[0001] This application is associated with and claims priority from US Provisional Patent Application No. 62/455,821, filed on 7 February 2017, entitled "A method of treatment", the entire contents of which, are incorporated herein by reference, in their entirety.

FIELD

[0002] The present invention relates to a method of treating a fibrotic disease characterized by excessive collagen formation. The present invention is further directed to formulations and protocols for the treatment of fibrotic conditions.

BACKGROUND

[0003] Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.

[0004] Reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.

[0005] Fibrosis results from connective tissue thickening. This may occur following any of a number of conditions but injury is one common cause which leads to the process of wound healing. The latter is a complex physiological process with intertwining phases of inflammation, proliferation and remodelling (Guo et al. (2010) Journal Dent Res 89:219- 229; Shih et al. (2010) Wound Repair Regeneration 18: 139- 153). In certain situations, during the process of wound healing, aberrant conditions arise such as inflammation, cell migration and proliferation, neovascularization, angiogenesis, granulation tissue formulation and collagen deposition (Mustoe et al. (2004) Amer Journal of Surgery 87:655-705; Usui et al. (2008) Journal ofHistochem Cytochem 5(5:687-696).

[0006] One potential consequence of wound fibrosis is the development of keloids. Keloids are a benign form of tumor caused by fibrosis during and after wound healing. A keloid or keloidal scar (Rapini et al. (2007) Dermatology: 2 volume set, St. Louis, Mosby at pl499) can form at the site of a healed wound and is a result of overgrowth of granulation tissue, containing generally type III (early) collagen. Over time, the collagen is replaced by type I (late) collagen. Whilst a keloid scar is benign it can result in discomfort to the affected subject. Keloids are fibrotic tumors characterized by an over population of fibroblasts which deposit an excessive amount of components of the extracellular matrix (ECM) such as collagen, fibronectin, elastin and prostaglandins. Treatment of keloids is complex and difficult and can be age dependent, causation dependent and ranges from preventative to interventionist procedures including surgery and radiotherapy (Amo et al. (2014) BUMS 40(7): 1255-1266; Gauglitz et al. (2011) Molecular Medicine 17(1 -2 ): 113-125; Andrews et al. (2016) Matrix Biology 5 :37- -46).

[0007] Another form of fibrotic disease is fibromatosis. Dupuytren's disease (also known as Dupuytren's contracture, morbus Dupuytren or palmar fascial fibromatosis) is a fascial fibromatosis characterized by the formation of nodules in the palmar and digital fascia. The nodules eventually grow into cords of contracted tissue which gradually pull one or more of the sufferer's fingers towards their palm resulting in that finger adopting a permanently flexed position.

[0008] The underlying cause of Dupuytren's disease is not well understood. It is believed that the disease develops in three stages whereby, in the first stage, a proliferation of myofibroblast cells is observed. In the second stage, the myofibroblasts align along lines of tension in the fascia leading to the third stage wherein the affected tissue becomes mostly acellular and only thick bands of collagen remain. Studies have shown that these bands show a high ratio of type III to type I collagen which is in contrast to the predominantly type I collagen found in normal palmar fascia. [0009] Dupuytren's disease is a relatively common condition with its prevalence varying in different populations. Over 30 percent of Northern European males may be affected at 50 years old and 40 percent for those 80 years and older. It has a negative effect on a patient's quality of life, since, once contracture reaches an advanced stage, they find themselves unable to perform simple tasks requiring fine control of the fingers.

[0010] The traditional treatment for Dupuytren's disease, in so far as it returns hand function, has, until recently, been largely surgical. A number of incisions made on the skin of the palm and affected fingers and the thickened cords are excised. A fasciectomy is sometimes performed, to varying extents, to remove some of the diseased fascia. The surgery is followed by an extensive period of rehabilitation of the hand involving initial splinting and then a program of physiotherapy.

[0011] There are a number of concerns regarding this type of surgical procedure including the risk of nerve or artery damage as well as postoperative infection. Major complications have been estimated to occur in up to 16% of cases and a typical initial recovery time is 4 to 6 weeks.

[0012] Another fibromatotic disease is Peyronie's disease (penile fascial fibromatosis) and Ledderhose disease (plantar fascial fibromatosis) which are considered to be related diseases to Dupuytren's disease due to the similar underlying collagen and connective tissue problems. Peyronie's disease is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis which may result in an abnormal curvature. It has been reported that approximately 30% of men who suffer from Peyronie's disease will also develop fibrosis in other parts of the body such as the hand (Dupuytren's disease) or the foot (Ledderhose disease). Ledderhose disease is a non-malignant thickening of the feet's deep connective tissue. In the initial stages of the disease nodules or cords start growing along tendons of the foot (in the same manner as occurs in Dupuytren's disease) which may become tender. Eventually the cords thicken, the toes stiffen and bend and walking becomes extremely painful. It has been found that the histological and ultrastructural features of Ledderhose and Dupuytren's disease are the same and so it is believed they have a common etiology and pathogenesis. Treatments for Ledderhose disease are limited as surgery can worsen the condition with further plantar fascia thickening and formation of nodules causing further discomfort for the patient and postoperative rehabilitation is relatively long and painful.

[0013] Australian Patent No. 2012255624 provided an effective non-surgical approach to the treatment of fascial fibromatosis. There is a need, however, to extend this development to less invasive procedures to treat fibrotic conditions in general including keloids.

SUMMARY

[0014] The present invention enables a non- surgical approach to the treatment of fibrotic conditions associated with excessive collagen formation in a subject such as a human. Fibrotic conditions contemplated herein requiring treatment include a fascial fibromatosis and a scar such as a keloid scar. The treatment comprises the administration of an activator of a collagenase production pathway such as a plasminogen activator. Examples include tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, Factor XII or a functional analog thereof. In an embodiment, the activator is tPA or uPA. When the condition to be treated is a fascial fibromatosis, then the activator of the collagenase production pathway is administered in combination with a steroid, such as a corticosteroid. More particularly, the corticosteroid is a triamcinolone or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. Examples of triamcinolone derivatives include an acetonide, benetonide, furetonide, hexacetonide and a diacetate of triamcinolone or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. The administration may further include an antimetabolite such as a pyrimidine antagonist, a folic acid antagonist, a purine antagonist or a deaminase inhibitor. In an embodiment, the antimetabolite is selected from the group consisting of 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. In an embodiment, the antimetabolite is 5-fluorouracil or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0015] Hence, the present invention contemplates a medical protocol for the management of a fibrotic disease associated with excessive collagen production, the protocol comprising the steps of:

(i) determining the nature of the fibrotic disease; (ii) if the fibrotic disease is a keloid scar, administering at or near the site of the keloid scar a medicament selected from the group consisting of:

(a) an activator of a collagenase pathway;

(b) an activator of a collagenase pathway and a steroid; and

(c) an activator of a collagenase pathway, a steroid and an antimetabolite;

with the proviso that:

(iii) if the fibrotic disease is a fascial fibromatosis, administering an activator of a collagenase pathway and a steroid and optionally with an antimetabolite.

[0016] The "medicament" includes a combination of separate formulations for administration via different routes or the same route or a single formulation comprising all the active agents combined. In an embodiment, the activator is tPA, uPA, kallikrein, Factor XII or a functional or synthetic analog thereof. In an embodiment, the activator is tPA or uPA including recombinant forms thereof. In an embodiment, the steroid is a corticoidsteroid such as a triamcinolone or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. In an embodiment, the antimetabolite is 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0017] The present invention contemplates a method for treating a fibrotic condition associated with excessive collagen formation in a subject, said method comprising the administration of an activator of a collagenase production pathway wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a steroid. Further taught herein is an activator of a collagenase production pathway for use in the treatment of a fibrotic condition associated with excessive collagen in a subject herein if the fibrotic condition is fascial fibromatosis, then the activator is used in combination with a steroid. The present invention extends to the use of an activator of a collagenase production pathway and optionally a steroid and further optionally an activator and a steroid with an antimetabolite in the manufacture of separate or combined medicaments in the treatment of a fibrotic disease associated with excessive collagen production. The use is with the proviso that if the fibrotic disease is a fascial fibromatosis, then the activator of the collagenase production pathway is used in combination with the steroid and optionally the antimetabolite.

[0018] Formulations comprising combined or separate medicaments of an activator of collagen production, optionally with a steroid and further optionally with an antimetabolite are also taught herein. For example, in an embodiment, the activator of a collagenase pathway and the antimetabolite may be injected whereas the steroid may be taken orally. Hence, a "medicament" includes a pharmaceutical kit comprising separate formulations for each active agent wherein the nature of the formulations depends on the route of administration.

BRIEF DESCRIPTION OF THE FIGURES

[0019] Figure 1 is a diagrammatic representation of a collagenase production pathway.

[0020] Figure 2A is a diagrammatic representation of both hands of a patient suffering from Dupuytren's disease prior to treatment; Figure 2B is a diagrammatic representation of both hands of the same patient shown in Figure 2A after treatment with tPA and triamcinolone.

[0021] Figure 3A is a diagrammatic representation of the left hand of a patient suffering from Dupuytren's disease prior to treatment; Figure 3B is a diagrammatic representation of the left hand of the same patient shown in Figure 3A after treatment with tPA and triamcinolone.

[0022] Figure 4A is a diagrammatic representation of the right hand of a patient suffering from Dupuytren's disease prior to treatment; Figure 4B is a diagrammatic representation of the right hand of the same patient shown in Figure 4A after treatment with tPA, triamcinolone and 5-fluorouracil.

[0023] Figure 5A is a diagrammatic representation of both hands of a patient suffering from Dupuytren's disease prior to treatment; Figure 5B is a diagrammatic representation of both hands of the same patient shown in Figure 5A after treatment with tPA, triamcinolone and 5-fluorouracil.

[0024] Figure 6 is a photographic representation showing non-surgical treatment of keloid scarring.

[0025] Figure 7 is a photographic representation showing response on non-surgical treatment of keloid scarring. DETAILED DESCRIPTION

[0026] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or method step or group of elements or integers or method steps but not the exclusion of any other element or integer or method steps or group of elements or integers or method steps.

[0027] As used in the subject specification, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a fibrotic disease" includes a single fibrotic disease, as well as two or more fibrotic diseases; reference to "an agent" includes a single agent, as well as two or more agents; reference to "the disclosure" includes single and multiple aspects taught by the disclosure; and so forth. Aspects taught and enabled herein are encompassed by the term "invention". Any variants and derivatives contemplated herein are encompassed by "forms" of the invention. All aspects of the invention are enabled across the width of the claims.

[0028] As used herein, "subject" or "individual" or "patient" refers to any subject for whom or which therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the present invention. The subject is a mammal. In an embodiment, the mammal is a human. In another embodiment, the mammal is a domestic livestock animal (e.g. a sheep, cow, pig, goat, alpaca, Llama, camel or an equine animal such as a horse) , a laboratory test animal (e.g. rat, mouse, guinea pig, hamster or rabbit) or a companion animal (e.g. dog or cat). In a particular embodiment, the subject is a human of any age or gender.

[0029] As used herein, unless the context demands otherwise, the terms "treat," "treating," or "treatment" means to counteract a medical condition (e.g., palmar and/or plantar and/or penile fascial fibromatosis or ameliorate keloids) to the extent that the medical condition is improved, at least temporarily, according to clinically acceptable standard(s). For example, "treating palmar and/or plantar fascial fibromatosis" means to improve the fibromatosis or relieve symptoms of the particular fibromatosis in a patient, such as improving the range of motion of the affected finger(s), wherein the improvement and relief are evaluated with a clinically acceptable standardized test (e.g., a patient self-assessment scale involving improvement in the range of motion of affected digits) and/or an empirical test and wherein the improvement may be permanent or temporary. In another example, the amelioration of keloid scarring means to reduce the level of keloid formulation to acceptable aesthetic and/or comfortability standards. "Treat," "treating," or "treatment" as used herein may also include prophylactic treatment unless the context requires otherwise.

[0030] As used herein, the term "activator" in the context of a collagenase production pathway, means any agent which results in an increase in levels of a desired end product due to activation of one or more elements of a natural pathway or cascade. For example, an "activator of the collagenase production pathway" or "activator" may be any agent which results in an increased production of endogenous collagenase. Examples include a tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), kallikrein and Factor XII or a functional analog thereof. Such functional analogs include recombinant and synthetic forms. In an embodiment, the activator is a plasminogen activator selected from the group consisting of tPA and uPA or their recombinant or synthetic forms.

[0031] Hence, it will be appreciated that the "activator" may be in the form of a pharmacologically active and pharmaceutically effective or acceptable salt and the activator may be one which has been isolated from a tissue or generated synthetically or by use of recombinant DNA techniques.

[0032] The term "fibromatosis" refers to a condition characterized by the proliferation of generally mature fibroblasts associated with mature collagen and the formation of fibrous nodules and/or cords arising from the fascia. The term is particularly used herein in relation to fibromatosis of the fascia of the palmar (Dupuytren's disease), plantar (Ledderhose disease) and penile (Peyronie's disease) tissue.

[0033] The terms palmar, plantar and penile fascial fibromatosis are used interchangeably with the terms Dupuytren's disease, Ledderhose disease and Peyronie's disease, respectively.

[0034] Other fibrotic diseases contemplated herein include a keloid or keloid scar or aftermath following injury or surgical trauma or wound, microbial or viral infection, an insect bite, pimples or other skin lesions. Reference to a "skin lesion" includes an ulcer, psoriasis, limited or diffuse scleroderma, eczema, a scratch mark, stretch marks (striae), a burn, sunburn, a site of body piercing or the effects of skin cancer such as a melanoma.

[0035] The terms "keloids", a "keloid", a "keloid scar" or "keloid scarring" are all used interchangeably to refer to a benign form of tumor caused by fibrosis during and after wound healing. A keloid forms at the site of a healed wound and is a result of overgrowth of granulation tissue generally containing type III collagen. Hence, this aspect of the present invention relates to the treatment of post-healed wounds.

[0036] Accordingly, taught herein is a therapeutic method or protocol for treating a fibrotic disease associated with excessive collagen production. The treatment protocol is selected from the group consisting of:

(i) the administration of an activator of a collagenase production pathway;

(ii) the administration of an activator of a collagenase production pathway and a steroid; and

(iii) the administration of an activator of a collagenase production pathway and a steroid and an antimetabolite.

[0037] There is a proviso that if the fibrotic condition is a fascial fibromatosis, then the activator is administered with the steroid or an activator, steroid and the antimetabolite are administered.

[0038] Hence, the present invention provides a medical protocol to treat or manage a fibrotic disease associated with excessive collagen production. The protocol initiates with a determination of whether the fibrotic disease is a fascial fibromatosis. This is referred to herein as determining the nature of the nature of the fibrotic disease. If it is a fascial fibromatosis then the protocol comprises one or more of the administration of an activator of a collagenase pathway and a steroid and/or the administration of the activator, steroid and an antimetabolite. If the fibrotic disease is not a fascial fibromatosis, then the protocol comprises one or more of:

(i) an activator of a collagenase pathway;

(ii) an activator of a collagenase pathway and a steroid; and

(iii) an activator of a collagenase pathway and a steroid and an antimetabolite.

[0039] Hence, enabled herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a steroid.

[0040] In an embodiment, taught herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a corticosteroid.

[0041] The present specification is further instructional of a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a triamcinolone.

[0042] In an embodiment, taught herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a corticosteroid and an antimetabolite. [0043] Further enabled herein is an activator of a collagenase production pathway for use in the treatment of a fibrotic condition associated with excessive collagen in a subject wherein if the fibrotic conditions is fascial fibromatosis, then the activator is used in combination with a steroid.

[0044] As indicated above, examples include a tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), kallikrein and Factor XII or a functional analog thereof. Such functional analogs include recombinant and synthetic forms. In an embodiment, the activator is a plasminogen activator selected from the group consisting of tPA and uPA.

[0045] A steroid includes a corticosteroid and in particular a triamcinolone or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. Examples of triamcinolones include triamcinolone, acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate. In an embodiment, the corticosteroid is triamcinolone or triamcinolone acetonide or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0046] An antimetabolite includes a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase inhibitor. Examples include 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptropurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof. In an embodiment, the antimetabolite is 5-fluorouracil.

[0047] Hence, taught herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein the activator is selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a corticosteroid.

[0048] Enabled herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein the activator is selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0049] The present specification is instruction for a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein the activator is selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a triamcinolone selected from the group triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and an antimetabolite selected from the group consisting of a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist.

[0050] Enabled herein is a method for treating a fibrotic condition associated with excessive collagen formation in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein the activator is selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof wherein if the fibrotic condition is a fascial fibromatosis, the activator is given in combination with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and an antimetabolite selected from the group consisting of a 5- fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptopurine, 6- thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof

[0051] Enabled herein is the treatment of fascial fibromatosis.

[0052] Accordingly, taught herein is a method for treating a fascial fibromatosis in a subject, the method comprising the administration of an activator of a collagenase production pathway in combination with a steroid.

[0053] Enabled herein is a method for treating a fascial fibromatosis in a subject, the method comprising the administration of an activator of a collagenase production pathway wherein the activator is a plasminogen activator selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof in combination with a corticosteroid.

[0054] The present specification is instructional on a method for treating a fascial fibromatosis in a subject, the method comprising the administration of an activator of a collagenase production pathway selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof with a corticosteroid and an antimetabolite selected from the group consisting of a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist. [0055] In an embodiment, taught herein is a method for treating a fascial fibromatosis in a subject, the method comprising the administration of an activator of a collagenase production pathway selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and optionally an antimetabolite selected from the group consisting of 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6- mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0056] Also enabled herein is the treatment of an inflammatory condition of the skin or its layers including the epidermal, dermal and hypodermal layers such leading to keloidal scarring. This may arise from trauma or surgery or other wound, microbial or viral infection, an insect bite, pimples or other skin lesions including ulcers, psoriasis, limited or diffuse scleroderma, eczema, scratching, stretch marks, burns, sunburn and body piercing as well as a skin cancer such as a melanoma.

[0057] The keloids may occur at any site of trauma or injury and includes at or near the central chest region, back, shoulders, neck, head including face, and nose, earlobes, arms (upper arms and lower arms including elbows, wrists, hands, fingers and thumbs), legs (upper and lower leg including knees, feet, ankles, toes and thighs), pelvic region and collar bone region.

[0058] Accordingly, taught there is a method for treating a fibrotic condition associated with a scar in a subject, the method comprising the administration of an activator of a collagenase production pathway.

[0059] Enabled herein is a method for treating a fibrotic condition associated with a scar in a subject, the method comprising the administration of an activator of a collagenase production pathway in combination with a steroid.

[0060] Taught herein is a method for treating a fibrotic condition associated with a scar in a subject, the method comprising the administration of an activator of a collagenase production pathway with a corticosteroid.

[0061] Enabled herein is a method for treating a fibrotic condition associated with a scar in a subject, the method comprising the administration of an activator of a collagenase production pathway in combination with a steroid and an antimetabolite selected from the group consisting of a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist.

[0062] Enabled herein is a method for treating a fibrotic condition associated with a scar in a subject, the method comprising the administration of an activator selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof of a collagenase production pathway in combination with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and optionally an antimetabolite selected from the group consisting of a 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0063] In an embodiment, a medical protocol is provided for the treatment of a fibrotic disease associated with excessive collagen production, the protocol comprising determining the nature of the fibrotic disease wherein if it is a fascial fibromatosis, then administering a group of medicaments selected from the list consisting of (i) tPA or uPA and a triamcinolone; and

(ii) tPA or uPA and a triamcinolone and 5-fluorouracil;

and if it is not a fascial fibromatosis, then administering a group of medicaments selected from the list consisting of:

(i) tPA or uPA;

(ii) tPA or uPA and a triamcinolone; and

(iii) tPA or uPA and a triamcinolone and 5-fluorouracil.

[0064] Reference to a fascial fibromatosis includes palmar, plantar and penile fascial fibromatosis (also referred to as Dupuytren's disease, Ledderhose disease and Peyronie's disease, respectively). A non-fascial fibromatosis fibrotic disease includes keloids.

[0065] Hence, in an embodiment, a medical protocol is provided for the treatment of a fibrotic disease associated with excessive collagen production, the protocol comprising determining the nature of the fibrotic disease wherein if it is a fascial fibromatosis, selected from the group consisting of Dupuytren's disease, Ledderhose disease and Peyronie's disease, then administering a group of medicaments selected from the list consisting of

(i) tPA or uPA and a triamcinolone; and

(ii) tPA or uPA and a triamcinolone and 5-fluorouracil;

and if it is keloids, then administering a group of medicaments selected from the list consisting of:

(i) tPA or uPA;

(ii) tPA or uPA and a triamcinolone; and

(iii) tPA or uPA and a triamcinolone and 5-fluorouracil.

[0066] The administration of the activator (e.g. tPA or uPA) alone or in combination with the steroid and optionally an antimetabolite to treat a wound means to administration at or near that particular wound or site of skin condition by, for example, injection or topically with a skin. Reference to ameliorating the fibrotic condition includes reducing the extent to which fibroblasts secrete excessive amounts of extracellular matrix (ECM) compounds such as collagen. The amelioration may also result from a reduction in the number of fibroblasts or active fibroblasts. The amelioration further includes reducing the extent to which the fibrotic condition forms or reduces its continued development if already formed. By "topically administering" includes transcutaneous, subcutaneous, transdermal, transepithelial, subepithelial, administration and the like. The treatment may be on or near a surface or subsurface skin wound or at or near the site(s) of the collagen deposition in the fascial fibromatosis.

[0067] The therapeutic protocol comprises the use of one or more of an activator of a collagenase pathway (e.g. tPA or uPA), a steroid such as a triamcinolone and an antimetabolite such as 5-fluorouracil. Two or more of the activator, steroid and antimetabolite may be co-formulated into one medicament for administration such as by intravenous, topical or oral administration. Alternatively, each is administered separately including sequentially or simultaneously in different formulations such as by intravenous administration of the activator and/or antimetabolite and by oral administration for the steroid. Yet in another alternative, each active agent is administered by a different route selected from intravenous, oral and topical.

[0068] As indicated above, reference to a subject being treated includes humans and non- human primates, as well as a cow, horse or other equine animal, sheep, pig, goat, alpaca, llama, camel, dog or cat as well as laboratory test animal such as a mouse, rat, guinea pig, hamster or rabbit. As indicated above, the fibrotic or associated inflammatory condition to be treated includes fascial fibromatosis such as Dupuytren's disease, Ledderhose disease or Peyronie's disease and wounds including post-healed wounds and other trauma or conditions arising from or comprising injury, surgery, microbial or viral infection, an insect bite, pimples or other skin lesions including ulcers, psoriasis, scleroderma (limited or diffuse), eczema, hypertrophic scars, scratch marks, stretch marks (striae) burns, sunburn, sites of body piercing as well as melanomas and cancer scars such as skin cancer scars and hypertrophic scars.

[0069] Other topical media may also be employed to facilitate penetration of the outer and inner skin and epithelial layers and include lotions, creams, gels, drops, suppositories, sprays, liquids, powders and ointments. The activator and optionally together with a steroid and further optionally an antimetabolite (separately or co -formulated) may also be part of a slow or sustained release formation(s). The formulation(s) may include an antimicrobial agent (e.g. an antibiotic) and/or an anesthetic.

[0070] Taught herein is Aa activator of a collagenase production pathway for use in the treatment of a fibrotic condition associated with excessive collagen in a subject herein if the fibrotic condition is fascial fibromatosis, then the activator is used in combination with a steroid. Enabled herein is the use of an activator of a collagenase production pathway in the manufacture of a medicament in the treatment of a fibrotic condition associated with excessive collagen in a subject wherein if the fibrotic condition is a fascial fibromatosis, then the activator is used in combination with a steroid and optionally an antimetabolite.

[0071] Taught herein is the use of an activator of a collagen production pathway selected from selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof in the manufacture of a medicament in the treatment of a fibrotic condition associated with excessive collagen in a subject wherein if the fibrotic condition is a fascial fibromatosis, then the activator is used in combination with steroid and in particular a corticosteroid and optionally an antimetabolite selected from the group consisting of a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist.

[0072] Enabled herein is the use of an activator of a collagen production pathway selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof in the manufacture of a medicament in the treatment of a fibrotic condition associated with excessive collagen in a subject wherein if the fibrotic condition is a fascial fibromatosis, then the activator is used in combination with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and optionally an antimetabolite selected from the group consisting of a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist.

[0073] Taught herein is the use of a plasminogen activator of a collagenase production pathway selected from the group consisting of tPA, uPA, kallikrein and Factor XII or a functional analog thereof in the manufacture of a medicament in the treatment of a fibrotic condition associated with excessive collagen in a subject wherein if the fibrotic condition is a fascial fibromatosis, then the activator is used in combination with a triamcinolone selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide and triamcinolone diacetate or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof and an antimetabolite selected from the group consisting of 5-fluorouracil, foxuridine, cytarabine, capacetabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine and pentostatin or a pharmacologically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative, biosimilar or prodrug form thereof.

[0074] Pharmaceutical formulations comprising an active agent such as the activator, steroid and antimetabolite are described in Remington's Pharmaceutical Sciences (1990) 18th Ed., Mack Publishing, Company. The term "pharmaceutically acceptable salt" (or solvate) refers to physiologically and pharmaceutically acceptable salts of the steroid or antimetabolite and, if relevant, agents used in combination with either.

[0075] The formulated compound(s) of the present invention include or pharmaceutically active and pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, derivative or biosimilar thereof may be administered as such or in the form of a suitable prodrug as well as recombinant and purified naturally occurring forms or synthetic forms of the activator (e.g. tPA and uPA). Recombinant and synthetic forms of the activator are encompassed by the term "functional analog".

[0076] The term "prodrug" refers to a compound, which is a drug precursor and which, following administration and absorption, release the drug in vivo via some metabolic process.

[0077] Prodrugs include those that increase the bioavailability of the active agent (e.g. by allowing an administered compound to be more readily absorbed into the tissue) or which enhance delivery of the active agent to a specific biological site (e.g. site of wound or fascial fibromatosis). Thus, examples of suitable prodrugs of the substances according to the present invention include compounds modified at one or more reactive or derivatizable groups of the active agent (e.g. a triamcinolone).

[0078] The agents according to the present invention including a triamcinolone and/or an antimetabolite may be in the form of salts. The salts of the compounds of the present invention are pharmaceutically acceptable, but it will be appreciated that non- pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.

[0079] The pharmaceutically acceptable salts include acid addition salts, base addition salts, salts of pharmaceutically acceptable esters and the salts of quaternary amines and pyridiniums. The acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicyclic, sulfamic or tartaric acids. The counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate and tartrate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium. The salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.

[0080] The compounds useful according to the present invention may be in crystalline form and/or in the form of solvates (e.g. hydrates) and it is intended that all of these forms be within the scope of the present invention. The term "solvate" is a complex of variable stoichiometry formed by a solute and a solvent. Such solvents should not interfere with the biological activity of the solute. Methods of solvation are generally known within the art.

[0081] In an aspect, the activator of a collagenase production pathway alone or in combination with another active agent such as a steroid and optionally an antimetabolite is/are provided as a composition with a pharmaceutically acceptable carrier or diluent or excipient. Pharmaceutically acceptable vehicles and/or diluents and/or excipients include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active agent, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0082] The compounds or pharmaceutical compositions of the present invention may be administered parenterally, orally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The administration as used herein includes intravenous, intraperitoneal, intrauterine, percutaneous, intranasal, subcutaneous, intramuscular, intra- articular or by infusion techniques. In an embodiment, the route of administration is via injection or a combination of injection, oral and/or topical administration. Hence, in an embodiment, taught herein is a therapeutic protocol for the treatment of a fibrotic disease associated with excessive collagen production, the protocol comprises selecting medicaments form the group:

(i) an activator of a collagenase production pathway;

(ii) a steroid;

(iii) an antimetabolite;

(iv) an activator of a collagenase production pathway and a steroid;

(v) an activator of a collagenase production pathway, a steroid and an antimetabolite; and (vi) a steroid and an antimetabolite,

and administering any of (i) through (vi) by the same or different route of administration wherein if the fibrotic disease is a fascial fibromatosis, then the activator is administered with a steroid and optionally with a steroid and an antimetabolite.

[0083] Hence, in one aspect, the activator of a collagenase production pathway or pharmaceutical composition comprising same or together with another agent such as a steroid and optionally an antimetabolite are administered in any acceptable dosage form in the same or different formulations and by the same or different routes of administration.

[0084] Sterile injectable forms of the compositions of the present invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the purposes of formulation.

[0085] In another aspect, the active agent(s) or pharmaceutical compositions comprising same are administered topically. For topical applications, the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0086] As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the subject (e.g. human or non-human animal) to be treated. The choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the active agent, care should be taken to ensure that the activity of the agent is not destroyed in the process and that the agent is able to reach its site of action without being destroyed. Similarly the route of administration chosen should be such that the compound reaches its site of action.

[0087] It is especially advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle. The specification for the novel dosage unit forms of the present invention are dictated by and directly dependent on (a) the unique characteristics of the active agent (e.g. vinorelbine) and the particular therapeutic effect to be achieved; and (b) the limitations inherent in the art of compounding the active agent for use in treatment. In an example, an activator is generally administered at a dose of from O.Olmg to lOmg/kg patient. This means 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or lOmg/kg patient. Conveniently, administration is by injection or other form of intravenous administration. The steroid such as a corticosteroid including a triamcinolone may be administered from about O.lmg to lOOmg such as by oral, intravenous or topical administration. This range includes 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and lOOmg. The dosage may be per day or week or combinations thereof. The antimetabolite such as 5-fluoroucil is generally provided in intravenous or oral dosage form such as from O. lmg/kg patient to lOOmg/kg patient. This includes 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and lOOmg/kg patient.

[0088] Therapeutic kits or pharmaceutical packs are further contemplated herein. In an embodiment, the activator of a collagenase production pathway may be administered as the sole active agent or in combination with one or more active agents such as a steroid (e.g. corticosteroid such as a triamcinolone) and optionally an antimetabolite such as a pyrimidine antagonist, a folic acid antagonist, a purine antagonist and a deaminase antagonist. In this regard, the activator may be co-formulated with the other active agent(s) or a pharmaceutical kit is provided whereby an activator and one or more other active agents are co-mixed prior to administration or co-administered separately. Administration of each agent may be simultaneous or sequential. By "sequential" means within seconds, minutes or hours, in either order. "Simultaneous" means in the same or different formulation. [0089] The term "effective amount" or "therapeutically effective amount" means that amount of active agent (activator alone or in combination with the steroid and optionally with the antimetabolite) that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a clinician, researcher or veterinarian, which includes alleviation of one or more of the symptoms of the fibrotic disease or disorder being treated; reduction of the severity of one or more of the symptoms of the disease or disorder being treated; or otherwise provides the desired effect. The precise dosage may vary according to a variety of factors such as subject-dependent variables (e.g., age, medical history, etc.), the disorder or condition, and the treatment being affected. Effective amounts are, for example, those listed above.

[0090] The "medicament" may comprise one or two or more active agents or multiple medicaments may be provided each with a single active agent.

[0091] Reference herein to a "collagenase production pathway" is directed to a pathway such as that shown in Figure 1 , which results in the production of endogenous collagenase.

EXAMPLE

[0092] Aspects disclosed herein are further described by the following non-limiting Example.

EXAMPLE 1

Treatment of Dupuytren 's disease using alteplase (atPA)

[0093] Subjects suffering from Dupuytren's disease or from Ledderhose disease are treated with, initially, a single injection of 10-20mg of alteplase (tPA) dissolved in 5 mL of sterilized water together with triamcinolone. A local anaesthetic can be applied to the area of the skin to be injected to reduce discomfort for the patient.

[0094] The injection is placed either directly into the visible cord or partially into the cord and the remainder into the surrounding fascia. The patient is then free to go home without the need for splinting or isolation of the hand or affected fingers. The full effect of the treatment will be felt after a period of approximately 2 weeks.

[0095] At this point if the affected fingers are not fully extendable then a second injection may be necessary.

[0096] For many patients this treatment regime is sufficient to return a substantial range of motion to the affected fingers and no further treatment is necessary.

[0097] Figures 2A through to 5B show diagrammatical representations of before and after results Dupuytren's sufferers treated by the present method and indicate the benefits provided.

[0098] Figures 2A and 2B show what would be a dramatic change from the pre-treatment (Figure 2A) to post-treatment (Figure 2B) state. Both of the hands of this patient are affected by Dupuytren's disease and most of the fingers are permanently flexed. Figure 2B shows a patient after two rounds of injection followed by stripping of the large cord. It is clear that the fingers are now all close to being fully extended apart from the little finger. For the little finger the problem is that the flexion is at the proximal interphalangeal (PIP) joint and this is not due to a cord or collagen band but rather a different underlying issue within the joint itself. Thus surgery is also required to unlock the PIP joint (focusing on the volar plate) and no existing non-surgical treatment exists for this problem. The result achieved in Figure 2B thus would represent an excellent clinical outcome.

[0099] In Figure 3A the cord extending to the patients little finger is highly visible and has brought about a pronounced flexion. The treatment involved a single round of injection with alteplase, as described above, followed by surgical stripping of the cord. Figure 3B shows the same hand after treatment and the improvement in the range of extension of the little finger is clear. The cord is still partially visible but the present treatment has softened or broken it down to such an extent that a near normal range of motion has been achieved. It is likely a further treatment round would diminish the cord even further.

[0100] The contracture of another patient's right hand is shown in Figure 4A. Flexion of the ring finger is particularly prominent. Figure 4B shows the same hand after treatment involving 2 rounds of injection with alteplase, as described, followed by stripping of the cord and the return to normal motion of the fingers is shown.

[0101] Treatment of the patient whose hands are shown in Figure 5A is potentially complicated as this patient may also be a diabetic. Surgery can be high risk for diabetic Dupuytren's sufferers as the risk of post-operative complications is greater. The patient is treated with a single injection according to the method of the invention and no surgical stripping of the cord was considered necessary.

[0102] Figure 5B shows the considerable improvement in finger function/range of motion following only this single injection.

[0103] Those skilled in the art will appreciate that the disclosure described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure contemplates all such variations and modifications. The disclosure also enables all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of the steps or features or compositions or compounds.

[0104] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

BIBLIOGRAPHY

Amo et al. (2014) BUMS 40(7): 1255- 1266

Andrews et al. (2016) Matrix Biology 51:37-46

Gauglitz et al. (2011) Molecular Medicine 17(1-2): 113- 125

Guo et al. (2010) Journal Dent Res 89:219-229

Mustoe et al. (2004) Amer Journal of Surgery 87:655-705

Rapini et al. (2007) Dermatology: 2 volume set, St. Louis, Mosby at pl499

Remington's Pharmaceutical Sciences (1990) 18th Ed., Mack Publishing, Company

Shih et al. (2010) Wound Repair Regeneration 18: 139-153

Usui et al. (2008) Journal of Histochem Cytochem 5(5:687-696