EP1311252A2 - Wundbehandlung - Google Patents

Wundbehandlung

Info

Publication number
EP1311252A2
EP1311252A2 EP01954296A EP01954296A EP1311252A2 EP 1311252 A2 EP1311252 A2 EP 1311252A2 EP 01954296 A EP01954296 A EP 01954296A EP 01954296 A EP01954296 A EP 01954296A EP 1311252 A2 EP1311252 A2 EP 1311252A2
Authority
EP
European Patent Office
Prior art keywords
inhibitor
mmp
chronic
wounds
inhibitors
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01954296A
Other languages
English (en)
French (fr)
Inventor
Michael John Davies
Jonathan Paul Huggins
Dinah Velta Parums
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Pfizer Inc
Original Assignee
Pfizer Ltd
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP1311252A2 publication Critical patent/EP1311252A2/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • This invention relates to the use of cyclic guanosine 3', 5'-monophosphate type five (cGMP PDE5) inhibitors (hereinafter PDE5 inhibitors), including in particular the compound sildenafil, for the treatment of chronic wounds of a non-diabetic origin including in particular chronic venous ulcers, chronic decubitus (pressure sores) and arterial ulcers; and acute wounds.
  • PDE5 inhibitors cyclic guanosine 3', 5'-monophosphate type five
  • PDE5 inhibitors including in particular the compound sildenafil
  • Chronic wounds by definition, take a long time to heal. Part of the process of repair requires a good blood supply and a pro-healing environment that allow the healing process to occur. Typical phases in the healing of a wound include haemostasis, inflammation, repair and regeneration and finally re-modeling. In a chronic wound, one or more of these mechanisms is impaired.
  • the method of treating a wound depends on its type.
  • Chronic venous ulcers also known as venous leg ulcers or venous stasis ulcers, common in patients with venous insufficiency, are characterised by increased healing time and resistance to treatment. They are treated by simply applying the appropriate dressing and applying a compressive bandage.
  • Chronic arterial ulcers are caused typically by plaque in the arteries which lead to blockage and impaired blood supply. They heal slowly because of poor oxygen supply and nutrition. Treatment requires support and re-vascularistion if possible.
  • Chronic decubitus ulcers or pressure sores are caused by exerting pressure on an area of the body for extended periods, typically longer than 3 hours. Decubitus ulcers are treated by dressing the wound and removing the pressure. If the sore is small enough then the sores can be closed surgically.
  • Acute wounds e.g. cuts and grazes to the skin
  • the rate of healing is rapid.
  • the elderly or immunocompromised healing can be prolonged.
  • Healing will also be prolonged if the wound becomes infected.
  • cGMP PDE5 inhibitors increase intracellular concentrations of nitric oxide derived cGMP, thereby enhancing the effect of nitric oxide, which is responsible for the efficacy of sildenafil in the treatment of male erectile dysfunction.
  • cGMP PDE5 we have found elevated levels of the enzyme cGMP PDE5 in wounded tissue.
  • tissue is inflamed or scarred.
  • Myofibroblasts in healing wounds i.e skin and areas of organising infarction in, for example, cardiac tissue from patients with ischaemic heart disease express PDE 5 whereas fibroblasts populating those areas in non-pathological conditions demonstrate no PDE 5 expression.
  • Myofibroblasts from granulation tissue in normally healing wounds temporarily express a smooth muscle phenotype whereas myofibroblasts with a smooth muscle phenotype persist in abnormally healing wounds and fibro- proliferative conditions.
  • cGMP inhibits smooth muscle cell proliferation and thus potentiation of cGMP levels potentially leads to improved wound healing.
  • the wound healing effect is due to improved blood supply to the wound region.
  • PDE 5 inhibition at an appropriate stage in the wound-healing cycle in conjunction with an appropriate signal such as NO-mediated smooth muscle relaxation results in vasodilation leading to wound healing.
  • Other factors may also be involved.
  • the invention provides a method of treating wounds in a patient which comprises treating the patient with an effective amount of a cGMP PDE5 inhibitor, or a pharmaceutical composition thereof, wherein the wound type is selected from: chronic venous ulcers, chronic arterial ulcers, chronic decubitus and acute wounds.
  • the invention provides the use of a cGMP PDE5 inhibitor for the manufacture of a medicament for the treatment of wounds, selected from the following types: chronic venous ulcers, chronic arterial ulcers, chronic decubitus and acute wounds.
  • PDE5 inhibitors it is meant a compound which is a potent and selective inhibitor of the cGMP PDE5 isoenzyme.
  • Suitable PDE5 inhibitors for use in the pharmaceutical combinatiions according to the present invention are the cGMP PDE5 inhibitors hereinafter detailed. Particularly preferred for use herein are potent and selective cGMP PDE5 inhibitors.
  • Suitable cGMP PDE5 inhibitors for the use according to the present invention include:
  • Preferred type V phosphodiesterase inhibitors for the use according to the present invention include:
  • Still other type cGMP PDE5 inhibitors useful in conjunction with the present invention include:4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]- 3(2H)pyridazinone; 1 -[4-[(1 ,3-benzodioxol-5- ylmethyl)amiono]-6-chloro-2- quinozolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a- hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent- 4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-
  • a pharmaceutical pack comprising: a pharmaceutical composition comprising a PDE5 inhibitor, directions relating to the use of the composition for treating wounds, and a container.
  • a pharmaceutical composition comprising a PDE5 inhibitor
  • directions relating to the use of the composition for treating wounds and a container.
  • cGMP PDE5 inhibitor The suitability of any particular cGMP PDE5 inhibitor can be readily determined by evaluation of its potency and selectivity using literature methods followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc in accordance with standard pharmaceutical practice.
  • the cGMP PDE5 inhibitors have an IC50 for PDE5 at less than 100 nanomolar, more preferably, at less than 50 nanomolar, more preferably still at less than 10 nanomolar.
  • IC50 values for the cGMP PDE5 inhibitors may be determined using established literature methodology, for example as described in EP0463756-B1 and EP0526004-A1.
  • the cGMP PDE5 inhibitors used in the invention are selective for the PDE5 enzyme. Preferably they are selective over PDE3, more preferably over PDE3 and PDE4. Preferably, the cGMP PDE5 inhibitors of the invention have a selectivity ratio greater than 100 more preferably greater than 300, over PDE3 and more preferably over PDE3 and PDE4.
  • IC50 values for the PDE3 and PDE4 enzyme may be determined using established literature methodology, see S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171.
  • the compounds of the invention are preferably orally bioavailable.
  • Oral bioavailablity refers to the proportion of an orally administered drug that reaches the systemic circulation.
  • the factors that determine oral bioavailability of a drug are dissolution, membrane permeability and metabolic stability.
  • a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavailablity.
  • the solubilisation of the drug by the aqueous contents of the gastrointestinal tract can be predicted from in vitro solubility experiments conducted at appropriate pH to mimic the GIT.
  • the compounds of the invention have a minimum solubility of 50 mcg/ml. Solubility can be determined by standard procedures known in the art such as described in Adv. Drug Deliv. Rev. 23, 3-25, 1997.
  • Membrane permeability refers to the passage of the compound through the cells of the GIT. Lipophilicity is a key property in predicting this and is defined by in vitro Log D 74 measurements using organic solvents and buffer. Preferably the compounds of the invention have a Log D 74 of -2 to +4, more preferably -1 to +2. The log D can be determined by standard procedures known in the art such as described in J. Pharm. Pharmacol. 1990, 42:144.
  • caco-2 Cell monolayer assays such as caco-2 add substantially to prediction of favourable membrane permeability in the presence of efflux transporters such as p-glycoprotein, so-called caco-2 flux.
  • compounds of the invention have a caco-2 flux of greater than 2x10 "6 cms "1 , more preferably greater than 5x10 "6 cms "1 .
  • the caco flux value can be determined by standard procedures known in the art such as described in J. Pharm. Sci, 1990, 79, 595-600
  • Metabolic stability addresses the ability of the GIT or the liver to metabolise compounds during the absorption process: the first pass effect.
  • Assay systems such as microsomes, hepatocytes etc are predictive of metabolic liability.
  • the compounds of the Examples show metabolic stability in the assay system that is commensurate with an hepatic extraction of less then 0.5.
  • the cGMP PDE5 inhibitor is Sildenafil.
  • cGMP PDE5 inhibitors can be administered alone but, in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the cGMP PDE5 inhibitors can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, or controlled-release applications.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropylcellulose, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate,
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the cGMP PDE5 inhibitors of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the cGMP PDE5 inhibitors can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70 kg.
  • the skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.
  • the dosage of cGMP PDE5 inhibitor in such formulations will depend on its potency, but can be expected to be in the range of from 1 to 500 mg for administration up to three times a day.
  • the daily dosage level of the cGMP PDE5 inhibitor will usually be from 5 to 500 mg (in single or divided doses).
  • a preferred dose is in the range 10 to 100 mg (e.g. 10, 25, 50 and 100 mg) which can be administered once, twice or three times a day (preferably once).
  • the precise dose will be as determined by the prescribing physician and will depend on the age and weight of the patient and severity of the symptoms.
  • tablets or capsules of the cGMP PDE5 inhibitor may contain from 5 to 250 mg (e.g. 10 to 100 mg) of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the cGMP PDE5 inhibitors can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane or 1
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the cGMP PDE5 inhibitor, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the cGMP PDE5 inhibitor and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains from 1 to 50 mg of the cGMP PDE5 inhibitor, for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the cGMP PDE5 inhibitors can be administered in the form of a suppository or pessary.
  • the cGMP PDE5 inhibitor may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the cGMP PDE5 inhibitors may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • topical administration is a preferred route of administration.
  • the cGMP PDE5 inhibitors can be formulated as a suitable ointment containing the inhibitor suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the cGMP PDE5 inhibitors may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug- cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A- 98/55148.
  • oral administration of the cGMP PDE5 inhibitors is the preferred route, being the most convenient.
  • the drug may be administered parenterally, sublingually or buccally.
  • cGMP PDE5 inhibitors of the invention can also be administered in combination with one or more of the following:
  • ⁇ -Adrenergic receptor antagonist compounds also known as ⁇ - adrenoceptors or ⁇ -receptors or ⁇ -blockers.
  • Suitable compounds for use herein include: the ⁇ -adrenergic receptors as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to ⁇ -adrenergic receptors are incorporated herein by reference and include, selective ⁇ r adrenoceptors or ⁇ 2 -adrenoceptors and non- selective adrenoceptors, suitable o ⁇ -adrenoceptors include: phe ⁇ tolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolf
  • ⁇ 2 - Adrenoceptors include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine;
  • NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl brinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy - L- arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S- nitroso - N-cysteine, diazenium diolates
  • vasodilator agents Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone, pentoxifylline;
  • Calcium channel blockers such as amlodipine
  • MMP Matrix metalloprotease inhibitors
  • Urokinase type plasminogen activator inhibitors uPA
  • MMP inhibitors particularly inhibitors of MMP-3, MMP-12 and MMP-13
  • uPA inhibitors particularly inhibitors of MMP-3, MMP-12 and MMP-13
  • vasodilator agents particularly pentoxyfyline
  • MMP inhibitors are those specifically and generically disclosed in WO99/35124, EP 931788, WO99/29667 or WO00/74681.
  • MMP inhibitors are those of the Examples of W099/35124, EP 931788, WO99/29667 and WO00/74681.
  • the uPA inhibitor is selected from those specicially and generically disclosed in WO99/20608, EP 1044967 or WO00/05214.
  • Especially preferred uPA inhibitors are those of the Examples of WO99/20608, EP 1044967 and WO00/05214.
  • Figure 1 is a photomicrograph of a paraffin section of skin at 10 x magnification
  • Figure 2 is a photomicrograph of a paraffin section of skin at 20 x magnification
  • Figure 3 is a photomicrograph of a paraffin section of skin at 20 x magnification
  • Figure 4 is a photomicrograph of a paraffin section of skin at 40 x magnification
  • Figure 5 is a photomicrograph of a paraffin section of skin at 60 x magnification.
  • Figure 6 is a photomicrograph of a paraffin section of skin at 60 x magnification.
  • Anti-human polyclonal antiserum was raised in rabbits and affinity purified against the LIP-1 [MERAGPSFGQQR] peptide n accordance with the method of Fawcett et al (Proc Natl Acod Sci USA 2000; 97:3702-3707), corresponding to amino acid residues 1-12 of human PDE5A1.
  • LIP-1 is specific for PDE5 A1.
  • Figure 1 illustrates a section of reactive but non-inflamed skin at the edge of a skin wound.
  • the positive staining of the smooth muscle cells within the media of the venules and negative fibroblasts indicates the expression of PDE5 in the healing wound.
  • Hyperplastic but intact squamous epithelium 1 is negative.
  • the underlying dermis contains mature scar tissue with small and large venules 2.
  • Figure 2 is a paraffin section taken from the border between a healing ulcer of 14 days (left) and intact epithelium (right). Again, the positive staining of the smooth muscle cells within the media of the venules (right) and the spindle cells (myofibroblasts) within the base of the ulcer (left) indicates PDE5 expression. Hyperplastic but intact squamous epithelium (right) and necrotic inflammatory exudate 3 is negative. Note the positive dark staining of the smooth muscle cells within the media of the venules 4 and of spindle cells within the base of the ulcer 5 (original mag. x20).
  • Figure 3 is a paraffin section taken from the healed ulcer base where fascicles of young scar tissue have replaced normal dermal structures. Positive staining of some of the spindle cells (myofibroblasts) (8) and of some vascular structures is again indicative of PDE 5 expression. (Original mag x20).
  • Figure 4 is a higher power view of the paraffin section of skin of Figure 3. The section is taken from the healed ulcer base where fascicles of young scar tissue have replaced normal dermal structures. PDE 5 expression is illustrated by the positive staining of some of the spindle cells (myofibroblasts) (9) and of some of the microvessels which have thin media (10). (Original mag x40).
  • Figure 5 is a higher powered view of Figure 4 and shows a section taken from the healed ulcer base of Figure 4 where fascicles of young scar tissue have replaced normal dermal structures.
  • spindle cells myofibroblasts
  • the immunolocalisation in the cytoplasm of some of these spindle cells has a patchy distribution.
  • Positive staining of the medial smooth muscle cells within a small arteriole (12) indicates PDE 5 expression.
  • Figure 6 is also a higher powered view of Figure 4 showing a section from the healed ulcer base in an area of relatively young scar tissue. Again, positive staining of some of the spindle cells (myofibroblasts) (14) and medial smooth muscle cells within the small arteriole (centre) (15) is indicative of PDE 5. In some of these spindle cells the immunolocalisation has a patchy distribution. (Original mag. x60).
  • Active ingredient means a cGMP PDE5 inhibitor.
  • a tablet is prepared using the following ingredients : Sildenafil citrate (50 mg) is blended with cellulose (microcrystalline), silicon dioxide, stearic acid (fumed) and the mixture is compressed to form tablets.
  • An intravenous formulation may be prepared by combining the active ingredient

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP01954296A 2000-08-21 2001-08-16 Wundbehandlung Withdrawn EP1311252A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0020588 2000-08-21
GBGB0020588.0A GB0020588D0 (en) 2000-08-21 2000-08-21 Treatment of wounds
PCT/IB2001/001470 WO2002015893A2 (en) 2000-08-21 2001-08-16 Treatment of wounds

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Publication Number Publication Date
EP1311252A2 true EP1311252A2 (de) 2003-05-21

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EP (1) EP1311252A2 (de)
JP (1) JP2004519425A (de)
KR (1) KR20030097778A (de)
AU (1) AU2001276636A1 (de)
CA (1) CA2415791A1 (de)
GB (1) GB0020588D0 (de)
HU (1) HUP0303029A3 (de)
IL (1) IL154011A0 (de)
WO (1) WO2002015893A2 (de)
ZA (1) ZA200301156B (de)

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KR20030097778A (ko) 2003-12-31
WO2002015893A2 (en) 2002-02-28
AU2001276636A1 (en) 2002-03-04
ZA200301156B (en) 2004-04-16
HUP0303029A2 (hu) 2003-12-29
CA2415791A1 (en) 2002-02-28
IL154011A0 (en) 2003-07-31
WO2002015893A3 (en) 2003-03-13
HUP0303029A3 (en) 2004-11-29
JP2004519425A (ja) 2004-07-02
GB0020588D0 (en) 2000-10-11

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