WO2007067036A2 - New use of carbonic anhydrase inhibitors - Google Patents

New use of carbonic anhydrase inhibitors Download PDF

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Publication number
WO2007067036A2
WO2007067036A2 PCT/NL2005/050070 NL2005050070W WO2007067036A2 WO 2007067036 A2 WO2007067036 A2 WO 2007067036A2 NL 2005050070 W NL2005050070 W NL 2005050070W WO 2007067036 A2 WO2007067036 A2 WO 2007067036A2
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Prior art keywords
dermatitis
carbonic anhydrase
skin
treatment
inhibitor
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PCT/NL2005/050070
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French (fr)
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WO2007067036A3 (en
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Josephus Schalkwijk
Marijke Kamsteeg
Gerardus Johannes De Jongh
Patrick Laurentiu Johannes Maria Zeeuwen
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Stichting Katholieke Universiteit
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Priority to PCT/NL2005/050070 priority Critical patent/WO2007067036A2/en
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Publication of WO2007067036A3 publication Critical patent/WO2007067036A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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

Definitions

  • the present invention is in the field of medicaments for the treatment of dermatitis.
  • Eczema is an inflammation of the skin (dermatitis), typically of the upper layers of the skin, usually characterized by redness, swelling, blister formation, oozing, scabbing, scaling and practically always by itching. Itching is a peculiar tingling or uneasy irritation of the skin that causes a desire to scratch the affected area.
  • the term eczema which formerly referred to the blistered, oozing state of inflamed skin, has by common usage come to have the same meaning as dermatitis.
  • the inflammatory process in the skin involves the upper dermis and epidermis.
  • the epidermis exhibits swelling of the keratinocytes and accumulation of fluid between them (spongiosis). In the severe form of spongiosis, blisters form within the epidermis.
  • dermatitis affect only specific parts of the body, whereas others can occur anywhere. Some types of dermatitis have a known cause; others do not. However, dermatitis is always the skin's way of reacting to severe dryness, scratching, a substance that is causing irritation, or an allergen. Typically, that substance comes in direct contact with the skin, but sometimes the substance is swallowed. In all cases, continuous scratching and rubbing may eventually lead to thickening and hardening of the skin. Dermatitis may be a brief reaction to a substance. In such cases it may produce symptoms, such as itching and redness, for just a few hours or a day or two. Chronic dermatitis persists over a period of time.
  • the hands and feet are particularly vulnerable to chronic dermatitis, because the hands are in frequent contact with many foreign substances and the feet are in the warm, moist conditions created by socks and shoes that favour fungal growth. Because chronic dermatitis produces cracks and blisters in the skin, any type of chronic dermatitis may lead to bacterial infection.
  • a distinction of several types of dermatitis has been made. Two very common types of dermatitis are contact dermatitis and atopic dermatitis. Contact dermatitis is skin inflammation caused by direct contact with a particular substance; the rash is very itchy, is confined to a specific area, and often has clearly defined boundaries.
  • Substances can cause skin inflammation by one of two mechanisms— irritation (irritant contact dermatitis) or allergic reaction (allergic contact dermatitis).
  • Irritant contact dermatitis occurs when a chemical substance causes direct damage to the skin.
  • Allergic contact dermatitis is a reaction by the body's immune system to a substance contacting the skin.
  • Atopic dermatitis is one of the most common skin diseases, affecting 15 million people in the United States. Almost 66% of people with the disorder develop it before age 1, and 90% by age 5. In half of these people, the disorder will be gone by the teenage years; in others, it is lifelong. Atopic dermatitis is chronic, itchy inflammation of the upper layers of the skin that often develops in people who have hay fever or asthma and in people who have family members with these conditions.
  • atopic dermatitis Compared to for example psoriasis, which is characterized by sharply demarcated chronic erythematous non-itching plaques covered by silvery white scales, in atopic dermatitis itching is an important clinical symptom that leads to scratching, lichenification and prurigo papules.
  • atopic dermatitis a Th2 mediated immune response is found and cytokines as IL-4 and IL- 13 can be detected.
  • spongiosis and cell death is a hallmark of atopic dermatitis (Leung and Bieber Lancet 361, 151-160 (2003)).
  • the skin pH of atopic dermatitis patients is significantly higher than normal skin (Eberlein-Konig.
  • Treatments include avoiding triggers such as frequent bathing and hydrating of the skin, liberal use of moisturizers and lubricants, the use of (cortico)steroid creams and the use of creams containing an immune modulator, antibiotics, antihistamines and, for adults, phototherapy.
  • nummular dermatitis which is a persistent, usually itchy, rash and inflammation characterized by coin-shaped spots with tiny blisters, scabs, and scales
  • stasis dermatitis which is inflammation on the lower legs from pooling of blood and fluid
  • localized scratch dermatitis lichen simplex chronicus, neurodermatitis
  • pompholyx sometimes called dyshidrosis
  • seborrheic dermatitis which manifests itself by yellowish, oily, scaly patches on the scalp, face, and sometimes other parts of the body
  • dermatitis herpetiformis is a chronic, extremely itchy rash consisting of bumps and blisters and exfoliative dermatitis which is a common clinical condition of multiple skin disorders characterized by widespread scaling, often with itching (prur
  • the present inventors surprisingly found that in dermatitis affected skin the enzyme carbonic anhydrase is upregulated compared to normal skin.
  • carbonic anhydrase now is a target in the treatment of dermatitis. Therefore the present invention provides a method for the treatment of dermatitis, said method comprising administering a therapeutically effective amount of a carbonic anhydrase inhibitor to a subject in need thereof.
  • the present invention concerns the use of an inhibitor of carbonic anhydrase for the preparation of a medicament for the treatment of dermatitis.
  • Carbonic anhydrase in particular carbonic anhydrase 2, is expressed in various tissues of mammals, in particular humans, and is highly active in cells of the renal proximal tubule and in erythrocytes. Carbonic anhydrase is involved in the pH regulation by catalyzing the reaction: H 2 O + CO 2 O H 2 CO 3 in either direction. Depending on the cell type, blocking or inhibiting carbonic anhydrase leads to an alteration in the intracellular pH.
  • the invention concerns the treatment of patients with dermatitis in which itching is one of the symptoms.
  • the invention concerns the treatment of patients with one selected from the group consisting of nummular dermatitis, stasis dermatitis, localized scratch dermatitis (lichen simplex chronicus, neurodermatitis), pompholyx (dyshidrosis), seborrheic dermatitis, dermatitis herpetiformis and exfoliative dermatitis.
  • the present invention is particularly aimed at the treatment of contact dermatitis, in an embodiment either irritant contact dermatitis or allergic contact dermatitis or both.
  • the present invention concerns the treatment of atopic dermatitis.
  • An inhibitor of the enzyme carbonic anhydrase is a compound that, when in the presence of the enzyme and substrate for the enzyme, is capable of reducing the activity of the enzyme compared to the same circumstances of the enzyme when the compound is not present. It is well known to the skilled person to ascertain whether or not a compound is an inhibitor of carbonic anhydrase, using standard enzyme kinetic measurements and using known assays developed for carbonic anhydrase. Suitable assays are described for example in Dodgson et al J Appl Physiol 1990;68:2443-2450, Forster RE. Chapter 6 in SJ Dodgson, et al, eds. The Carbonic Anhydrases: Cellular Physiology and Molecular Genetics.
  • Carbonic anhydrase is a known target for treatment in patients with glaucoma. In the past, these patients were treated with acetazolamide orally. Later, more lipophilic carbonic anhydrase inhibitors, like dorzolamide and brinzolamide, were developed.
  • dorzolamide is used as a topical drug for the treatment of glaucoma. This drug has much less side effects than acetazolamide (Hutzelmann et al. Acta Ophthalmol. Scand. 76, 717-722 (1998)) because of its topical use.
  • Other approved carbonic anhydrase inhibitors include dichlorphenamide and methazolamide.
  • the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, dichlorphenamide and methazolamide.
  • Other effective carbonic anhydrase inhibitors in particular topically effective inhibitors, are reported in for example US 4,383,098, US 4,416,890, US 4,426388, US 4,677,115, US 4,797,413, US 4,820,848, US 4,824,968, US 4,863,922, US 5,157,044, US 5,225424, WO 91/14683 and WO 92/0287 which all are incorporated herein by reference.
  • Also useful inhibitors are reported in for example Puccetti et al. Bioorg Med Chem Lett.
  • the composition is for oral treatment of dermatitis. This is particularly useful for patients with widespread eczema over large parts or the entire body and where a systemic treatment is preferred.
  • acetazolamide, dichlorphenamide and methazolamide are suitable to be used as carbonic anhydrase inhibitor.
  • the carbonic anhydrase inhibitor is selected form the group consisting of acetazolamide and methazolamide. In another embodiment the carbonic anhydrase inhibitor is acetazolamide.
  • the treatment is topical, or in other words that the medicament is suitable for topical application.
  • dorzolamide and brinzolamide are preferred carbonic anhydrase inhibitors to be applied topically for the treatment of dermatitis.
  • the carbonic anhydrase inhibitor in one embodiment in a composition for topical treatment of dermatitis is dorzolamide. In another embodiment the carbonic anhydrase inhibitor is brinzolamide.
  • CA carbonic anhydrase
  • CA2 carbonic anhydrase 2
  • Fig 1 shows real-time PCR of epidermis of normal skin (N) and lesional skin of atopic dermatitis (AD).
  • Fig 2 shows Western blot for CA2 of epidermis of normal skin (N) and atopic dermatitis (AD). Each lane represents a different patient.
  • Fig 3 shows the ELISA result for CA2 for epidermis of normal skin (N) and atopic dermatitis (AD).
  • Fig 4 shows real-time PCR for CA2 of keratinocytes from normal skin, untreated (C) or treated with a mix of ThI cytokines or treated with Th2 cytokines
  • Fig 5 shows a Western blot of CA2 in keratinocytes of normal skin untreated (C), treatment with ThI cytokines or Th2 cytokines.
  • Fig 6 shows the Elisa result of CA2 in cultured keratinocytes of normal skin untreated (C) or treated with ThI or Th2 cytokines.
  • mRNA profiles from epidermis of lesional skin of patients with chronic atopic dermatitis were analysed (see de Jongh et al. J Invest Dermatol 125:1163-1173, 2005 for the methodology used).
  • the analysis was limited to the epidermal compartment to exclude immune cells, blood and connective tissue cells that are mainly present in the dermis.
  • CA2 is expressed at higher levels in AD epidermis than in normal epidermis and in PS epidermis.
  • Carbonic anhydrase 2 is upregulated in atopic dermatitis compared to normal skin
  • CA2 carbonic anhydrase 2
  • mRNA was 8-fold higher in epidermis of atopic dermatitis (AD) patients compared to normal epidermis, see fig 1.
  • More carbonic anhydrase 2 is present in lesional keratinocytes of atopic dermatitis compared to normal skin and psoriasis
  • CA2 expression in epidermis of atopic dermatitis was higher than in normal skin (fig 2).
  • an ELISA was performed with the same protein extracts, revealing that CA2 was increased 2-fold in AD compared to normal skin (fig 3).
  • Carbonic anhydrase 2 is localized in the cytoplasm of mainly subcorneal keratinocytes
  • immunohistochemistry was performed to analyze which cells of the epidermis express CA2, and where in the cell this protein is found.
  • Carbonic anhydrase 2 is upregulated after stimulation with Th2 cytokines
  • ThI cytokine mix consisted of 30 ng/ml IL-l ⁇ , 30 ng/ml TNF- ⁇ and 10 U/ml EFN- ⁇ .
  • Th2 cytokine mix 30 ng/ml IL-4 and IL- 13 was used.
  • CA2 was not upregulated by ThI cytokine stimulation in keratinocytes of normal skin. However, after stimulation with Th2 cytokines, there was an almost 5-fold increase in the amount of CA2 mRNA. This effect was shown in normal keratinocytes, as well as in those of AD patients (not shown), indicating there is not a genetic difference between these groups concerning CA2 upregulation.
  • the upregulation found in microarray analysis in AD skin is probably due to an increase in Th2 cytokines.
  • composition comprising dorzolamide is applied topically on a representative patch of affected skin of a patient with atopic dermatitis.
  • symptoms of atopic dermatitis such as swelling and itching ameliorate compared to an untreated similar patch of skin on the same patient.

Abstract

A treatment for in particular atopic dermatitis is provided by using an inhibitor of carbonic anhydrase.

Description

New use of carbonic anhydrase inhibitors
FIELD OF THE INVENTION
The present invention is in the field of medicaments for the treatment of dermatitis.
BACKGROUND OF THE INVENTION
Eczema, is an inflammation of the skin (dermatitis), typically of the upper layers of the skin, usually characterized by redness, swelling, blister formation, oozing, scabbing, scaling and practically always by itching. Itching is a peculiar tingling or uneasy irritation of the skin that causes a desire to scratch the affected area. The term eczema, which formerly referred to the blistered, oozing state of inflamed skin, has by common usage come to have the same meaning as dermatitis. The inflammatory process in the skin involves the upper dermis and epidermis. The epidermis exhibits swelling of the keratinocytes and accumulation of fluid between them (spongiosis). In the severe form of spongiosis, blisters form within the epidermis.
Some types of dermatitis affect only specific parts of the body, whereas others can occur anywhere. Some types of dermatitis have a known cause; others do not. However, dermatitis is always the skin's way of reacting to severe dryness, scratching, a substance that is causing irritation, or an allergen. Typically, that substance comes in direct contact with the skin, but sometimes the substance is swallowed. In all cases, continuous scratching and rubbing may eventually lead to thickening and hardening of the skin. Dermatitis may be a brief reaction to a substance. In such cases it may produce symptoms, such as itching and redness, for just a few hours or a day or two. Chronic dermatitis persists over a period of time. The hands and feet are particularly vulnerable to chronic dermatitis, because the hands are in frequent contact with many foreign substances and the feet are in the warm, moist conditions created by socks and shoes that favour fungal growth. Because chronic dermatitis produces cracks and blisters in the skin, any type of chronic dermatitis may lead to bacterial infection. A distinction of several types of dermatitis has been made. Two very common types of dermatitis are contact dermatitis and atopic dermatitis. Contact dermatitis is skin inflammation caused by direct contact with a particular substance; the rash is very itchy, is confined to a specific area, and often has clearly defined boundaries. Substances can cause skin inflammation by one of two mechanisms— irritation (irritant contact dermatitis) or allergic reaction (allergic contact dermatitis). Irritant contact dermatitis occurs when a chemical substance causes direct damage to the skin. Allergic contact dermatitis is a reaction by the body's immune system to a substance contacting the skin.
Atopic dermatitis is one of the most common skin diseases, affecting 15 million people in the United States. Almost 66% of people with the disorder develop it before age 1, and 90% by age 5. In half of these people, the disorder will be gone by the teenage years; in others, it is lifelong. Atopic dermatitis is chronic, itchy inflammation of the upper layers of the skin that often develops in people who have hay fever or asthma and in people who have family members with these conditions.
Compared to for example psoriasis, which is characterized by sharply demarcated chronic erythematous non-itching plaques covered by silvery white scales, in atopic dermatitis itching is an important clinical symptom that leads to scratching, lichenification and prurigo papules. In atopic dermatitis a Th2 mediated immune response is found and cytokines as IL-4 and IL- 13 can be detected. At the histological level, spongiosis and cell death is a hallmark of atopic dermatitis (Leung and Bieber Lancet 361, 151-160 (2003)). Furthermore, the skin pH of atopic dermatitis patients is significantly higher than normal skin (Eberlein-Konig. et al. Acta Derm. Venereol. 80, 188-191 (2000)). Since an increase in the surface pH affects the integrity and cohesion of the skin (Hachem et al. J. Invest Dermatol. 121, 345-353 (2003)), this might affect the barrier function of the skin in atopic dermatitis. There is no cure for this common condition. Besides developing a good skin care routine and avoiding things that lead to flares, symptoms are treated when they occur. The main treatments are aimed at controlling and preventing inflammation and itching with topical or oral drugs. Treatments include avoiding triggers such as frequent bathing and hydrating of the skin, liberal use of moisturizers and lubricants, the use of (cortico)steroid creams and the use of creams containing an immune modulator, antibiotics, antihistamines and, for adults, phototherapy. Other types of dermatitis are known such as nummular dermatitis, which is a persistent, usually itchy, rash and inflammation characterized by coin-shaped spots with tiny blisters, scabs, and scales, stasis dermatitis which is inflammation on the lower legs from pooling of blood and fluid, localized scratch dermatitis (lichen simplex chronicus, neurodermatitis) which is chronic, itchy inflammation of the top layer of the skin, pompholyx (sometimes called dyshidrosis) which is a chronic dermatitis characterized by itchy blisters on the palms and sides of the fingers and sometimes on the soles of the feet, seborrheic dermatitis which manifests itself by yellowish, oily, scaly patches on the scalp, face, and sometimes other parts of the body, dermatitis herpetiformis is a chronic, extremely itchy rash consisting of bumps and blisters and exfoliative dermatitis which is a common clinical condition of multiple skin disorders characterized by widespread scaling, often with itching (pruritus), skin redness (erythroderma), and hair loss.
Since no cure for dermatitis exists, there is an ongoing need for new treatments of this condition and/or at least for the treatments of symptoms of this condition, of which itching is considered particularly annoying and bothersome as itching triggers scratching which triggers and/or deteriorates other symptoms such as swelling, blister formation, oozing, scabbing and scaling. SUMMARY OF THE INVENTION
The present inventors surprisingly found that in dermatitis affected skin the enzyme carbonic anhydrase is upregulated compared to normal skin. In view of this finding carbonic anhydrase now is a target in the treatment of dermatitis. Therefore the present invention provides a method for the treatment of dermatitis, said method comprising administering a therapeutically effective amount of a carbonic anhydrase inhibitor to a subject in need thereof. In other words the present invention concerns the use of an inhibitor of carbonic anhydrase for the preparation of a medicament for the treatment of dermatitis.
DETAILED DESCRIPTION OF THE INVENTION
Carbonic anhydrase, in particular carbonic anhydrase 2, is expressed in various tissues of mammals, in particular humans, and is highly active in cells of the renal proximal tubule and in erythrocytes. Carbonic anhydrase is involved in the pH regulation by catalyzing the reaction: H2O + CO2 O H2CO3 in either direction. Depending on the cell type, blocking or inhibiting carbonic anhydrase leads to an alteration in the intracellular pH. In bovine corneal epithelial cells, blocking of carbonic anhydrase resulted in an slight decrease in the intracellular pH, while cells of the chorioid plexus show an increase in the pH following treatment with an inhibitor of carbonic anhydrase (Bonanno et al. Exp. Eye Res. 60, 425-434 (1995)). Furthermore, carbonic anhydrase plays a major role in osteoclast differentiation and bone resorption by affecting the steady state intracellular pH and calcium.
Carbonic anhydrase now has become a target for the treatment of patients with dermatitis. In one embodiment the invention concerns the treatment of patients with dermatitis in which itching is one of the symptoms. In an embodiment the invention concerns the treatment of patients with one selected from the group consisting of nummular dermatitis, stasis dermatitis, localized scratch dermatitis (lichen simplex chronicus, neurodermatitis), pompholyx (dyshidrosis), seborrheic dermatitis, dermatitis herpetiformis and exfoliative dermatitis. The present invention is particularly aimed at the treatment of contact dermatitis, in an embodiment either irritant contact dermatitis or allergic contact dermatitis or both. In a preferred embodiment the present invention concerns the treatment of atopic dermatitis.
An inhibitor of the enzyme carbonic anhydrase is a compound that, when in the presence of the enzyme and substrate for the enzyme, is capable of reducing the activity of the enzyme compared to the same circumstances of the enzyme when the compound is not present. It is well known to the skilled person to ascertain whether or not a compound is an inhibitor of carbonic anhydrase, using standard enzyme kinetic measurements and using known assays developed for carbonic anhydrase. Suitable assays are described for example in Dodgson et al J Appl Physiol 1990;68:2443-2450, Forster RE. Chapter 6 in SJ Dodgson, et al, eds. The Carbonic Anhydrases: Cellular Physiology and Molecular Genetics. New York:Plenum Press;1991:79-98., Bruns W, Gros G. Chapter 9 in SJ Dodgson, et al, eds. The Carbonic Anhydrases: Cellular Physiology and Molecular Genetics. New York:Plenum Press; 1991:127-131, and Stadie and O'Brien J Biochem 1933;103:521-529.
Several specific inhibitors for carbonic anhydrase are known. Carbonic anhydrase is a known target for treatment in patients with glaucoma. In the past, these patients were treated with acetazolamide orally. Later, more lipophilic carbonic anhydrase inhibitors, like dorzolamide and brinzolamide, were developed. Nowadays, dorzolamide is used as a topical drug for the treatment of glaucoma. This drug has much less side effects than acetazolamide (Hutzelmann et al. Acta Ophthalmol. Scand. 76, 717-722 (1998)) because of its topical use. Other approved carbonic anhydrase inhibitors include dichlorphenamide and methazolamide.
Therefore in one embodiment according to the present invention the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, dichlorphenamide and methazolamide. Other effective carbonic anhydrase inhibitors, in particular topically effective inhibitors, are reported in for example US 4,383,098, US 4,416,890, US 4,426388, US 4,677,115, US 4,797,413, US 4,820,848, US 4,824,968, US 4,863,922, US 5,157,044, US 5,225424, WO 91/14683 and WO 92/0287 which all are incorporated herein by reference. Also useful inhibitors are reported in for example Puccetti et al. Bioorg Med Chem Lett. 2005 May 2;15(9):2359-64; Winum Jet al. Bioorg Med Chem Lett. 2005 Feb l;15(3):579-84; Cecchi et al. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5775-80; Bonnac et al. J Enzyme Inhib Med Chem. 2004 Jun;19(3):275-8; Innocenti et al. J Med Chem. 2004 Oct 7;47(21):5224-9; Garaj et al. Bioorg Med Chem Lett. 2004 Nov l;14(21):5427-33 which all are incorporated herein by reference.
In general terms the skilled person will be aware that certain types of sulfonamides and sulfamates can be suitable inhibitors of carbonic anhydrase, in particular heteroaromatic nitrogen containing sulfonamides and sulfamates. In one embodiment according to the present invention the composition is for oral treatment of dermatitis. This is particularly useful for patients with widespread eczema over large parts or the entire body and where a systemic treatment is preferred. In case of a composition for oral treatment, acetazolamide, dichlorphenamide and methazolamide are suitable to be used as carbonic anhydrase inhibitor. In one embodiment in a composition for oral treatment of dermatitis the carbonic anhydrase inhibitor is selected form the group consisting of acetazolamide and methazolamide. In another embodiment the carbonic anhydrase inhibitor is acetazolamide.
However, in view of the local and topical character of dermatitis and of the side effects of carbonic anhydrase inhibitors when administered enterally, it is preferred according to the present invention that the treatment is topical, or in other words that the medicament is suitable for topical application. Further, because of their proven topical effectiveness, according to the present invention dorzolamide and brinzolamide are preferred carbonic anhydrase inhibitors to be applied topically for the treatment of dermatitis. In one embodiment in a composition for topical treatment of dermatitis the carbonic anhydrase inhibitor is dorzolamide. In another embodiment the carbonic anhydrase inhibitor is brinzolamide.
Several isoenzymes of carbonic anhydrase (CA) are known, such as CAl, CA2, CA3, CA4, CA5 and CA6. In one embodiment the present invention relates to human carbonic anhydrase, and in a preferred embodiment to carbonic anhydrase 2 (CA2). It is well within the reach of one skilled in the art to formulate a carbonic anhydrase inhibitor into a preparation or composition suitable to be administered for the treatment of dermatitis, in particular to formulate a preparation or composition suitable for topical application. It is also well within the reach of one skilled in the art to select an effective amount and/or optimize the concentration of the carbonic anhydrase inhibitor in a preparation or composition suitable for the treatment of dermatitis, in particular suitable for topical treatment of dermatitis. DESCRIPTION OF THE FIGURES
Fig 1 shows real-time PCR of epidermis of normal skin (N) and lesional skin of atopic dermatitis (AD).
Fig 2 shows Western blot for CA2 of epidermis of normal skin (N) and atopic dermatitis (AD). Each lane represents a different patient.
Fig 3 shows the ELISA result for CA2 for epidermis of normal skin (N) and atopic dermatitis (AD).
Fig 4 shows real-time PCR for CA2 of keratinocytes from normal skin, untreated (C) or treated with a mix of ThI cytokines or treated with Th2 cytokines
Fig 5 shows a Western blot of CA2 in keratinocytes of normal skin untreated (C), treatment with ThI cytokines or Th2 cytokines.
Fig 6 shows the Elisa result of CA2 in cultured keratinocytes of normal skin untreated (C) or treated with ThI or Th2 cytokines. EXAMPLES
Using microarray analysis, mRNA profiles from epidermis of lesional skin of patients with chronic atopic dermatitis were analysed (see de Jongh et al. J Invest Dermatol 125:1163-1173, 2005 for the methodology used). The analysis was limited to the epidermal compartment to exclude immune cells, blood and connective tissue cells that are mainly present in the dermis. In this analysis it was found that CA2 is expressed at higher levels in AD epidermis than in normal epidermis and in PS epidermis.
Results
Carbonic anhydrase 2 is upregulated in atopic dermatitis compared to normal skin With real-time PCR analysis it was found that the epidermal amount of carbonic anhydrase, in particular carbonic anhydrase 2 (CA2), mRNA was 8-fold higher in epidermis of atopic dermatitis (AD) patients compared to normal epidermis, see fig 1.
More carbonic anhydrase 2 is present in lesional keratinocytes of atopic dermatitis compared to normal skin and psoriasis
To analyze whether the changes in CA2 mRNA result in changes in protein level, the expression of this protein using Western blotting was analysed. Clearly, CA2 expression in epidermis of atopic dermatitis was higher than in normal skin (fig 2). To be able to quantify the amount of CA2, an ELISA was performed with the same protein extracts, revealing that CA2 was increased 2-fold in AD compared to normal skin (fig 3). Carbonic anhydrase 2 is localized in the cytoplasm of mainly subcorneal keratinocytes Next, immunohistochemistry was performed to analyze which cells of the epidermis express CA2, and where in the cell this protein is found. For this, sections of normal skin, lesional skin of AD was incubated with antibodies to CA2, followed by AEC staining. This revealed staining of the keratinocytes, mainly in those residing in the upper layers of the epidermis, while keratinocytes of the basal layer showed weaker staining (data not shown). The subcellular localization of CA2 was cytoplasmic.
Carbonic anhydrase 2 is upregulated after stimulation with Th2 cytokines
Atopic dermatitis is a Th2 mediated immune response whereas for example in psoriasis mainly ThI cytokines are present. To examine the influence of ThI and Th2 cytokines on the expression of CA2, keratinocytes of normal skin were cultered in dishes. At confluence, cells were left untreated or stimulated with either ThI cytokines or Th2 cytokines. ThI cytokine mix consisted of 30 ng/ml IL-lα, 30 ng/ml TNF- α and 10 U/ml EFN-γ. As Th2 cytokine mix, 30 ng/ml IL-4 and IL- 13 was used. After 2 days of stimulation, Trizol was added for RNA extraction or cells were harvested for cell lysis to obtain protein. A real-time PCR was carried out, see fig 4. CA2 was not upregulated by ThI cytokine stimulation in keratinocytes of normal skin. However, after stimulation with Th2 cytokines, there was an almost 5-fold increase in the amount of CA2 mRNA. This effect was shown in normal keratinocytes, as well as in those of AD patients (not shown), indicating there is not a genetic difference between these groups concerning CA2 upregulation. The upregulation found in microarray analysis in AD skin is probably due to an increase in Th2 cytokines. Also the CA2 protein level of normal skin keratinocytes after stimulation with Th2 cytokines was increased (figure 5 and figure 6). In order to analyze whether IL-4 or IL- 13 was responsible for this increase, the experiment was repeated with IL-4 and IL- 13 added separately and incubated for 5 hours, 1 day or 2 days. Both IL-4 and IL- 13 stimulation had no effect after 5 hours of incubation. However, after 1 day of stimulation, a significant increase in the amount of CA2 in the IL-4 stimulated group, in contrast to the IL- 13 stimulated group was found (data not shown). After 2 days, both groups show a significant increase in CA2. No additional effect can be found by stimulating with both cytokines (not shown). Without being bound by theory it is hypothesized that the increase in pH of the epidermis of patients with AD is a result of overexpression of CA2, which may participate in the onset of AD or its severity. By inhibiting CA2 in the epidermis, less cell death and spongiosis as result of cell death occurs, leading to an improvement of the skin symptoms and a decrease in itching.
Treatment of atopic dermatitis
In an un-optimized test a composition comprising dorzolamide is applied topically on a representative patch of affected skin of a patient with atopic dermatitis. Upon prolonged treatment several times per day the symptoms of atopic dermatitis such as swelling and itching ameliorate compared to an untreated similar patch of skin on the same patient.

Claims

Claims
1. Use of an inhibitor of carbonic anhydrase for the preparation of a medicament for the treatment of dermatitis.
2. Use according to claim 1 wherein the medicament is for the treatment of contact dermatitis.
3. Use according to claim 2 wherein the medicament is for the treatment of irritant contact dermatitis
4. Use according to claim 1 wherein the medicament is for the treatment of atopic dermatitis.
5. Use according to any one of claims 1-4 wherein the inhibitor of carbonic anhydrase is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, dichlorphenamide and methazolamide.
6. Use according to any one of claims 1-5 wherein the medicament is for oral use.
7. Use according to claim 6 wherein the inhibitor of carbonic anhydrase is selected form the group consisting of acetazolamide and methazolamide.
8. Use according to any one of claims 1-5 wherein the medicament is for topical use.
9. Use according to claim 8 wherein the inhibitor of carbonic anhydrase is selected from the group consisting of dorzolamide and brinzolamide.
PCT/NL2005/050070 2005-12-09 2005-12-09 New use of carbonic anhydrase inhibitors WO2007067036A2 (en)

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WO2017058370A1 (en) * 2015-09-30 2017-04-06 Rutgers, The State University Of New Jersey Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type 2 inflammation
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Publication number Priority date Publication date Assignee Title
US9623000B2 (en) 2008-07-31 2017-04-18 Dekel Pharmaceuticals Ltd Compositions and methods for treating inflammatory disorders
WO2010061185A3 (en) * 2008-11-25 2010-08-19 Union Life Sciences Ltd Carbonic anhydrase inhibitors for treating dandruff and related disorders
WO2017058370A1 (en) * 2015-09-30 2017-04-06 Rutgers, The State University Of New Jersey Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type 2 inflammation
US10758537B2 (en) 2015-09-30 2020-09-01 Rutgers, The State University Of New Jersey Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type 2 inflammation
US11406637B2 (en) 2015-09-30 2022-08-09 Rutgers, The State University Of New Jersey Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type 2 inflammation

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