WO2006085127A1

WO2006085127A1 - Topical compositions

Info

Publication number: WO2006085127A1
Application number: PCT/IB2005/000316
Authority: WO
Inventors: John Wallace
Original assignee: Antibe Therapeutics, Inc.
Priority date: 2005-02-08
Filing date: 2005-02-08
Publication date: 2006-08-17

Abstract

Topical compositions for local treatment of pathological diseases and disorders caused by insects' bites, jelly fish and hemorrhoids or other anal disorders, are described, comprising Sangre de grado (SDG) and a NTFs modulator.

Description

TITLE OF THE INVENTION

Topical compositions

Background of the invention

Sangre de grado or Sangre de drago, (SdG) , also

known as "Dragon' s Blood, " is a viscous red tree sap

derived from the bark of various Croton species ( C.

dracanoides, C. erythrochilus, C. gossypif±lius, C. lechleri, C. palanostigma, C. sakutaris and C. urucurana)

that is used extensively by indigenous cultures of the

Amazon River basin for its remarkable healing properties

(Duke J. , Vasquez R. Amazonian Ethnobotanical Dictionary,

Boca Raton, FL, CRC Press , Inc . 1994) .

The genus Croton is a large one, with 750 species of trees and shrubs distributed across the tropical and subtropical regions of both hemispheres . Crotons are rich

in active alkaloids , and several species are well-known medicinal plants used as purgatives and tonics,.

Sangre de grado resin or sap, is composed by several

components including proanthocyanidins (antioxidants) , simple phenols , diterpenes , phytosterols, and

biologically active alkaloids and lignans .

The biologically active properties of the sap are due to three main "active" constituents : an alkaloid

named taspine, a dihydrobenzofuran lignan named dimethylcedrusine and a group of polyphenols called

proanthocyanidins .

Taspine was shown to be the active cicatrizing

principle by an in vivo test in mice . This alkaloid exhibited a dose-related cicatrizing effect and an ED50

of 0.375 mg/kg. Experiments with taspine hydrochloride in

order to study its mechanism of action in cell culture systems showed that the alkaloid was non-toxic to human

foreskin fibroblasts at concentrations below 150 ng/ml and that it had no effect on cell proliferation. On the

other hand, taspine hydrochloride was found to increase the migration of human foreskin fibroblasts . This effect on the migration of fibroblasts is probably the mechanism by which Sangre de Grado and taspine hydrochloride accelerate the wound healing process (Vaisberg AJ; et al . Planta Med, 55 : 2 , 1989 Apr, 140-3 ) .

Also the lignan dimethylcedrusine was shown to play a central role in SdG' s effective wound-healing action. A

study revealed that the crude resin stimulated contraction of wounds , helped in the formation of a

crust/scab at the wound site, regenerated skin more rapidly, and assisted in the formation of new collagen

(Pieters L; et al . J Nat Prod, 56 : 6 , 1993 Jun, 899-906) .

Proanthocyanidins are an important group of polyphenols present in SdG. They are responsible of the antioxidant activity due to their properties as free

radical scavenger, chelants of transition metals and

inhibitors of enzymes . In addition, proanthocyanidins have a protective role against lipid peroxidation and

peroxynitrite, as well as antimicrobial properties . More

recently the role of proanthocyanidins on apoptosis , gene expression, and transcription factors , such as NF-kB has

been established (Cos P . et al . Proanthocyanidins in health care : Current new trends , Current Medicinal Chemistry, 11 (n. 10) pag . 1345-1359 , 2004 ) .

Field of the invention

One embodiment of this invention relates to an composition for the treatment of bites, stings or wounds caused by animals and insects such as fire ants , j ellyfish, sea lice, related arthropods and cnidarians , as well as other biologically-caused wounds and envenomations . Fire ants (Solenopsis Invicta) , sea lice (one of 1000 species of cnidarians) , and related arthropods and cnidarians and other species are prevalent in tropical and sub-tropical areas , and can cause painful bites and stings . Fire ants in particular behave very aggressively, and can inflict very painful and toxic stings . The sting, which is extremely painful to the recipient, can form a raised pustule , which can rupture and become infected, leading to scarring.

Sea lice , which are the larval stage of the thimble jellyfish (Linuche Unguiculata) and stings from other cnidarians j ellyfish) , can also cause painful stings , which if left untreated can cause a rash and blistering of the affected area, due to nematocysts left in the wound which continue to release toxins .

Current treatments for envenomation by fire ants and cnidarians are similar, and are typically topical measures such as the application of a cortisone cream, colloidal preparation or calamine solution. In more severe cases , antihistamines , steroids, and epinephrine may be administered by I .M. , I .V. , and/or orally. Folk remedies included the use of garlic, athlete' s foot spray, lemon, hydrogen peroxide, rubbing alcohol , spray starch, Epsom salts, and meat tenderizer etc .

Another embodiment of this invention is directed to compositions and methods for treating anorectal disorders such as anal fissures , anal ulcer, hemorrhoidal diseases by administering to an appropriate anal area (for example, the internal anal canal) of a subject in need of such treatment an agent or combination of agents which relaxes the internal anal sphincter muscle . More specifically, this invention relates to compositions and methods for treating anorectal disorders with agents which not only reduce itching and inflammation but also induce an increase in cyclic nucleotides in the anal sphincter muscle or which mimic the actions of cyclic nucleotides or reduce intracellular calcium concentrations in the affected anal sphincter muscle tissue, thereby reducing internal anal sphincter (IAS) hypertonicity and/or spasm in patients afflicted with such disorders .

Anal fissure is one of the most common causes of anorectal pain. Anal fissures are tears in the mucosa of the distal anal canal , usually along the posterior midline . The exact causes of anal fissures remain unknown. They are often associated with trauma, e . g . , passage of a hard stool , but can also occur during bouts of diarrhea, childbirth, or ulceration of a hemorrhoid

(Lund, J. N. et al . , Br J Surg . 83 (10) : 1335-44 (1996) ) .

The most common symptom is pain at defecation, which can be quite severe and last for a variable time afterwards .

Acute anal fissures, which do not heal , become chronic anal fissures or anal ulcers . There is clearly a large unmet medical need to develop effective, non-surgical treatments for anal fissure and other colorectal conditions , including acute hemorrhoidal disease, hemorrhoidectomy pain, proctalgia fugax, and severe constipation.

Hemorrhoids are specialized vascular areas lying subjacent to the anal mucosa. Bleeding, thrombosis and/or prolapse of the hemorrhoidal tissues manifest symptomatic hemorrhoidal diseases . Commonly, internal hemorrhoidal tissue bulges into the anal canal during defecation and results in bleeding and pain. As the tissue enlarges, further bleeding, pain, prolapsed and thrombosis can ensue . The thrombosis of hemorrhoids is yet another cause of bleeding and pain.

A number of potent vasodilators and smooth muscle relaxants are known to chemically release NO on or within target cells , and thus are known as NO donors . Some NO donors, e . g. , nitroglycerin, are widely used therapeutically as coronary vasodilators to treat heart disease . In keeping with the role of NO as an inhibitory neurotransmitter mediating relaxation of the IAS, NO donors are beginning to be explored clinically as drugs to treat anal disorders associated with IAS hypertonicity. Significantly, nitroglycerin (Gorfine , S . R. , Dis Colon Rectum, 38 (5) : 453 -6 (1995) ; Lund, J. N. et al . , Lancet 349 : 9044 (1997) ) and isosorbide dinitrate have been used to effect a reversible chemical sphincterotomy in patients with chronic anal fissure . These drugs reduce maximal resting anal pressure and, improve anodermal blood flow, reduce pain, and heal fissures in a majority of the patients . Nitroglycerin has also been shown to reduce the throbbing pain of acute hemorrhoidal thrombosis and proctalgia fugax (Gorfine, S .

R. , Dis Colon Rectum 38 (5) : 453-6 (1995) .

U. S . Pat . Nos . 5 , 504 , 117 and 5 , 693 , 676 describe the use of NO donors for the treatment of anorectal conditions . However, the development of adverse side effects such as the development of headaches has limited the use of NO donors in mono-therapy, especially at higher doses .

Description of the Invention It was now surprisingly found that the properties of

SdG can be further enhanced when it is combined in topical composition with compounds that can interact and modulate the transcription factors (NTFs) .

Accordingly, the present invention relates to topical compositions for local treatment of pathological diseases and disorders caused by insects' bites, jelly fish and hemorroids or other anal disorders, comprising: a) Sangre de grado (SDG) , b) a NTFs modulator. Preferably, in said topical compositions according to the invention SDG is present at a concentration of from 0.1 to 50% by weight of the composition and the NTFs modulator at a concentration of from 0.1 to 10% by weight of the composition. As a further preferred embodiment the topical compositions according to the present invention further comprise vehicle/s or carrier/s and/or adjuvant/s such as active ingredient, i . e . local anesthetics , vasoconstrictors , counterirritants , astringents and anticholinergics , and/or other wound healing promoter/s and/or antimicrobial agent/s and/or optional component/s, the later selected in view of the dosage form for the topical administration of the compositions according to the present invention. In particular the balance for 100% by weight of the compositions being given by the above said vehicle/s or carrier/s and/or adjuvant/s and/or other wound healing promoter/s and/or antimicrobial agent/s and/or optional component/s .

Tissue damage by infections , traumas , toxins , and other reasons such as hemorrhoids , usually leads to formation of increased amounts of pathogenetic mediators , such as prostaglandins , cytokines , leukotrienes , interleukins , oxy- , thiyl-and nitrogen-free radicals , interacting each other. A serious , outstanding medical need is the development of compounds that afford an efficacious treatment while minimizing unwanted effects . It is part of the present invention to develop compounds able to both counteract aggressive and pathogenetic factors and potentiate defensive substances . This is obtained by combining a compound (SdG) , known to counteract one or more of the above-mentioned pathogenetic mediators , with other moieties able to regulate the activation of NTF .

A further advantage of the invention is related to SdG intense color, as suggested by the reference to blood in its name that limits its ability to be used topically. Practically a combination of SdG with other NFkB modulators could reduce the dose of SdG and the proanthocyanidin content (and hence color) of the composition whilst retaining full biological properties . Compounds that have been found to be useful in combination with SdG are compounds able to modulate the inhibition of transcription factors such as compounds that releases nitric oxide (NO) directly or indirectly eg. arginine, agmatine, aminoguanidine . These compounds can be added in a quantity ranging from 0.1% to 50% and preferably from 1% to 10 % by weight of the composition.

NF-regulating moieties that can be included in the

topical composition in combination with SdG include α-

lipoic acid, α-tocoferol, butylated hydroxyanisole (BHA) ,

caffeic acid derivatives , catechol derivatives , cinnamic acid, curcumin, epigallocatechin-3-gallate, ergothioneine, N- (p-aminobenzoyl) glutamic acid, glutathione, hematein, magnolol , nordihydroguaiaretic acid (NDGA) , phenolic antioxidants, pyrrolidine dithiocarbamate (PDTC) , quercetin, resveratrol , Vitamin C, vitamin E, salicylic acid derivatives (such as cresotic acid isomers and 4 -hydroxyisophthalic acid) .

Other substances releasing or stimulating the release of hydrogen sulfide and NF-regulating that can be added to SdG topical compositions are N-acetyl-penicillamine, S-allyl-cysteine, bucillamine, carbocysteine, cysteamine, cystathionine, homocysteine, mecysteine, methionine, pantetheine, penicillamine, penicillamine disulfide, thioacetic acid, thiodiglycolic acid, thioglycolic acid, thiolactic acid, 2 -thiolhistidine, thiomalic acid, thiosalicylic acid, tiopronin.

Other substances releasing and/or stimulating the release of hydrogen sulfide and NF-regulating that can be added are also 5- (p-hydroxyphenyl) -3H-1 , 2-dithiol-3- thione, 1 , 3 dithiol-2 -thione-5-carboxylic acid, 3-thioxo- 3H-l , 2-dithiole-5-carboxylic acid, 3 -thioxo-3H-l , 2- dithiole-4 carboxylic acid.

More groups NF-regulating by releasing H₂S also in combination with groups that release nitric oxide or carbon oxide or that release nitric oxide or carbon oxide per se are part of the present invention.

In one aspect, the present invention thus provides compositions for the treatment of topical disorders , including anal disorders , comprising a topical composition as described above of SdG in combination with a second agent as NTFs modulator, typically one which modulates levels of cAMP or cGMP . This second agent can be a phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase type II (PDE II ) inhibitor, a phosphodiesterase type IV (PDE IV) inhibitor, a nonspecific PDE inhibitor .

Preferred PDE inhibitors are sildenafil , taladafil , verdenafil and their derivatives .

As stated above, the pharmaceutical composition of the present invention may also contain as adjuvant the active agents from other plants and/or from different pharmacological groups such as local anesthetics, vasoconstrictors , counterirritants , astringents and anticholinergics .

Preferably, it would be beneficial to include other wound healing promoter and antimicrobial agents, which will result in the improvement of the effectiveness of the composition.

The local anesthetics and/or their salts, include but are not limited . to such as benzocaine, diperodon, pramoxine, camphor, dibucaine, phenol , tetracaine, lidocaine and phenacaine . The amount of such anesthetics could vary between 0.25% and 5% by weight of the composition.

The vasoconstrictors include but are not limited to ephedrine, naphazoline, phenylephrine and/or their salts .

The amount of such vasoconstrictors may vary between 0.005% and 1.5% by weight of the composition.

The counterirritant includes but is not limited to menthol in aqueous solution. The menthol is present in an amount of between about 0.1% and about 3% by weight and preferably between about 0.2% and about 2% by weight of the composition. Even more preferably, the menthol is present in an amount of between about 0.3% and about 1% by weight of the composition. It remains as a protective coating and, especially in the case of hemorrhoids , relieves the pain of and also shrinks them. It has an astringent effect that contracts the tissues, diminishing discharges , and promoting healing. On application, it feels cool and it reduces the itching. This cooling effect is due primarily to the presence of the correct proportion of menthol .

The astringents include but are not limited to calamine, zinc oxide, hamamelis water, bismuthresorcinol compound, bismuth subgallate, peruvian balsam, aluminium chlorhydroxy allantoinate, tannic acid and tannins . The amount of such astringents may vary from 0.2% to 60.0% by weight of the composition.

The wound healing promoter agents include but are. not limited to vitamin A and vitamin D in an amount by weight of the composition in the range of 0.005% to 0.05% . Also cod liver oil can be included in an amount by weight of the composition in the range 1.0% to 6.0% . Also live yeast cell derivative can be included in an amount of between 2 -50 , 000 units per gram.

The antimicrobial agents , include but are not limited to benzethonium chloride, benzalkonium chloride, boric acid, 8-quinolinol benzoate, secondary amyltricresols , cetylpyridinium chloride, phenol , chlorothymol , camphor and 8-hydroxyquinoline sulfate . The amount of such antimicrobial agents varies between 0.02% and 5.0% by weight of the composition. The anticholinergics include but are not limited to atropine or other solanaceous type alkaloids, either alone or in combination. The amount of such anticholinergics may vary between 0.02% and 0.1% by weight of the composition.

The vehicle/s or carrier/s or optional component/s , such as polymers , preservatives , buffers , propellants, diluents , oily base, aqueous base, thickening and/or gelling agents, stabilizing agents , emulsifying agents,

dispersing agents , suspending agents , colouring agents ,

perfumes , powder base, solubilizing agents , excipients , surfactants are selected in view of the dosage forms for

the topical administration of the compositions according

to the present invention.

Dosage forms for the topical administration of this

invention include sprays , ointments, pastes , creams , lotions, gels , solutions , foams , sticks solid or roll-

sticks , powders , patches, suppositories and liposome

compositions .

The dosage forms may also be formulated with

mucoadhesive polymers for sustained release of the active

compound (s) at the site of action. The active compounds may be mixed with a pharmaceutically acceptable

carrier, and with any preservatives , buffers , or

propellants , which may be required. Topical compositions can be prepared by combining the active agents with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol

compositions .

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents . Such bases may include water and/or oil such as liquid paraffin or a

vegetable oil such as peanut oil or castor oil .

Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum

stearate, cetostearyl alcohol , propylene glycol ,

polyethylene glycols , woolfat , hydrogenated lanolin,

beeswax, and the like .

Lotions may be formulated with an aqueous or oily base and, in general , also include one or more of the

following : stabilizing agents , emulsifying agents,

dispersing agents , suspending agents , thickening agents , coloring agents , perfumes , and the like .

Powders may be formed with the aid of any suitable

powder base , e .g . , talc, lactose, starch, and the like .

Drops may be formulated with an aqueous base or nonaqueous base also comprising one or more dispersing

agents , suspending agents , solubilizing agents , and the like .

The ointments , pastes , creams and gels also may

contain excipients, such as animal and vegetable fats, oils , waxes , paraffins , starch, tragacanth, cellulose derivatives , polyethylene glycols , silicones , bentonites , silicon dioxide , talc and zinc oxide , or mixtures thereof .

Powders and sprays also can contain excipients such

as lactose, talc, silicon dioxide, aluminum hydroxide,

calcium silicates and polyamide powder, or mixtures of these substances .

Sprays and foams can additionally contain customary

propellants , such as chlorofluorohydrocarbons ,

hydrofluorocarbons and volatile unsubstituted

hydrocarbons, such as butane and propane, isobutene and combinations thereof . Surfactants are added for the

foams . The compositions of the present invention may be

applied either by an applicator or other means . The

affected area should be washed prior to applying the product .

The product should be applied morning and evening with not more than six applications per day.

Alternatively, the composition could be incorporated in a

substrate as a "wipe" and then applied. The following non-limitative examples further describe and enable an ordinary skilled in the art to make and use the invention. EXAMPLE 1. Proctological cream with arginine

100 g of cream contain:

SdG 5.00g

Lidocaine HCl l . OOg

1-Arginine 5.0Og

Menthol 0.25g

Xalifin 15 13.0Og Cetostearyl alcohol 3.0Og

Mineral oil 10.0Og

Methyl p-hydroxybenzoate 0.15g

Propyl p-hydroxybenzoate 0.05g

Purified water qb . 100.00g, Dilute SdG in 20 g of purified water (ratio 1 : 4 ) and

filter through a 0.45 μm membrane filter . Warm the remaining quantity of purified water at 90 ⁰C, dissolve

under mixing methyl p-hydroxybenzoate and propyl p- hydroxybenzoate .

Add to the obtained solution, always under mixing, lidocaine hydrochloride and 1-arginine, _. menthol accurately weighed.

Weight and melt at 80 ⁰C in a suitable apparatus the following ingredients : mineral oil , cetostearyl alcohol ,

C12-20 PEWG-8 ester (Xalifin 15) . Add the melted fat mass obtained to the solution previously prepared, mix and cool at 40⁰C . Add the filtered solution containing SdG .

Let cool at room temperature and perform the primary packaging in tubes .

EXAMPLE 2. Proctological cream

100 g of cream contain:

SdG 5.0Og

Lidocaine HCl l . OOg

α-lipoic acid 3.0Og

Menthol 0.25g

Propylen glycol 7.0Og

Stearyl alcohol 5.0Og

Cetyl alcohol 5.0Og Mineral oil 30.0Og

Methyl p-hydroxybenzoate 0.15g

Propyl p-hydroxybenzoate 0.05g

Polisorbate 60 5.0Og Purified water qb . 100.0Og

Dilute SdG in 20 g of purified water (ratio 1 : 4 ) and filter through a 0.45 μm membrane filter . Warm the remaining amount of purified water at 90⁰C , dissolve

under mixing methyl p-hydroxybenzoate and propyl p- hydroxybenzoate and polysorbate 60. Add to the obtained solution, always under mixing, lidocaine hydrochloride and menthol accurately weighed.

Weight and melt at 80 ⁰C in a suitable apparatus the following ingredients mineral oil , cetostearyl alcohol ,

stearyl alcohol , propylene glycol , a lipoic acid. Add the melted fat mass obtained to the solution previously prepared, mix and cool at 40⁰C . Add the filtered solution

containing SdG.

Let cool at room temperature and perform the primary

packaging in tubes .

EXAMPLE 3. Topical cream

100 g of topical cream contain: SDG 3.0Og

2-phenoxyethanol l . OOg PEG-NO 2.0Og

PEG 400 36.0Og

PEG 1500 17.0Og

PEG 4000 17.0Og Mineral oil 2.0Og

Cetyl alcohol 0.5Og Stearyl alcohol 0.5Og Glycerin 4.5Og

Sorbitol 8.25g Lavander essence 0.05g

Dilute SdG in 20 g of purified water (ratio 1 : 4) and filter through a 0.45 μm membrane filter. Warm the remaining quantity of purified water at 90 ⁰C, dissolve under mixing 2-phenoxyethanol , PEG-NO, PEG 400 , PEG 1500 , PEG 4000. Weight and melt at 80 ⁰C in a suitable apparatus

the following ingredients mineral oil , cetostearyl alcohol and stearyl. alcohol .

Add the melted fat mass obtained to the solution previously prepared, mix and cool at 40⁰C . Add the filtered solution containing SdG.

Let cool at room temperature and perform the primary

packaging in tubes .

EXAMPLE 4. Topical foam against j elly fish

100 g of topical foam contain: SdG 5.0Og

1-arginine 3.0Og

Vitamin E acetate 0.5Og

Phospholipon 8OH l . OOg

Labrasol 10.0Og

Benzyl alcohol 0.5Og

Potassium sorbate O . lOg

Tween 80 2.0Og

Purified water qb . 100.0Og Propellent butane-isobutane

(10% on the solution) 5.0Og

Dilute SdG in 20 g of purified water (ratio 1 : 4 ) and filter through a 0.45 μm membrane filter. Warm the remaining quantity of purified water at 80 ⁰C, dissolve under mixing hydrogenated soy lecithin (Phospholipon

80H) , 1-arginine, vitamin E acetate, caprylocaproyl macrogolglycerides (labrasol) , benzyl alcohol , potassium sorbate, and polysorbate 80 (Tween 80) .

Let cool at room temperature and add the filtered

solution containing SdG.

Proceed to filling operations (bulk . solution and

propellent mixture) : fill the solution in canisters ,

crimp the valve and fill with the propellent mixture of

butane-isobutane . EXAMPLE 5. Solid sticks

100 g of composition contain:

SdG 3.0Og

1-Arginine 3.0Og

Castor oil 65.0Og

Carnauba wax 12.0Og

Semisynthetic glycerides 9.0Og

Beeswax 7.9Og

Butylhydroxyanisol (BHA) O . lOg

The composition was prepared dissolving carnauba wax, semisynthetic glycerides and beeswax under stirring in castor oil heated to 80 ⁰C .

After dissolution SdG, arginine and BHA were added maintaining the composition melted.

Special plastic containers fitted into moulds were filled to a dose of 2.5 g. The sticks were cooled to ambient temperature, then removed and finally closed with

caps .

EXAMPLE 6. Roll-stick

A solution containing 3% SdG and 3% α-lipoic acid in

a vehicle made up of :

Glyceryl monostearate 4.0%

Ethylen glycol 5.0%

Propylene glycol 20.0% Water 65 . 0%

was prepared.

The solution was filled into 10-ml roll-sticks Example 7. Biological activity: Antipruritic activity

The proctological cream of example 1 was tested

in a model of pruritis induced by intradermal injection

of serotonin (5-HT) , with the number of scratching events counted for the hour that follows blindly.

The topical composition of example 1 was tested in two ways . First, the cream was applied right after the 5-

HT inj ection. Then it was applied 30 minutes before the

5-HT inj ection. The results are reported in the following table I .

Table I : Antipruritic activity. Numbers refer to

average total scratching events . Number of animals per group = 8.

* Numbers in the brackets refers to min. max. number of scratching events .

Claims

1. Topical compositions for local treatment of pathological diseases and disorders caused by insects' bites, jelly fish and hemorroids or other anal disorders, comprising : a) Sangre de grado (SDG) , b) a NTFs modulator.

2. Topical compositions according to claim 1, characterized in that SDG is present at a concentration of from 0.1 to 50% by weight of the composition and the NTFs modulator at a concentration of from 0.1 to 10% by weight of the composition.

3. Topical compositions according to claim 1, wherein SDG is derivated from croton species .

4. Topical compositions according to claim 1, wherein the NTFs modulator is a nitric oxide releasing compound.

5. Topical compositions according to claim 3 , wherein the nitric oxide releasing compound is arginine and/or agmatine .

6. Topical compositions according to claim 1, wherein the NTFs modulator is a hydrogen sulphide releasing compound.

7. Topical compositions according to claim 1, wherein the NTFs modulator is lipoic acid.

8. Topical compositions according to claim 1, wherein the NTFs modulator is an inhibitor of PDE .