles and approximately 2nmoles of the antagonist of LXR activity per cm of length of a wound.
  • the antagonist of LXR activity may be fenofibrate ester.
  • Such a medicament may prevent, reduce or inhibit scarring that would otherwise result from the healing of a wound.
  • the invention provides the use of an antagonist of LXR activity in the preparation of a medicament for administering between about 13 pmoles and 2 nmoles of the antagonist of LXR per cm 2 of scarring associated with a fibrotic disorder.
  • the antagonist of LXR activity may be fenofibrate ester.
  • Such a medicament may prevent, reduce or inhibit scarring associated with the fibrotic disorder.
  • the invention provides the use of an antagonist of LXR activity in the preparation of a medicament for the prevention, reduction or inhibition of scarring, wherein the administration pattern for administering the medicament comprises administering a therapeutically effective amount of the antagonist of LXR activity prior to formation of a wound, or fibrotic tissue, and administering a further therapeutically effective amount of the antagonist of LXR activity after formation of the wound and/or fibrotic tissue.
  • Fenofibrate ester represents a preferred antagonist of LXR activity that may be used in accordance with this aspect of the invention.
  • Administration of the further therapeutically effective amount of an antagonist of LXR activity may preferably occur approximately 24 hours after formation of the wound and/or fibrotic tissue.
  • the use recited above may further comprise the repetition of administration of therapeutically effective amounts of an antagonist of LXR activity for as long as necessary to achieve prevention, reduction or inhibition of scarring.
  • references in the present specification to "inhibition" of scarring utilising antagonists of LXR activity should be taken, except where the context requires otherwise, to also encompass the prevention or reduction of scarring utilising such antagonists.
  • references to "prevention" of scarring utilising antagonists of LXR activity should, except where the context requires otherwise, be taken also to encompass the treatment of scarring utilising antagonists of LXR activity.
  • the extent of inhibition of scarring that may be required in order to achieve a therapeutic effect will be apparent to, and may readily be determined by, a clinician responsible for the care of the patient.
  • the clinician may determine a suitable assessment of the extent of inhibition of scarring that has been achieved through utilisation of an antagonist of LXR activity in order to assess whether or not a therapeutic effect has been achieved, or is being achieved. Such an assessment may, but need not necessarily, be made with reference to suggested methods of measurement described herein.
  • the extent to which inhibition of scarring utilising an antagonist of LXR activity is achieved may be assessed with reference to the effects that an antagonist of LXR activity may achieve in human patients treated with the methods or medicaments of the invention.
  • inhibition of scarring that may be achieved by an antagonist of LXR activity may be assessed with reference to experimental investigations using suitable in vitro or in vivo models.
  • the use of experimental models to investigate inhibition of scarring may be particularly preferred in assessing the therapeutic effectiveness of particular antagonists of LXR activity, or in establishing therapeutically effective amounts of such an antagonist.
  • Animal models of scarring represent preferred experimental models for in vivo assessment of the extent of scar inhibition that may be achieved using the medicaments or methods of the invention. Suitable models may be used specifically to investigate scarring that results from healing of a wound, and, additionally or alternatively, to investigate scarring associated with fibrotic disorders. Suitable models of both types will be known to those skilled in the art. Examples of such models are described below for illustrative purposes.
  • Therapeutically effective antagonists of LXR activity may be selected with reference to any or all of the considerations described in the present specification.
  • Treatment of wounds with a therapeutically effective antagonist of LXR activity may result in the inhibition of scarring that may otherwise be expected to occur on healing of untreated wounds.
  • the inventors believe that treatment in this manner may have an impact on both the macroscopic and microscopic appearance of scars formed from treated wounds; macroscopically the scars may be less noticeable and blend better with the surrounding normal tissue, microscopically the scars may exhibit an internal structure more akin to that found in normal unwounded tissue.
  • a treated scar may, when viewed microscopically, exhibit an abundance and orientation of ECM molecules such as collagen that is more similar to that found in normal skin than that found in untreated scars.
  • an "untreated wound” should be considered to be any wound that has not been exposed to a therapeutically effective amount of an antagonist of LXR activity.
  • a "diluent control-treated wound” will be an untreated wound to which a control diluent has been administered, and a “na ⁇ ve control” will be an untreated wound made without administration of an antagonist of LXR activity, or a suitable control diluent, and left to heal without therapeutic intervention.
  • a "treated wound” may be considered to be a wound exposed to a therapeutically effective amount of an antagonist of LXR activity.
  • a treated wound may be a wound which has been provided with a medicament of the invention, or which has received treatment in accordance with the methods of the invention.
  • Treatment of fibrotic disorders with a therapeutically effective antagonist of LXR activity may result in the inhibition of scarring that may otherwise be expected to be associated with the fibrotic disorder.
  • the inventors believe that treatment in this manner may have an impact on both the macroscopic and microscopic appearance of scars associated with fibrotic disorders, such that the macroscopic and/or microscopic structure of a scar at a treated site of fibrosis will be more akin to that found in normal non-fibrotic tissue.
  • a treated scar may, when viewed microscopically, exhibit an abundance and orientation of ECM molecules, such as collagen, that is more similar to that found in normal skin than that found in untreated scars.
  • a "treated scar" should be taken to encompass:
  • a scar that results from healing of a treated wound i.e. a wound treated with a therapeutically effective amount of an antagonist of LXR activity
  • a scar to which a therapeutically effective amount of an antagonist of LXR activity has been administered i.e. a wound treated with a therapeutically effective amount of an antagonist of LXR activity
  • a scar that results from healing of an untreated wound for example a wound treated with a placebo, control, or standard care
  • a scar to which a therapeutically effective amount of an antagonist of LXR activity has not been administered for example a wound treated with a placebo, control, or standard care.
  • Untreated scars may typically be used as comparators in assessing the inhibition of scarring that may be evident in a treated scar.
  • Suitable comparator untreated scars of this type may preferably be matched to the treated scar with reference to one or more criteria selected from the group consisting of: scar age; scar size; scar site; patient age; patient race and patient gender.
  • Inhibition of scarring using the medicaments and methods of the invention, can be effected at any body site and in any tissue or organ so far investigated.
  • the scar inhibitory activity of medicaments and methods of the invention will primarily be described with reference to inhibition of scarring that may be brought about in the skin (the body's largest organ).
  • the skilled person will immediately appreciate that many of the factors that are relevant when considering inhibition of scarring in the skin are also relevant to inhibition of scarring in other organs or tissues. Accordingly the skilled person will recognise that, except for where the context requires otherwise, the parameters and assessments considered below in respect of scars of the skin may also be applicable to scarring in tissues other than the skin.
  • treatment may improve the macroscopic and microscopic appearance of scars; macroscopically the scars may be less visible and blend with the surrounding skin, microscopically the collagen fibres within the scar may have morphology and organisation that is more similar to those in the surrounding skin.
  • the prevention, reduction or inhibition of scarring within the context of the present invention should be understood to encompass any degree of prevention, reduction or inhibition in scarring as compared to the level of scarring occurring in a control-treated or untreated wound, or at an untreated site of a fibrotic disease (as defined above).
  • the inhibition of scarring achieved using methods and medicaments of the invention may be assessed and/or measured with reference to either the microscopic or macroscopic appearance of a treated scar as compared to the appearance of an untreated scar. Inhibition of scarring may also suitably be assessed with reference to both macroscopic and microscopic appearance of a treated scar.
  • the extent of scarring, and hence the magnitude of any inhibition of scarring achieved may be assessed with reference to any of a number of parameters.
  • holistic assessment of the scar by means of assessment of macroscopic photographs by an independent expert panel, by means of an independent lay panel or clinically by means of a macroscopic assessment by a clinician of the patients themselves.
  • Assessments are captured by means of a VAS (visual analogue scale) or a categorical scale.
  • Macroscopic characteristics of a scar which can be assessed objectively include: i) Colour of the scar. Scars may typically be hypopigmented or hyperpigmented with regard to the surrounding skin. Inhibition of scarring may be demonstrated when the pigmentation of a treated scar more closely approximates that of unscarred skin than does the pigmentation of an untreated scar. Similarly, scars may be redder than the surrounding skin. In this case inhibition of scarring may be demonstrated when the redness of a treated scar fades earlier, or more completely, or to resemble more closely the appearance of the surrounding skin, compared to an untreated scar. Colour can be measured by use of a spectrophotometer. ii) Height of the scar. Scars may typically be either raised or depressed as compared to the surrounding skin.
  • Inhibition of scarring may be demonstrated when the height of a treated scar more closely approximates that of unscarred skin (i.e. is neither raised nor depressed) than does the height of an untreated scar. Height of the scar can be measured on the patient by means of profilometry, or profilometry of moulds taken from a scar.
  • Inhibition of scarring may be demonstrated when the surface texture of a treated scar more closely approximates that of unscarred skin than does the surface texture of an untreated scar.
  • Stiffness of the scar The abnormal composition and structure of scars means that they are normally stiffer than the undamaged skin surrounding the scar. In this case, inhibition of scarring may be demonstrated when the stiffness of a treated scar more closely approximates that of unscarred skin than does the stiffness of an untreated scar.
  • a treated scar will preferably exhibit inhibition of scarring as assessed with reference to at least one of the parameters for macroscopic assessment set out in the present specification. More preferably a treated scar may demonstrate inhibited scarring with reference to at least two of the parameters, even more preferably at least three of the parameters, and most preferably at least four of these parameters (for example, all four of the parameters set out above).
  • Suitable parameters for the microscopic assessment of scars may include:
  • ECM fibres Thickness of extracellular matrix (ECM) fibres. Scars typically contain thinner ECM fibres than are found in the surrounding skin. This property is even more pronounced in the case of keloid and hypertrophic scars. Inhibition of scarring may be demonstrated when the thickness of ECM fibres in a treated scar more closely approximates the thickness of ECM fibres found in unscarred skin than does the thickness of fibres found in an untreated scar.
  • Orientation of ECM fibres ECM fibres found in scars tend to exhibit a greater degree of alignment with one another than do those found in unscarred skin (which have a random orientation frequently referred to as "basket weave").
  • the ECM of pathological scars such as keloids and hypertrophic scars may exhibit even more anomalous orientations, frequently forming large "swirls" or "capsules" of ECM molecules. Accordingly, inhibition of scarring may be demonstrated when the orientation of ECM fibres in a treated scar more closely approximates the orientation of ECM fibres found in unscarred skin than does the orientation of such fibres found in an untreated scar.
  • ECM composition of the scar The composition of ECM molecules present in scars shows differences from that found in normal skin, with a reduction in the amount of elastin present in ECM of scars.
  • the inventors find that the properties of the dermis, or neo-dermis, present within the scar have greater impact on the perception of extent of scarring, as well as on the function of the scarred tissue. Accordingly assessments of criteria associated with the dermis, rather than epidermis, may prove to be the most useful in determining inhibition of scarring.
  • the thickness of ECM fibres and orientation of ECM fibres may be favoured parameters, for assessing inhibition of scarring.
  • a treated scar may preferably have improved ECM orientation (i.e. orientation that is more similar to unscarred skin than is the orientation in an untreated scar).
  • a treated scar will preferably demonstrate inhibition of scarring as assessed with reference to at least one of the parameters for microscopic assessment set out above. More preferably a treated scar may demonstrate inhibition of scarring with reference to at least two of the parameters, even more preferably at least three of the parameters, and most preferably all four of these parameters.
  • the inhibition of scarring occurring at a treated wound may further be assessed with reference to suitable parameters used in the:
  • inhibition of scarring achieved using the medicaments or methods of the invention may be indicated by improvement of one or more of such suitable parameters, and that in the case of inhibition as assessed with reference to a number of parameters that these parameters may be combined from different assessment schemes (e.g. inhibition as assessed with reference to at least one parameter used in macroscopic assessment and at least one parameter used in microscopic assessment).
  • Inhibition of scarring may be demonstrated by an improvement in one or more parameters indicating that a treated scar more closely approximates unscarred skin with reference to the selected parameter(s) than does an untreated or control scar.
  • Suitable parameters for the clinical measurement and assessment of scars may be selected based upon a variety of measures or assessments including those described by Beausang et al (1998) and van Zuijlen et al (2002).
  • suitable parameters may include:
  • VAS Visual Analogue Scale
  • a suitable VAS for use in the assessment of scars may be based upon the method described by Beausang et al. (1998). This is typically a 10cm line in which 0cm is considered an imperceptible scar and 10cm a very poor hypertrophic scar.
  • Prevention, reduction or inhibition of scarring may be determined by allocating scars to different categories based on either textual descriptions e.g. "barely noticeable”, “blends well with normal skin”, “distinct from normal skin”, etc., by comparing a treated scar and a an untreated or control scar, noting any differences between these, and allocating the differences to selected categories (suitable examples of which may be "mild difference", “moderate difference”, “major difference”, etc.). Assessment of this sort may be performed by the patient, by an investigator, by an independent panel, or by a clinician. Assessments of this type may be performed either directly on the patient or on photographs or moulds taken from the patient. Inhibition of scarring may be demonstrated when an assessment indicates that treated scars are generally allocated to more favourable categories than are untreated or control scars.
  • the height and width of scars can be measured directly upon the subject, for example by use of manual measuring devices such as callipers, or automatically with the use of prof ⁇ lometers.
  • Scar width, perimeter and area may be measured either directly on the subject, by image analysis of photographs of the scar, or using plaster casts of impressions of the scar.
  • suitable parameters including silicone moulding, ultrasound, optical three-dimensional profilimetry and high resolution Magnetic Resonance Imaging.
  • Inhibition of scarring may be demonstrated by a reduction in the height, width, area, perimeter or volume, or any combination thereof, of a treated scar as compared to an untreated scar.
  • the appearance or colour of a treated scar may be compared to that of surrounding unscarred skin, and the differences (if any) compared with the difference between the appearance and colour of untreated scars and unscarred skin. Such a comparison may be made on the basis of a visual assessment of the respective scars and unscarred skin.
  • the appearance of a scar may be compared with unscarred skin with reference to whether the scar is lighter or darker, or redder, than the unscarred skin.
  • the respective colours of the scars and skin may be perfectly matched to one another, slightly mismatched, obviously mismatched or grossly mismatched.
  • non-invasive colorimetric devices which are able to provide data with respect to pigmentation of scars and unscarred skin, as well as redness of the skin (which may be an indicator of the degree of vascularity present in the scar or skin).
  • examples of such devices include the X-rite SP-62 spectrophotometer, Minolta Chronometer CR-200/300; Labscan 600; Dr. Lange Micro Colour; Derma Spectrometer; laser-Doppler flow meter; and Spectrophotometric intracutaneous Analysis (SIA) scope.
  • SIA Spectrophotometric intracutaneous Analysis
  • Inhibition of scarring may be demonstrated by a smaller magnitude of difference between the appearance or colour of treated scars and unscarred skin than between untreated scars and unscarred skin.
  • Scar distortion may be assessed by visual comparison of a scar and unscarred skin. A suitable comparison may categorise a selected scar as causing no distortion, mild distortion, moderate distortion or severe distortion.
  • the mechanical performance of scars can be assessed using a number of non-invasive methods and devices based upon suction, pressure, torsion, tension and acoustics.
  • Suitable examples of devices capable of use in assessing mechanical performance of scars include Indentometer, Cutometer, Reviscometer, Visco-elastic skin analysis, Dermaflex, Durometer, Dermal Torque Meter and Elastometer.
  • Inhibition of scarring may be demonstrated by a reduction in distortion caused by treated scars as compared to that caused by untreated scars. It will also be appreciated that inhibition of scarring may be demonstrated by the mechanical performance of unscarred skin being more similar to that of treated scars than of untreated scars.
  • Scar contour may be investigated by means of visual assessment. Suitable parameters to consider in such an assessment include whether or not a scar is flush with surrounding skin, slightly proud, slightly indented, hypertrophic or keloid.
  • the texture of a scar may be assessed with reference to the scar's appearance, and this may also be undertaken by a visual assessment as to whether the scar is, for instance, matt or shiny or has a roughened or smooth appearance as compared to unscarred skin.
  • Scar texture may additionally be assessed with reference to whether the scar has the same texture as unscarred skin (normal texture), is just palpable, firm or hard compared to unscarred skin.
  • the texture of scars may also be assessed with reference to the Hamilton scale (described in Crowe et al, 1998).
  • non-invasive profilimetry devices that use optical or mechanical methods for assessment of scar contour and/or texture.
  • assessments may be carried out on the body of the subject or, for example, on silicone mould impressions of scars, or on positive casts made from such impressions.
  • Inhibition of scarring may be demonstrated in the event that treated scars have scar profiles and textures more comparable to unscarred skin than do untreated scars.
  • Photographic assessment of treated and untreated scars may be performed by an independent lay panel of assessors using standardised and calibrated photographs of the scars.
  • the scars may be assessed by an independent lay panel to provide categorical ranking data (e.g. that a given treated scar is "better”, “worse” or “no different” when compared to an untreated scar) and quantitative data using a Visual Analogue Scale (VAS) based upon the method described by Beausang et al. (1998).
  • VAS Visual Analogue Scale
  • the capture of these data may make use of suitable software and/or electronic system(s) as described in the applicant's co-pending patent application filed as PCT/GB2005/004787.
  • Photographic assessment of treated and untreated scars may alternatively or additionally be performed by a panel of expert assessors using standardised and calibrated photographs of the scars to be assessed, and/or positive casts of silicone moulds.
  • the panel of experts may preferably consist of individuals skilled in the art, suitable examples of which include plastic surgeons, dermatologists or scientists having relevant technical backgrounds.
  • Suitable assessment may provide categorical data, as described above, or assessments with respect to the comparison of a time-course of images of selected treated and untreated scars.
  • assessments that may be useful in assessing inhibition of scarring include:
  • the best scar within a series of scars, which may for example, be a series comprising treated scars and control and/or untreated scars.
  • the best scar may be considered to be the one that most closely resembles unscarred skin.
  • the magnitude of the difference between scars may be considered, for example, whether the difference between scars is mild, moderate or major.
  • Further parameters that may be considered include the earliest time after scar formation at which a difference between scars may be detected, the time post-formation at which the difference between scars is most obvious (or alternatively the finding that the difference continues after the last timepoint assessed), as well as considering whether or not the best scar identified remains consistently better than other scars assessed.
  • a suitable panel of assessors may also consider whether or not one of a treated or untreated scar is consistently paler than the other, or paler than unscarred skin. In the event that a difference in paleness is detectable, consideration may be given to the time after scar formation at which the difference may be detected, the time at which the difference is most obvious, and the time at which the difference disappears.
  • a further parameter that may be assessed by a suitable panel of assessors is the texture of treated and untreated scars.
  • the panel may consider which of the scars has the texture most similar to that of unscarred skin, the earliest time after scar formation at which any difference in texture may be detected, the time post formation at which any difference is most obvious, and the time at which any difference disappears
  • Comparison of treated and untreated scars may further assess which of the scars is narrowest, and which of the scars is shortest. Consideration may also be given to the shape of the scar and the proportion of the scar margin that is distinguishable from the surrounding skin. As with previously described visual assessments and assessments of colour, the presence, degree and location of hyper-pigmentation may also be considered.
  • a clinician, or an independent panel of clinicians may assess the scar(s) on a patient using any of the forgoing parameters e.g. VAS, colour, categorical scales, etc.
  • a suitable clinician may be a clinician responsible for care of a patient, or may be a clinician investigating efficacy of therapies for inhibition of scarring.
  • a patient may assess their own scars and/or compare scars by means of a structured questionnaire.
  • a suitable questionnaire may measure parameters such as: the patient's satisfaction with their scar; how well the scar blends with the unscarred skin; as well as the effect of the scar on their daily life (suitable questions may consider whether the patient uses clothes to hide the scar, or otherwise avoids exposing it); scar symptoms (examples of which may include itch, pain or paresthesia). Inhibition of scarring may be indicated by the treated scar receiving a more positive rating from the patient, and/or causing the patient fewer problems, and/or causing fewer or less scar symptoms, and/or an increase in patient satisfaction compared to an untreated scar.
  • Microscopic assessment may also provide a suitable means by which the quality of treated and untreated or control scars may be compared.
  • Microscopic assessment of scar quality may typically be carried out using histological sections of scars.
  • the process of microscopically assessing and measuring scars may take into consideration categorical data based on suitable parameters, which may include the following:
  • Collagen organisation, hi assessing collagen organisation reference may be made to the orientation of collagen fibres present in the scar, the density of such fibres and collagen fibre thickness in the papillary and reticular dermis.
  • An inhibition of scarring may be indicated when a treated scar contains collagen organisation that more closely approximates that found in unwounded skin than does the organisation in untreated or control treated scars.
  • Scars typically contain an increased amount of ECM components such as collagen when compared to unscarred skin.
  • An inhibition of scarring may be indicated when a treated scar contains reduced abundance of ECM components when compared to untreated or control treated scars, or when a treated scar contains an abundance of ECM components that is more similar to unscarred skin than the abundance contained in an untreated or control scar.
  • VAS Visual analogue scale
  • assessments described above allow the generation of scar ranking data which is able to provide an indication as to whether a treated scar is better, worse or no different compared to a control, untreated or other suitable comparator scar.
  • quantitative data (preferably relating to the above parameters) can be generated using image analysis in combination with suitable visualisation techniques.
  • suitable visualisation techniques that may be employed in assessing scar quality are specific histological stains or immuno-labelling, wherein the degree of staining or labelling present may be quantitatively determined by image analysis
  • Quantitative data may be usefully and readily produced in relation to the following parameters:
  • Preferably inhibition of scarring may be demonstrated with reference to more than one parameter. More preferably inhibition of scarring may be demonstrable with reference to both a clinical (i.e. observed on the subject) parameter and a photographic parameter. Even more preferably inhibition of scarring may be demonstrable with reference to a clinical parameter, a photographic parameter, and also a microscopic assessment parameter (for instance a histological parameter). Most preferably inhibition of scarring may be demonstrable with reference to a clinical VAS score, external lay panel VAS score and ranking (from photographic images) and microscopic VAS score of the reticular dermis.
  • the assessments and parameters discussed above are suitable for assessment of the effects of antagonists of LXR activity on scar formation, as compared to control, placebo or standard care treatment in animals or humans.
  • assessments and parameters may be utilised in determining therapeutically effective antagonists of LXR activity for scar prevention, reduction or inhibition; and in determining therapeutically effective amounts of such antagonists. Appropriate statistical tests may be used to analyse data sets generated from different treatments in order to investigate significance of results.
  • Scarring associated with fibrotic disorders may be assessed with reference to trichrome staining (for example Masson's trichrome or Mallory's trichrome) of biopsy samples taken from a tissue believed to be subject to the fibrotic disorder. These samples may be compared with non-scarred tissues that have been taken from tissues not subject to the fibrotic disorder, and with reference tissues representative of staining in the same tissue (or a range of tissues) subject to different extents of scarring associated with the fibrotic disorder. Comparisons of such tissues may allow assessment of the presence and extent of scarring associated with a fibrotic disorder that is present in the tissue of interest. Protocols for trichrome staining are well known to the skilled person, and kits that may be used to conduct trichrome staining are commercially available.
  • trichrome staining for example Masson's trichrome or Mallory's trichrome
  • scar assessment methods of the type described above may be used to determine therapeutically effective antagonists of LXR activity suitable for inhibition of scarring associated with a fibrotic disorder, as well as determining therapeutically effective amounts of such antagonists.
  • the use of methods and medicaments of the invention to inhibit scarring may bring about a notable improvement in the cosmetic appearance of an injured area thus treated.
  • Cosmetic considerations are important in a number of clinical contexts, particularly when scars may be formed at prominent body sites such as the face, neck and hands. Consequently it is a further preferred embodiment that the medicaments and methods of the invention be used to inhibit scarring at sites where it is desired to improve the cosmetic appearance of a scar formed. Indeed, it is a preferred embodiment that the medicaments and methods of the invention be used to inhibit scarring associated with cosmetic surgery. Since the great majority of cosmetic surgeries consist of elective surgical procedures it is readily possible to administer a therapeutically effective amount of an antagonist of LXR activity prior to surgery, and/or immediately following closure of the wound (e.g.
  • a preferred route by which an antagonist of LXR activity may be administered is via intradermal injection.
  • Such injections may form raised blebs, which may then be incised as part of the surgical procedure, or alternatively the bleb may be raised by injecting the wound margins after the wound has been closed e.g. by sutures.
  • scarring of the skin is responsible for a number of deleterious effects afflicting those suffering from such scarring.
  • scarring of the skin may be associated with reduction of physical and mechanical function, particularly in the case of contractile scars (such as hypertrophic scars) and/or situations in which scars are formed across joints.
  • contractile scars such as hypertrophic scars
  • suitable medicaments and methods of the invention be used to inhibit scarring covering joints of the body (whether such scars result from the healing of wounds covering the joint, or are associated with fibrotic disorders covering the joint).
  • suitable medicaments and methods of the invention may be used to inhibit scarring at increased risk of forming a contractile scar (in the case of scarring that results from the healing of wounds this may include wounds of children, and/or wounds produced by burns).
  • burns injuries may extend over great areas of an individual so afflicted. Accordingly, burns may give rise to scar formation covering a large proportion of a patient's body. This great extent of coverage increases the risk that the scar formed will cover areas of elevated cosmetic importance (such as the face, neck, arms or hands) or of mechanical importance (particularly the regions covering or surrounding joints). Burns injuries caused by hot liquids are frequently suffered by children (for example as a result of upsetting pans, kettles or the like) and, due to the relatively smaller body size of children, are particularly likely to cause extensive damage over a high proportion of the body area. Furthermore, burns injuries, and particularly those suffered by children, have an elevated risk of producing pathological hypertrophic scars of the type described below. Such hypertrophic scars may increase both the cosmetic and mechanical impairment associated with scarring after burns.
  • medicaments and methods of the invention be used to inhibit scarring resulting from burns injuries.
  • the extent of scar formation, and hence extent of cosmetic or other impairment that may be caused by the scar may also be influenced by factors such as the tension of the site at which the scar is formed (and in the case of scarring that results from the healing of wound, the tension at the site where the wound is formed).
  • factors such as the tension of the site at which the scar is formed (and in the case of scarring that results from the healing of wound, the tension at the site where the wound is formed).
  • skin under relatively high tension such as that extending over the chest, or associated with lines of tension
  • suitable medicaments and methods of the invention may be used to inhibit scarring at sites of high skin tension.
  • the medicaments and methods of the invention may, for example, be used to inhibit scarring that results from healing of wounds located at sites of high skin tension.
  • Pathological scarring may have more pronounced deleterious effects than arise even as a result of relatively severe normal scarring.
  • Common examples of pathological scars include keloids, hypertrophic scars and pterygium.
  • Keloid scars constitute a notable example of pathological scarring, and are raised scars that spread beyond the margins of the original wound and invade the surrounding normal skin. Keloids continue to grow over time, do not regress spontaneously, and frequently recur following surgical excision. Keloid scars occur with equal frequency in men and women, mainly from ages 10 to 30, and can result from piercing, surgery, vaccination, tattoos, bites, blunt trauma and burns. A number of studies have suggested that there is an underlying genetic predisposition to keloid formation since keloid scars are more prevalent in dark skinned races, and in individuals of the African Continental Ancestry Group or Asian Continental Ancestry Group.
  • Keloids appear as elevated scars that may typically be hyperpigmented or hypopigmented in relation to the surrounding skin. Keloids may be characterised on the basis of their tendency to grow beyond the initial boundaries of the wound from which they result. At a microscopic level, keloids may be characterised by the presence of large whorls of collagen, and the predominantly acellular nature of the interior of the lesion.
  • Hypertrophic scars are raised scars which may have an appearance very similar to keloid lesions. Unlike keloids, hypertrophic scars do not expand beyond the boundaries of the original injury and are not prone to recurrence after excision. Hypertrophic scars may frequently undergo contraction, and it is believed that the contractile nature of hypertrophic scars may be associated with the elevated numbers of myofibroblasts that are frequently reported within these types of scars. Hypertrophic scars may commonly arise as a result of burn or scald injuries, and are particularly common amongst children.
  • Pterygium is a hypertrophied outgrowth of the subconjunctival tissue to the border of the cornea or beyond.
  • the outgrowth is typically triangular in shape, with the apex pointing towards the pupil.
  • Pterygium may interfere with vision, and may require surgery to remove the hypertrophied tissue.
  • the tissue may frequently re-grow after excision, in the same manner as keloid scars, thus requiring multiple incidences of surgery.
  • the ability of antagonists of LXR activity to inhibit scarring is of great utility in the inhibition of scarring associated with grafting procedures.
  • the medicaments and methods of the invention may be used to inhibit scarring that results from wounds associated with grafting procedures. Inhibition of scarring using the medicaments and methods of the invention is of benefit both at a graft donor sites and graft recipient sites.
  • the scar inhibitory effects of the medicaments and methods of the invention are able to inhibit scarring that may otherwise occur at sites where tissue for grafting is removed, or that may be associated with the healing and integration of grafted tissue.
  • the inventors believe that the methods and medicaments of the invention confer advantages in the inhibition of scarring that may otherwise be associated with grafts utilising skin, artificial skin, or skin substitutes.
  • the medicaments and methods of the invention may be used to inhibit scarring associated with encapsulation.
  • Encapsulation is a form of scarring that occurs around sites at which implant materials (such as biomaterials) have been introduced into the body.
  • Encapsulation is a frequent complication associated with breast implants, and the use of the medicaments or methods of the invention to inhibit encapsulation in this context is a preferred embodiment of the invention.
  • the medicaments and methods of the invention may be used to inhibit scarring that results from a wide range of wound types, which may occur at a wide range of body sites.
  • the medicaments and methods of the invention may be used to inhibit scarring that results from healing of wounds selected from the group consisting of: abrasions; avulsions; crush wounds; incisional wounds; lacerations; punctures; and missile wounds. All of these different types of wounds may be suffered by the skin, among other tissues or organs, and all may, to a greater or lesser extent, result in scarring.
  • Abrasions are also commonly referred to as "scrapes". Abrasions occur as a result of the skin being rubbed away by friction against another rough surface. Common examples of abrasions include rope burns and skinned knees. An abrasion may macroscopically appear as lines of scraped skin, possibly including tiny spots of bleeding. Although abrasions represent relatively "shallow” injuries they may give rise to scars, and frequently cover a relatively large area. Accordingly the medicaments and methods of the invention may advantageously be used in the inhibition of scarring resulting from abrasion wounds. Avulsions occur when an entire bodily structure, or a part of such a structure, is forcibly pulled away from its site.
  • avulsions include the loss of a permanent tooth or an ear lobe.
  • Avulsions may, for example, arise as a result of explosions, gunshots, and animal bites.
  • An avulsion may characteristically exhibit heavy, rapid bleeding, as well as a noticeable absence of tissue. It will be appreciated that the trauma associated with avulsion injuries may generally lead to extensive scarring, and so it will be appreciated that the medicaments and methods of the invention may advantageously be used in the inhibition of scarring resulting from avulsion wounds.
  • Crush wounds typically occur as a result of a heavy object falling onto an individual (or part of an individual). The force thus generated may split the skin and shatter or tear underlying structures.
  • a crush wound may have irregular margins, similar in appearance to those of a laceration; however, the wound will generally be deeper and trauma to underlying muscle and bone may be apparent.
  • the medicaments and methods of the invention may advantageously be used in the inhibition of scarring that results from both penetrative and non-penetrative injuries, and accordingly the medicaments and methods of the invention may be beneficial in inhibiting scarring resulting from crush wounds.
  • Incisional wounds are also commonly referred to as "cuts". Incisional wounds result from incision, or slicing, of a tissue with a sharp instrument, which results in a wound with relatively even edges. Incisional wounds can vary greatly in their severity, from minimal wounds (such as a paper cut) to significant wounds such as those arising as a result of surgical incision. An incisional wound may have little or profuse bleeding depending on the depth and length of the wound, and also on the tissue involved. The even edges of incisional wounds will generally readily line up, which may facilitate closure of such wounds.
  • Incisional wounds are a frequent cause of scarring, and it will be appreciated that the medicaments and methods of the invention may advantageously be used in the inhibition of scarring resulting from incisional wounds.
  • Lacerations are also frequently referred to a "tears". These wounds arise as a result of forcible separation of a tissue or organ, which will normally produce a wound having characteristic ragged edges. Lacerations are generally produced by the action of great mechanical forces against the body, either from an internal source as in childbirth, or from an external source like a punch. The laceration arises when the force exerted on a tissue or organ becomes too great for the tissue or organ to bear.
  • a laceration may exhibit little or profuse bleeding, in much the same manner as an incisional wound, hi contrast to incisional wounds however, the tissue damage is generally greater and the wound's ragged edges do not line up so readily. This frequent misalignment of the margins of lacerations may contribute to increase scarring resulting from the healing of such wounds, however, the inventors believe that the medicaments and methods of the invention may advantageously be used in the inhibition of scarring resulting from laceration wounds.
  • Punctures are deep, narrow wounds. Punctures may typically be produced by sharp objects such as nails, knives, and broken glass being driven into the body. The depth of a puncture wound will generally be greater than its length. As a consequence, there is generally little bleeding around the outside of the wound although more bleeding may occur inside the wound. This may lead to discoloration around the puncture wound. Although punctures may typically involve only a relatively small surface area of the body, their depth means that a number of different tissue types may frequently be subject to scarring as a result of puncture wounds. Given the ability of the medicaments and methods of the invention to prevent scarring in various different tissues, it will be appreciated that such medicaments and methods may advantageously be used in the inhibition of scarring resulting from puncture wounds.
  • Missile wounds are also known as "velocity wounds". Missile wounds are caused by an object entering the body at a high speed, typically a bullet. A missile entry wound may be accompanied by an exit wound, and bleeding may be profuse, depending on the nature of the injury. The inventors believe that the medicaments and methods of the invention may advantageously be used in the inhibition of scarring resulting from missile wounds. Incisional wounds constitute preferred wounds scarring resulting from which may be inhibited by the medicaments and methods of the invention. Surgical incisional wounds may constitute a particularly preferred group of wounds in respect of which scarring may be inhibited utilising the medicaments and methods of the invention.
  • tissues other than the skin such as the cornea, may also be subject to wounds of the type described above and elsewhere in the specification.
  • the medicaments and methods of the invention may also be of benefit in inhibiting scarring associated with such wounds in these tissues.
  • adhesions are formed by bands of fibrous scar tissue, and can connect the loops of the intestines to each other, or the intestines to other abdominal organs, or the intestines to the abdominal wall. Adhesions can pull sections of the intestines out of place and may block passage of food. Adhesions are also a common sequitur of surgery involving gynaecological tissues. Incidences of adhesion formation may be increased in wounds that are subject to infection (such as bacterial infection) or exposure to radiation.
  • the medicaments and methods of the invention may also be useful in the inhibition of scarring, including formation of adhesions, that may occur on healing of infected wounds or wounds exposed to radiation. Indeed, the skilled person will appreciate that the use of medicaments or methods of the invention in the inhibition of any scarring involving the peritoneum is a preferred embodiment.
  • Medicaments for this purpose may be administered by lavage, or in a parenteral gel/instillate or locally e.g.
  • the medicaments or methods of the invention are suitable for use in the inhibition of scarring in the eye, and their use in this context represents a preferred embodiment of the invention.
  • the inventors believe that the medicaments or methods of the invention may be used to inhibit scarring that results from healing of wounds to the eye, and/or to inhibit scarring associated with fibrotic disorders of the eye.
  • the medicaments or methods of the invention may be used to inhibit scarring associated with corneal surgery, glaucoma filtration surgery, or cataract surgery (where scarring may frequently be associated with contraction of the lens capsule)
  • Corneal scars may result from the healing of corneal wounds such as those produced by LASIK or PRK procedures. Corneal scarring may be assessed by measuring the opacity, or transmitting/refractory properties, of the cornea. Such assessments may, for example, be made using in vivo confocal microscopy.
  • a therapeutically effective amount of an antagonist of LXR activity may be delivered locally, for example by means of a device implanted in the eye, or by injection.
  • Scarring in the peripheral nervous system may be inhibited by the medicaments of the invention. Such scarring may arise as a result of surgery or trauma and may additionally be assessed by future assays of nerve function e.g. sensory or motor tests. Inhibitors of scarring should improve such future outcomes.
  • Scarring in the blood vessels e.g. following anastomotic surgery can lead to myointimal hyperplasia and reduction in the volume of the blood vessel lumen (restenosis). This can be measured directly e.g. using ultrasound, or indirectly by means of blood flow. Inhibition of scarring achieved using the medicaments or methods of the invention may lead to a reduction in narrowing of the blood vessel lumen and allow a more normal blood flow.
  • a therapeutically effective amount of an antagonist of LXR activity may be provided to blood vessels by any suitable means.
  • these may include direct injection into the walls of the blood vessel before suturing, bathing an anastomotic site in a medium comprising the antagonist of LXR activity, or administration of the antagonist by local applied devices, e.g. stents.
  • Effective inhibition of scarring in blood vessels may be indicated by the maintenance of a normal level of blood flow following blood vessel injury.
  • the medicaments or methods of the invention may be used to inhibit scarring in tendons and ligaments. Such scarring may otherwise be expected to occur following surgery or trauma involving tissues of this type. Successful inhibition of scarring may be indicated by restoration of function of tissues treated with the medicaments or methods of the invention. Suitable indicia of function may include the ability of the tendon or ligament to bear weight, stretch, flex, etc.
  • Preferred routes of administration by which therapeutically effective amounts of an antagonist of LXR activity may be administered to a tissue in which it is desired to inhibit scarring, are discussed more fully elsewhere in the specification, but it may generally be preferred that therapeutically effective antagonists are provided by local administration to the tissue the scarring of which is to be inhibited. Suitable methods by which such local administration may be achieved will depend on the identity of the tissue in question, and may also be influenced by whether the scarring to be inhibited is scarring resulting from the healing of a wound, or scarring associated with a fibrotic disorder.
  • Preferred routes of administration may include local injection (for example intradermal injection in the case where it is wished to inhibit scarring of the skin).
  • topical medicaments such as sprays; powders; drops (e.g. for the ear or eye); ointments or creams; or release from local devices e.g. stents, implants, polymers, dressings etc.
  • medicaments of the invention may be formulated and manufactured in any form that allows for the medicament to be administered to a patient such that a therapeutically effective amount of an antagonist of LXR activity is provided to a site where scarring is to be prevented, reduced or inhibited.
  • Scarring associated with fibrotic disorders will frequently occur in relatively inaccessible tissues and organs, and it may be preferred that when scarring associated with a fibrotic disorder is to be inhibited the antagonist of LXR activity be administered systemically.
  • Suitable routes of administration include, without limitation, oral, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal.
  • solid oral formulations (such as tablets or capsules) providing a therapeutically effective amount of an antagonist of LXR activity may be used for the inhibition of scarring associated with renal fibrosis or cirrhosis of the liver.
  • Aerosol formulations for inhalation may be preferred as means for providing antagonists of LXR activity in the event that it is wished to inhibit scarring associated with chronic obstructive pulmonary disease or other fibrotic disorders of the lungs and airways.
  • routes of administration described above may also be suitable for topical administration to a tissue in which it is wished to inhibit scarring (for example, inhalation or intranasal administration for inhibition of scarring in the respiratory system, whether as a result of the healing of a wound, or associated with a fibrotic disorder).
  • scarring for example, inhalation or intranasal administration for inhibition of scarring in the respiratory system, whether as a result of the healing of a wound, or associated with a fibrotic disorder.
  • Medicaments of the invention may preferably be provided in the form of one of more dosage units providing a therapeutically effective amount (or a known fraction or multiple of a therapeutically effective amount) of an antagonist of LXR activity.
  • Methods of preparing such dosage units will be well known to the skilled person; for example see Remington's Pharmaceutical Sciences 18 th Ed. (1990).
  • the methods or medicaments of the invention may be used prophylactically, i.e. prior to scar formation.
  • methods or medicaments of the invention may be utilised prior to wounding or prior to the onset of a fibrotic disorder.
  • this may involve administration of a therapeutically effective amount of an antagonist of LXR activity at sites where no wound presently exists, but where a wound that would otherwise give rise to a scar is to be formed.
  • a therapeutically effective amount of an antagonist of LXR activity may be administered to sites that are to undergo wounding as a result of elective procedures (such as surgery), or to sites that are believed to be at elevated risk of wounding.
  • the medicaments of the invention are administered to the site around the time of wounding, or immediately prior to the forming of a wound (for example in the period up to six hours before wounding) or the medicaments may be administered at an earlier time before wounding (for example up to 48 hours before a wound is formed).
  • the skilled person will appreciate that the most preferred times of administration prior to formation of a wound will be determined with reference to a number of factors, including the formulation and route of administration of the selected medicament, the dosage of the medicament to be administered, the size and nature of the wound to be formed, and the biological status of the patient (which may determined with reference to factors such as the patient's age, health, and predisposition to healing complications or adverse scarring).
  • the prophylactic use of methods and medicaments in accordance with the invention is a preferred embodiment of the invention, and is particularly preferred in the prevention, reduction or inhibition of scarring in the context of surgical wounds.
  • medicaments of the invention may be administered to a site at elevated risk of developing a fibrotic disorder prior to formation of said disorder.
  • Suitable sites may be those that are perceived to be at elevated risk of the development of fibrotic disorders.
  • An elevated risk of development of fibrotic disorders may arise as a result of disease, or as a result of environmental factors (including exposure to fibrotic agents), or as a result of genetic predisposition.
  • a therapeutically effective amount of an antagonist of LXR activity may be administered immediately prior to onset of a fibrotic disorder, or at an earlier time.
  • the skilled person will be able to establish the optimal time for administration of medicaments of the invention used to treat fibrotic disorders using standard techniques well known to those skilled in the art, and familiar with the clinical progression of scarring associated with fibrotic disorders.
  • the methods and medicaments of the invention are also able to inhibit scarring if administered after a wound has already been formed. It is preferred that such administration should occur as early as possible after formation of the wound, but agents of the invention are able to inhibit scarring at any time up until the healing process has been completed (i.e. even in the event that a wound has already partially healed the methods and medicaments of the invention may be used to inhibit scarring in respect of the remaining un-healed portion). It will be appreciated that the "window" in which the methods and medicaments of the invention may be used to inhibit scarring is dependent on the nature of the wound in question (including the degree of damage that has occurred, and the size of the wounded area). Thus, in the case of a large wound, the methods and medicaments of the invention may be administered relatively late in the healing response yet still be able to inhibit scarring, as a consequence of the relatively prolonged time that large wounds require to heal.
  • the methods and medicaments of the invention may, for instance, preferably be administered within the first 24 hours after a wound is formed, but may still inhibit scarring if administered up to ten, or more, days after wounding.
  • the methods and medicaments of the invention may be administered to a site at which a fibrotic disorder is already developing, in order to prevent further scarring associated with the fibrotic disorder taking place.
  • This use will obviously be advantageous in situations in which the degree of scarring that has occurred prior to administration of the antagonist of LXR activity is sufficiently low that the fibrotic tissue is still able to function.
  • Medicaments of the invention may preferably be administered within 24 hours of the onset of scarring associated with a fibrotic disorder, but may still be effective if administered considerably later in the fibrotic process.
  • medicaments may be administered within a month of the onset of the fibrotic disorder (or of the diagnosis that scarring associated with the fibrotic disorder is taking place), or within sixth months, or even one or more years, depending on the extent of scarring that has already occurred, the proportion of the tissue effected by the fibrotic disorder, and the rate at which the fibrotic disorder is progressing.
  • the methods and medicaments of the invention may be administered on one or more occasions (as necessary) in order to inhibit scarring.
  • therapeutically effective amounts of an antagonist of LXR activity may be administered to a wound as often as required until the healing process has been completed.
  • the medicaments of the invention may be administered daily or twice daily to a wound for at least the first three days following the formation of the wound.
  • the inventors have found that regimes involving two administrations of medicaments of the invention, the first prior to formation of a wound and the second after wounding, are particularly beneficial in inhibiting scar formation.
  • such regimes may involve a first administration immediately prior to formation of a wound and a second administration 24 hours after wounding.
  • the methods or medicaments of the invention may be administered both before and after formation of a wound.
  • the inventors have found that administration of the medicaments of the invention immediately prior to the formation of a wound, followed by daily administration of an antagonist of LXR activity for one or more days following wounding, is particularly effective in inhibiting scarring resulting from the healing of a wound, or associated with a fibrotic disorder.
  • a therapeutically effective amount of the antagonist of LXR activity may be provided by means of a number of administrations. Suitable regimes may involve administration monthly, weekly, daily or twice daily. The inventors believe that therapeutically effective amounts of an antagonist of LXR activity may also be used to reduce existing scars. This is applicable to existing scars that result from the healing of a wound, and/or existing scars associated with fibrotic disorders. Accordingly the use of methods and medicaments of the invention in the reduction of existing scars constitutes a preferred use according to the invention.
  • a therapeutically effective amount of an antagonist of LXR activity may be provided by means of any number of suitable administrations. Suitable regimes for these administrations may be readily devised by the skilled person using techniques (including in vitro studies, animal and human studies) well known in and established within the pharmaceutical industry.
  • agent or “agent of the invention” is meant a therapeutically effective antagonist of LXR activity. It will be appreciated that all such suitable agents may be incorporated in medicaments in accordance with the invention, and all may be used in the methods or uses of the invention.
  • the medicaments of the invention represent preferred compositions by which a therapeutically effective amount of an antagonist of LXR activity may be administered in order to put the methods of the invention into practice.
  • the amount of a medicament of the invention that should be provided to a wound or fibrotic disorder, in order that a therapeutically effective amount of an antagonist of LXR activity may be administered depends on a number of factors. These include the biological activity and bioavailability of the agent present in the medicament, which in turn depends, among other factors, on the nature of the agent and the mode of administration of the medicament. Other factors in determining a suitable therapeutic amount of a medicament may include:
  • the specific condition to be treated e.g. acute wounding or chronic fibrotic disorders.
  • the size of the site to be treated is also be influenced by the above-mentioned factors and particularly the half-life of the chosen agent within the subject being treated.
  • medicaments in accordance with the invention when medicaments in accordance with the invention are used to treat existing scars (whether resulting from healing of a wound, or associated with a fibrotic disorder) the medicament should be administered as early as possible in the scarring process or the fibrotic disorder begins, hi the case of wounds or fibrotic disorders that are not immediately apparent, such as those at internal body sites, medicaments may be administered as soon as the wound or disorder, and hence the risk of scarring, is diagnosed. Therapy with methods or medicaments in accordance with the invention should continue until scarring has been inhibited to a clinician's satisfaction.
  • Frequency of administration will depend upon the biological half-life of the agent used.
  • a cream or ointment containing an agent of the invention should be administered to a target tissue such that the concentration of the agent at a wound or site of fibrosis is maintained at a level suitable to inhibit scarring. This may require administration daily or even several times daily.
  • the inventors have found that administration of an agent of the invention immediately prior to wounding, with a further administration one day after wounding is particularly effective for the inhibition of scarring that would otherwise result from the healing of such a wound.
  • Medicaments of the invention may be administered by any suitable route capable of achieving the desired effect of inhibiting scarring, but it is preferred that the medicaments be administered locally at a wound site or site of a fibrotic disorder. It is particularly preferred that fibrate esters be administered locally at sites, such as the skin, where they are to exert their therapeutic activity, since these compounds may otherwise be converted to inactive forms through the actions of esterases.
  • a preferred medicament in accordance with the invention comprises an injectable solution of an agent of the invention (e.g. for injection around the margins of a wound, or at a site likely to be wounded). Suitable formulations for use in this embodiment of the invention are considered below.
  • medicaments of the invention may also be administered in a topical form to inhibit scarring (whether resulting from the healing of a wound, or associated with a fibrotic disorder).
  • a topical form to inhibit scarring (whether resulting from the healing of a wound, or associated with a fibrotic disorder).
  • such administration may be effected as part of the initial and/or follow up care for the wounded area.
  • the inventors have found that inhibition of scarring can be very beneficially effected by topical application of an agent of the invention to a wound or fibrotic disorder (or, in the case of prophylactic application, to a tissue or site where a wound or fibrotic disorder will occur).
  • compositions or medicaments containing agents of the invention may take a number of different forms depending, in particular, on the manner in which they are to be used. Thus, for example, they may be in the form of a liquid, ointment, cream, gel, hydrogel, powder or aerosol. All of such compositions are suitable for topical application to a site of scarring (for example, either a wound or a fibrotic disorder), and this represents a preferred means of administering agents of the invention to a subject (person or animal) in need of treatment.
  • a site of scarring for example, either a wound or a fibrotic disorder
  • the agents of the invention may be provided on a sterile dressing or patch, which may be used to cover a wound or fibrotic site where scarring is to be inhibited.
  • the agents of the invention may be released from a device or implant, or may be used to coat such a device e.g. a stent or controlled release device e.g. wound dressing.
  • a device or implant e.g. a stent or controlled release device e.g. wound dressing.
  • the vehicle of a composition comprising agents of the invention should be one that is well tolerated by the patient and allows release of the agent to the wound or fibrotic site.
  • Such a vehicle is preferably biodegradeable, bioresolveable, bioresorbable and/or non-inflammatory.
  • Medicaments and compositions comprising agents of the invention may be used in a number of ways.
  • a composition may be applied in and/or around a wound or fibrotic disorder in order to inhibit scarring.
  • the pharmaceutically acceptable vehicle will be one which is relatively "mild” i.e. a vehicle which is biocompatible, biodegradable, bioresolvable and non-inflammatory.
  • An agent of the invention may be incorporated within a slow or delayed release device.
  • Such devices may, for example, be placed on or inserted under the skin and the agent or nucleic acid may be released over days, weeks or even months.
  • Delayed release devices may be particularly useful for patients, such as those suffering from extensive or pathological scarring or from long-lasting scarring associated with a fibrotic disorder, who require long-term administration of therapeutically effective amounts of an antagonist of LXR activity. Such devices may be particularly advantageous when used for the administration of an agent or nucleic acid that would otherwise normally require frequent administration (e.g. at least daily administration by other routes).
  • Daily doses of an agent of the invention may be given as a single administration (e.g. a daily application of a topical formulation or a daily injection).
  • the agent of the invention may require administration twice or more times during a day.
  • a slow release device may be used to provide optimal doses of an agent of the invention to a patient without the need to administer repeated doses.
  • a dose of a composition comprising agents of the invention may preferably be sufficient to provide a therapeutically effective amount of an antagonist of LXR activity in a single administration.
  • each dose need not in itself provide a therapeutically effective amount of an antagonist of LXR activity, but that a therapeutically effective amount may instead be built up through repeated administration of suitable doses.
  • compositions comprising agents of the invention.
  • a pharmaceutical vehicle for administration of an agent of the invention may be a liquid and a suitable pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable vehicle is a solid and a suitable composition is in the form of a powder.
  • the agent of the invention may be formulated as a part of a pharmaceutically acceptable transdermal delivery system, e.g., a patch/dressing
  • a solid vehicle can include one or more substances that may also act as flavouring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also comprise an encapsulating material.
  • the vehicle is a finely divided solid that is in admixture with the finely divided agent of the invention.
  • the agent of the invention is mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the agent of the invention.
  • Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid vehicles may be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the agent of the invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil.
  • a solution comprising approximately 5% ethanol constitutes a particularly suitable liquid vehicle for compositions comprising fibrate esters (such as fenofibrate ester), which may otherwise be subject to limited solubility in water.
  • Solutions of approximately 5% v/v ethanol may be used in combination with other appropriate liquid vehicles (for instance buffered vehicles such as PBS) to achieve requisite solubility of agents such as fenofibrate ester.
  • the vehicle can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration.
  • the liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intradermal, intrastromal (cornea), intraadventitial (blood vessels) or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the agent of the invention may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium (such as PBS). Vehicles are intended to include necessary and inert binders, suspending agents, lubricants and preservatives.
  • the chosen agent will preferably be an agent having an elevated degree of resistance to degradation.
  • the agent of the invention may be protected (using the techniques well known to those skilled in the art) so that its rate of degradation in the digestive tract is reduced.
  • compositions of agents of the invention are suitable for use in inhibiting scarring in the eye (and particularly in the cornea or retina). Scarring of the cornea may result from corneal wounds, which may be caused by trauma to the cornea arising as a result of accidental injury or as a result of surgical operations (e.g. laser surgery on the cornea).
  • a preferred medicament of the invention may be in the form of an eye drop (including viscous or semi-viscous eye drops), cream, gel or ointment.
  • Scarring in the eye may also be associated with fibrotic disorders such as proliferative vitreoretinopathy.
  • it may be preferred to administer a therapeutically effective amount of an antagonist of LXR activity by means of intravitreal injection or localised (e.g. intraocular) release device.
  • intravitreal injection or localised (e.g. intraocular) release device.
  • Such injections may preferably follow surgery or intravitreal implantation procedures.
  • Agents of the invention may be used to inhibit scarring in a range of "internal" wounds or fibrotic disorders (i.e. wounds or fibrotic disorders occurring within the body, rather than on an external surface).
  • internal wounds include penetrative wounds that pass through the skin into underlying tissues, and wounds associated with surgical procedures conducted within the body.
  • the range of fibrotic disorders that effect internal sites is extensive, and includes lung fibrosis, liver fibrosis, kidney fibrosis and muscle fibrosis.
  • medicaments in accordance with the invention for use in the inhibition of scarring in the lungs or other respiratory tissues may be formulated for inhalation.
  • medicaments in accordance with the invention for use in the inhibition of scarring in the body cavities e.g. abdomen or pelvis may be formulated as a lavage, gel or instillate.
  • An antagonist of LXR activity for use in the medicaments or methods of the invention may be incorporated in a biomaterial, from which it may be released to inhibit scarring.
  • Biomaterials incorporating antagonists of LXR activity are suitable for use in many contexts, and at many body sites, where it is desired to inhibit scarring, but may be of particular utility in providing antagonists of LXR activity to the eye (for example after retina surgery or glaucoma filtration surgery), or to sites where it is wished to inhibit restenosis or adhesions.
  • biomaterials incorporating antagonists of LXR activity may be used in the manufacture of sutures, and such sutures represent a preferred embodiment of the invention.
  • compositions comprising agents of the invention and precise therapeutic regimes for administration of such compositions (such as daily doses of the active agent and the frequency of administration).
  • a suitable dose of an agent in accordance with the invention able to inhibit scarring may depend upon a range of factors including (but not limited to) the nature of the tissue to be treated, the area and/or depth of the wound or fibrosis to be treated, the severity of the wound or fibrosis, and the presence or absence of factors predisposing to pathological scar formation.
  • the amount of an antagonist of LXR activity that may be administered to a wound or site of fibrosis in a single incidence of treatment may preferably be in the region of 13pmoles to 2nmoles/cm of wound or cm 2 of fibrosis.
  • a linear centimetre of wound may be taken to comprise a site where a wound is to be formed, as well as a wounded site, or both margins of a wounded site (should such margins exist).
  • a centimetre of wound in the context of the present disclosure constitutes a unit by which the size of a wound to be treated may be measured.
  • a centimetre of wound may be taken to comprise any square centimetre of a body surface that is wounded in whole or in part.
  • a wound of two centimetres length and one centimetre width i.e. with a total surface area of two centimetres
  • a wound having a length of two centimetres and a width of two centimetres i.e. a total surface area of four centimetres 2
  • four wound centimetres will constitute four wound centimetres.
  • the size of a wound in wound centimetres should generally be assessed when the wound is in its relaxed state (i.e. when the body site bearing the wounded area is in the position adopted when the body is at rest). In the case of skin wounds, the size of the wound should be assessed when the skin is not subject to external tension.
  • the preferred amount of an antagonist of LXR activity to be administered to a wound or site of fibrosis over a period of approximately 24 hours may be in the region of approximately 13pmoles to approximately 1.3nmoles/cm of wound or cm 2 of fibrosis.
  • the amount of an antagonist of LXR activity to be administered via topical administration may be altered depending on permeability of the tissue or organ to which the topical composition is administered.
  • Such an increased amount of an antagonist of LXR activity may still represent a therapeutically effective amount, if the amount of the agent taken up into the tissue or organ where scarring is to be inhibited is therapeutically effective (i.e. if a therapeutically effective amount permeates the tissue or organ where scarring is to be inhibited, irrespective of the fact that a larger, non- therapeutic, amount of the agent may remain on the surface of, and unable to penetrate, the tissue or organ being treated).
  • an antagonist of LXR activity such as fenofibrate ester
  • the amount of an antagonist of LXR activity will preferably not exceed about 2nmoles/cm of wound, or cm 2 of fibrosis. More preferably the amount administered in a single incidence of treatment will be less than about 1.3 nmoles/cm of wound, or cm 2 of fibrosis, and most preferably it will be less than about 277 pmoles/cm of wound, or cm 2 of fibrosis.
  • the amount of an antagonist of LXR activity (such as fenofibrate ester) to be administered to a wound, or site of fibrosis, over a period of approximately 24 hours will not exceed about 2nmoles/cm of wound, or cm 2 of fibrosis. More preferably the amount to be administered over a period of approximately 24 hours will be less than about 1.3nmoles/cm of wound, or cm 2 of fibrosis, and most preferably it will be less than 277 pmoles/cm of wound, or cm 2 of fibrosis.
  • an antagonist of LXR activity such as fenofibrate ester
  • the total amount of an antagonist of LXR activity (such as fenofibrate ester) administered to a wound or site of fibrosis will not exceed about 2nmoles/cm of wound, or cm 2 of fibrosis. More preferably the total amount will not exceed 1.3 nmoles/cm of wound, or cm 2 of fibrosis, and most preferably it will not exceed 277 pmoles/cm of wound, or cm 2 of fibrosis.
  • the total amount of an antagonist of LXR activity (such as fenofibrate ester) that may be administered by local injection to a wound or site of fibrosis may be preferably be in the region of 27pmoles to 55pmoles/centimetre of wound or cm 2 fibrosis.
  • a suitable amount to be administered may be in the region of 27pmoles to 55pmoles/cm of wound or cm 2 or fibrosis.
  • An antagonist of LXR activity may preferably be provided in the form of an injectable solution at a concentration of between about 138 nM and about 20 ⁇ M. Preferably approximately lOO ⁇ L of such a solution administered per centimetre of wound or cm 2 of fibrosis over a 24 hour period.
  • An antagonist of LXR activity may more preferably be administered as an approximately 138 nM to 13 ⁇ M solution, or even more preferably as about a 277 nM to 554 nM solution. lOO ⁇ L of such a solution may be administered per linear centimetre of wound or cm 2 of fibrosis over a 24 hour period.
  • the antagonist of LXR activity (such as fenofibrate ester) may be administered as a 277 nM solution with lOO ⁇ L of such a solution administered per linear centimetre of wound or cm 2 of fibrosis over a 24 hour period.
  • an antagonist of LXR activity may be determined with reference to the concentration of the agent that is attained in the organ or tissue to which they are administered.
  • the information regarding therapeutically effective dosages set out herein will provide sufficient guidance to allow the skilled person to calculate the local concentrations of an antagonist of LXR activity established by intradermal injection, and, based on these values, to determine suitable amounts of such agents that may be administered by other routes in order to achieve equivalent local concentrations.
  • fenofibrate ester may be administered by way of an injectable solution containing between 5ng/100 ⁇ L and 750ng/100 ⁇ L in order to inhibit scarring or treat fibrosis when administered as an intradermal injection providing lOO ⁇ L of solution per linear cm of wound margin or cm 2 of fibrosis.
  • this volume may be administered to either one or both of the margins of a wound to be treated (i.e. in the.case of a reference to lOO ⁇ l of a medicament, this may be administered as lOO ⁇ l to the wound margins, or as 50 ⁇ l to each of the wound margins to be joined together).
  • Medicaments of the invention may be used to inhibit scarring as a monotherapy (e.g. through use of medicaments of the invention alone). Alternatively the methods or medicaments of the invention may be used in combination with other compounds or treatments for the inhibition of scarring. Suitable compounds that may be used as parts of such combination therapies will be well known to those skilled in the art. The skilled person will appreciate that therapeutically effective amounts of an antagonist of LXR activity may be administered at the sites of wounds or fibrotic disorders where it is wished to inhibit scarring or treat fibrosis by virtue of cellular expression (commonly referred to as gene therapy).
  • cells at a site where scarring is to be inhibited may be induced to express geranylgeranyl pyrophosphate, a known antagonist of LXR activity.
  • expressible antagonists of LXR activity such as siRNA, oligonucleotides, ribozymes or aptamers may also be expressed at sites where scarring is to be inhibited.
  • the invention provides a method of inhibiting scar formation, the method comprising inducing cellular expression of a therapeutically effective amount of an antagonist of LXR activity at a site where scarring is to be inhibited.
  • Figure 1 compares macroscopic VAS scores of treated scars and na ⁇ ve control scars, resulting from incisional skin wounds to which treatments were applied, via intradermal injection, on days 0 and 1 of the study. Results are shown in the form of a bar chart showing macroscopic VAS scores for scars formed 70 days after wounding. "*" indicates p ⁇ 0.05 versus na ⁇ ve control.
  • Figure 2 compares microscopic VAS scores of treated scars and na ⁇ ve control scars, resulting from incisional skin wounds to which treatments were applied via intradermal injection on days 0 and 1 of the study. Results are shown in the form of a bar chart showing microscopic VAS scores for scars formed 70 days after wounding. "*" indicates p ⁇ 0.05 versus na ⁇ ve and diluent control.
  • Figure 3 shows representative photographs comparing the macroscopic appearances of treated scars and na ⁇ ve control scars. Treatments were applied via intradermal injection on days 0 and 1 of the study. The images were taken 70 days after wounding.
  • the inventors investigated the effects of antagonists of LXR activity on scarring using in an in vivo model of scarring.
  • Fenofibrate ester (Catalogue number #F6020), an antagonist of LXR activity, was purchased from Sigma- Aldrich.
  • the fenofibrate ester was diluted in a solution comprising 5% v/v ethanol (absolute ethanol, 200 proof, for molecular biology, purchased from Sigma-Aldrich) in phosphate buffered saline (PBS) to produce three solutions having concentrations as follows:
  • Treated wounds were re-treated with the fenofibrate ester solutions day 1 post-wounding via injection of 50 ⁇ l to each of the two margins of the lcm wound.
  • each injection of the lng/lOO ⁇ l solution provided 2.77pmoles of fenofibrate ester
  • each injection of thel Ong/1 OO ⁇ l solution provided 27.7pmoles of fenofibrate ester
  • each injection of the lOOOng/lOO ⁇ l solution provided 2.77 nmoles of fenofibrate ester.
  • VAS visual analogue scale
  • the best scars (typically of small width, with colour, height and contour like normal skin) were scored towards the normal skin end of the scale (the left hand side of the VAS line) and bad scars (typically large width, raised with uneven contours and whiter colour) were scored towards the bad scar end of the scale (the right hand side of the VAS line).
  • the marks were measured from the left hand side to provide the final value for the scar assessment in centimetres (to 1 decimal place).
  • the scars were excised from the experimental rats (incorporating a small amount of surrounding normal tissue) and fixed in 10% (v/v) buffered formal saline. The fixed tissue was then processed for wax histology. Histological slides were stained using Masson's trichrome, and scarring assessed by a trained assessor using a microscopic visual analogue scale (VAS). This consisted of a 0- 10cm line representing a scale, from left to right, of 0 (corresponding to normal skin) to 10 (indicative of a bad scar). A mark was made on the 10cm line based on an overall assessment of the scar taking into account parameters such as collagen fibre spacing, orientation and thickness.
  • VAS microscopic visual analogue scale
  • the best scars typically narrow scars with thick and randomly organised collagen fibres that have normal spacing between fibres, similar to the surrounding normal dermis
  • bad scars typically wide scars with thin densely packed parallel collagen fibres
  • the marks were measured from the left hand side to provide the final value for the scar assessment in centimetres (to 1 decimal place).
  • FIG. 3 shows representative macroscopic images of a treated scar and na ⁇ ve control scar.
  • the scar resulting from a wound treated with a therapeutically effective amount an antagonist of LXR activity is considerably more difficult to detect than the scar produced on healing of a na ⁇ ve control wound.
  • results show that a therapeutically effective amount of an antagonist of LXR activity (such as fenofibrate ester) is capable of inhibiting scarring. These results also provide guidance as to how therapeutically effective and non-therapeutically effective amounts of such an antagonist may be determined.
  • an antagonist of LXR activity such as fenofibrate ester

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Abstract

La présente invention concerne un antagoniste de l'activité LXR utilisable en tant que médicament pour la prévention, la réduction ou l'inhibition de la formation de cicatrices. L'invention concerne également des procédés de traitement correspondants. Il est préférable que les cicatrices dont la formation est à inhiber soient des cicatrices associées à la guérison des blessures. Les antagonistes préférés de l'activité LXR incluent des esters fibrates (tels que l'ester fénofibrate ; l'ester bézafibrate ; l'ester gemfibrozil ; l'ester clofibrate) ; le géranyl-géranyl pyrophosphate, la riccardine F, un sulfate de cholestérol auto-oxydé, le Wy-14643, le 7-cétocholestérol-3-sulfate et le 5a,6a-époxycholestérol-3-sulfate. Selon des modes de réalisation avantageux, d'environ 13 pmoles à environ 2 nmoles de l'antagoniste de l'activité LXR peuvent être appliqués par cm linéaire de blessure ou par cm2 d'une blessure ou d'une fibrose, sur une période de 24 heures dans le but d'inhiber la formation de cicatrices.
PCT/GB2007/004958 2006-12-23 2007-12-21 Antagonistes du lxr pour la prévention, la réduction ou l'inhibition de la formation de cicatrices WO2008078099A1 (fr)

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US10844089B2 (en) 2004-10-25 2020-11-24 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US9321802B2 (en) 2004-10-25 2016-04-26 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US11384115B2 (en) 2004-10-25 2022-07-12 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US10144759B2 (en) 2004-10-25 2018-12-04 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US9581723B2 (en) 2008-04-10 2017-02-28 Schlumberger Technology Corporation Method for characterizing a geological formation traversed by a borehole
US8725477B2 (en) 2008-04-10 2014-05-13 Schlumberger Technology Corporation Method to generate numerical pseudocores using borehole images, digital rock samples, and multi-point statistics
US8311788B2 (en) 2009-07-01 2012-11-13 Schlumberger Technology Corporation Method to quantify discrete pore shapes, volumes, and surface areas using confocal profilometry
US9480692B2 (en) 2011-04-06 2016-11-01 Virginia Commonwealth University Sulfated-oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
US9034859B2 (en) 2011-04-06 2015-05-19 Virginia Commonwealth University Sulfated oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
US9428753B2 (en) 2013-03-15 2016-08-30 The Governing Council Of The University Of Toronto Use of LXR antagonists for treatment of side effects of elevated glucocorticoid levels
EP2988753A4 (fr) * 2013-04-25 2016-12-07 Univ Iowa Res Found Procédés pour moduler l'apport de rac1 et pour traiter la fibrose pulmonaire
EP2992910A4 (fr) * 2013-05-01 2016-12-07 Farnex Incorporated Matériau de prévention d'adhérence
CN105358190A (zh) * 2013-05-01 2016-02-24 法纳克斯株式会社 防粘剂
US10786517B2 (en) 2013-12-24 2020-09-29 Durect Corporation Uses of oxygenated cholesterol sulfates (OCS)
US11612609B2 (en) 2013-12-24 2023-03-28 Durect Corporation Uses of oxygenated cholesterol sulfates (OCS)
US11406646B2 (en) 2016-08-02 2022-08-09 Virginia Commonwealth University Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide

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