CA2076699A1 - Compositions for topical treatment of psoriasis and atopic dermatitis - Google Patents
Compositions for topical treatment of psoriasis and atopic dermatitisInfo
- Publication number
- CA2076699A1 CA2076699A1 CA002076699A CA2076699A CA2076699A1 CA 2076699 A1 CA2076699 A1 CA 2076699A1 CA 002076699 A CA002076699 A CA 002076699A CA 2076699 A CA2076699 A CA 2076699A CA 2076699 A1 CA2076699 A1 CA 2076699A1
- Authority
- CA
- Canada
- Prior art keywords
- pentoxifylline
- psoriasis
- cholecalciferol
- derivatives
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 52
- 201000004681 Psoriasis Diseases 0.000 title claims abstract description 36
- 230000000699 topical effect Effects 0.000 title claims abstract description 33
- 206010012438 Dermatitis atopic Diseases 0.000 title claims abstract description 22
- 201000008937 atopic dermatitis Diseases 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title claims description 26
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960001476 pentoxifylline Drugs 0.000 claims abstract description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 229960002934 propentofylline Drugs 0.000 claims abstract description 19
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 claims abstract description 18
- QSXXLDDWVCEBFP-UHFFFAOYSA-N 7-(ethoxymethyl)-1-(5-hydroxy-5-methylhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)(C)O)C(=O)C2=C1N=CN2COCC QSXXLDDWVCEBFP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229950011536 torbafylline Drugs 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 13
- 150000003431 steroids Chemical class 0.000 claims description 12
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- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 claims description 10
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 claims description 8
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- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 claims description 8
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 claims description 8
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 claims description 8
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- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
Use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline for topical treatment of psoriasis or atopic dermatitis and pharmaceutical compositions comprising them.
Use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline for topical treatment of psoriasis or atopic dermatitis and pharmaceutical compositions comprising them.
Description
2~76~99 ~ .
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Compositions for topical treatment oî psoriasis and atopic dermatitis, comprising a xantlline derivative .
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FIELD OF THE INVENTION
This invention relates to topical pharmaceutical composltions ;for and~a method~ ~of treating inflammatory~ and~ proliferat*e skin~ diseases such~ as~ psoriasis and atopic dermatitis.
BACKGROUND~OFTHEIN~ENTION~
Psoriasis is a~ common~ chronic relapsing inf~am-matory skin ;d;~sease~;~which~àf~ects 1-3% of the~ population.~It~is~characterised~by the clrcumscrlbed~ scaling erythomatous~plaques ;of:~various: s~zes and ~forms 10 ~ ~; which;~in~somè cases may~ extend to more~than SQ%~ of the skin~area. Thepsoriatic condition is composed of two~;main~ processes: cellular hyper-proliferation~and inflammation Despité extensive research the etiology of ~the . . : :
disease is still;unknown. ` ~
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~07669g Psoriasis is currently treated by a number of methods which include topical applications consisting of tar derivatives, steroids, vitamin D
and its derivatives or vitamin A and its derivatives (J.P. Callen, Drug Therapy, April 1987, pp. 29-35). These therapies are only partially S successful and may be accompanied by undesired side affects. Thus although steroids can be very effective, they are also frequently associated with side effects. Other therapies include phototherapy with or without concomitant systemic administration of psoralen derivatives. Additionally, systemic administration of steroic!s, methotrexate and cyclosporine have been used for treatment of severe cases of psoriasis. All of these therapies are associated with side effects. There is thus an urgent need for new effective, non-toxic therapeutics for psoriasis.
Atopic dermatitis is a chronic skin condition of unknown etiology, and which may be continuous from infancy to adulthood. There is about 4% incidence of atopic dermatitis from birth to 7 years (Halpern et al., J. Allergy Clin. Immunol. 51:139-151 (1973)). In childhood, it is charaçter-ized by papules, erytherna, thickening and lichenification. In the adolescent, Ihe main symptoms are thickening and lichenification with erythema and scaling. Pruritis is a general feature of the disease. Systemic therapy includesantihistamine drugs and steroids, but the latter are reserved for unmanage-able cases and used for the shortest period possible. Topical therapy includes fluorinated and fluorochlorinated corticosteroid preparations, but striae and cataracts are likely complications. Clearly there is as yet no satisfactory and safe drug treatment for atopis dermatitis. ~ ~
Xanth;ne derivatives have been proposed for the treatment of psoriasis and atopic dermatitis. US 4jl41,976 proposes certain pharmaceuti-cal preparations for the topical treatment of psoriasis. Among the compounds described are certain substituted alkylxanthme derivatives and subs~ituted thioxanthines. However data demonstratmg efhc~iveness is~shown ooly for ' .
,J' ' ~
2~76699 RO 20-17"4 (d,1-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, which is not a xanthine derivative. There is no data showing that the xanthine clerivatives are effective therapeutics when topically administered to patients suffering from proliferative skin disease.
S WO 9101730 describes the use of certain xanthine clerivatives for the treatment of asthma, urticaria, eczema and rhinitis. Suggested modes of administration are listed as oral, rectal, topical, parenteral, intravenous, or intramuscular or through the respiratory tract. EP 195,496 describes the use of certain xanthine derivatives for treating proliferative skin disease such as psoriasis. The xanthine derivatives are administered orally. US 4,716,165 describes the use of certain theobromine derivatives for treating asthma, allergic rhinitis, atopic dermatitis or eczema. WO 8905145 describes the use of certain xanthine derivatives for the treatment of a wide variety o~ disease states inclucling psoriasis. EP 260,127 describes the oral administration of certain xanthine derivatives for the treatment of proliferative skin disease.
US 4,341,783 describes the use of topical dyphylline for the treatment of psoriasis. There is no $eaching or suggestion in any of the above-listed patents and patent applications that the topical administration of the compounds of the instant invention would be more effective in the treatmen$
of psoriasis or atopic dermatitis than the topical application of other xanthinederivatives described in the above-cited patents and patent applications.
Ravid et al. (Ravid et al., J. Allergy Clin. Immunol. 86:881-885 (1990) and J. Clin. Endocrinol. Metab. 70:1687-1692 (1990)) have shown that certain compounds which increase the levels of cyclic adenosine monophosphate (cAMP) are capable of inhibiting the mitogenic induced proliferation of pheripheral bloocl mononuclear cells (PBMC) from both healthy and atopic patients. The only~ xanthine derivative tested in these articles was isobutylmethylxanthine (IBMX). However, there is no teaching or suggestion in these publications that other xanthine derivatives may have {~
different or supeIior properties to IBMX. There is certainly no mention of pentoxifylline (PTX), propentofylline (PPF) or torbafylline (TBF).
Pentoxifylline (PTX) (3,7-dimethyl~ 5-oxohexyl)-xanthine), propentofylline (PPF) (3-methyl-7-propyl-1-(5-oxohexyl)-S xanthine,) and torbafylline (TBE;) (3-methyl-7-ethoxymethyl-1-(~-hydroxy-5-methylhexyl)-,Yanthine are related methyl-xanthine derivatives which are well known in the art for treatment of a variety of disease states.
PTX is widely used systemically for the treatment of peripheral vasçular diseases. PTX and PPF have been administered systemically for the 10 treatment of senile d~mentia whil,e s,ystemic administration of TBF is under investigation for treatment of,senile dementia, peripheral vascular disease and myopathy.
PTX has been used systemically for the treatment of various cutaneous lesions associated with or due to impaired or deficient blood flow 15 in the dermis layer of skin ancl its effectiveness in the treatment of peripheral vascular diseases is describecl by H. Ely, Dermatologic Clinics 6:585-608 (1988). There is no teaching that PTX, or any of its congeners, PPF or TBF, were effeçtive in the treatment of psoriasis or atopic dermatitis, which are lesions of the epidermis layer of the slcin rather than one of the 20 peripheral blood vessels.
DET~ILEO DESCRIPIION OF THE INVENTION
ln acsordance with the present invention it has surprisingly been found Ihat the topical administration of a~pharmaceutlcal composition 25 comprising a compound selected from the group of pentoxifylline, propento-fylline and torbafylline dramatically improves the psoriatic lesions of patients, Most surprisingly the improvement is greater~ than that achieved with other xanthine derivatives such as dyphylline which are taught in the prior art as useful for the topical treatment of psorlatic lesions.
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~ 20766~
-- s --Accordingly, the present invention provides a pharmaceutical composition for the topical treatment of psoriasis or atopic dermatitis comprising an effective amount of an active compound selected from the group of pentoxifylline, propentofylline and torbafylline, and a pharmaceuti-cally acceptable carrier.
Preferably the concentration of the active compound is about 0.5%-5% (w/w). When the active compound is pentoxifylline its concen-tration is preferably 2% (w/w).
If desired, the compositions according to the invention may 10 additionally contain thërapeut~cally effectlve amounts of one or more compound which are known to be of use in the topical treatment of psoriasis and atopic dermatitis. These compounds are well known to those skilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and analogs, tar derivatives, steroids, vitamin A and its derivatives 15 vitamin D and its derivatives including l-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-cholecalciferol, 24,25-dihydroxy-cholecalciferol, 1,24-dihydroxy-cholecalciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
In addition or instead, the campositions according to the 20 invontion may contain one or more of the compounds adenosine and related purlnes, lipoxygenase inhibitors, substanco P an~agonists, delta~tocopherol, 2-heptanone, and fatty aclds and their esiers such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
The pharmaceutically acceptable carrier of the compositions 25 according to the invention may contain any of the components which are used in topical compositions and are well known to those skilled in the art.
:
If desired, thè pharmaceutically acceptable carrier of the compositions according to the invention may also contain penetration :
, , ' - 6 - 2076S~9 enhancers such as urea, lactic acid, ammonium lactate, salicylic acid or a C3-Cl~-straight chain alkanoic acid.
The compos;tions may be in the form of lotions, creams, ointments and gels, and also in the form of sprayable aerosols. Preferred S formulations of the compositions accorcling to the invention are creams, s which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, typically polyoxy-40-stearate.
The invention also ~rovides. a method for the treatment of a subject suffering from psoriasis or atopic dermatitis comprising topically applying to the subject a therapeutically effective amount of an active compound selected from the group consisting of pentoxifylline, propent-ofylline and torbafylline if c!esired together with a pharmaceutically acceptable carrier.
The preferred active compound for the performance of the method according to the invention is pentoxifylline.
If desired the said active compound may be applied together with a tkerapeutically effective amount of one or more additional compounds which are known to ~e of use in the topical troatment of psoriasis and atopic dermatitis. These compounds are well known to those sXilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and~analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, or vitamin D and its derivatives including 1-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-:
cholecalciferol24,25-dihydroxy-cholecalciferol,1,24-dihydroxy-cllolecal-ciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
Also if desired the said active substance may be applied together with an effective amount of at least one member of the group of adenosine and related purines, lipooxygenase inhibitors, ,ubstance P
2~ 39 , antagonists, delta tocopherol, ~-heptanone, and fatty acids and their esters such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
Still further the invention provides for use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline Eor the preparation of pharmaceutical compositions for the topical treatment of human patients suffering from psoriasis or atopic dermatitis.
BRIEF DESCRI~I:ION OF THE PICTURES
In the following E~ample 1 the advantages achieved in accordance with the invention are described, i.a. with reference to the annexed pictures in which:
Fig. 1 shows photomicrographs of transverse sections of human psoriatic skin transplants before and after treatment; and Fig. 2 shows two further similar photomicrographs.
Some embodiments of the present invention will now be described and exemplified in the following Examples, it being understood tha~ the invention is not limited thereto.
20 ~XAMPLE 1 . ~ Formulations A. Pentoxifylline was formulated mto a cream for topical application as follows:
:
207~99 ~o w/w Stearic Acid 15.0 Cetyl Alcohol 1.0 White Petrolatum 3.0 Polyoxy 40 Stearate 4.0 Methyl Paraben 0.025 Propyl Paraben 0.015 Pentoxifylline (PTX) 2.0 Propylene Glycol 9.5 Sorbitol 7.5 Purified Water To make up 100%
, ~
This formulation was used in Fxamples 2 and i.
15 B. Additional cream formulations of pentoxifylline suitable for topical application was prepared as follows:
: %w/w ~: :
:
Pentoxifylline (PTX) 2.0 ; 20 Urea 5.0 Lactic Acid ~ 2.0 Germaben ll 1.0 ~: : Sorbitol~70 solution : ; : 4.0 Glycerin ~ 4.0 ~ White Petrolatum ~ 3.0 Glyceryl monostearate : ~: ;3.0 : : Cetyl~ alcohol ~ 3.5 Heavy~ mineral o~ : IO.O
Eutanol G -Octylclodecanol : 5.0 ~ Acetylated lanolin (ModulanTM)~; 3.0 Myrg 52TM ~ ~ ~ 3.0 Span 601'M ~ .5 Ammonia solution to adjust pH to 4.S
Water ~ ~ To make up lOO%
:
:
, ~ : ;
.
,, 9_ ~76699 C. Pentoxifylline was formulated into an ointment for topical application as follows:
% wlw MîglyolT~I 840--B Gel 10.0 Eutanol G -Octyldodecanol 17~0 Cril 6 -Glyceryl isostearate 3.0 Hard paraffin wax 3.0 Zinc stearate 1.0 Amphisol K 0.5 Germaben II 1.0 Magnesium sulfate 0.2 Urea 10.0 Pentoxifylline (PTX) 2.0 Puri~ied water To make up to 100%
D. Pentoxifylline was formulated into a gel suitable for topical application as follows:
;%w/w Pentoxifylline (PTX) 2.0 Carbopol 940TM 1.5 Triethanolamine 1.5 Water 95.0 :
Nude mice with transplanted human skin Human psoriatic skin from psoriatic patients was transplanted to nude mice essentially according to the method of G. Kreuger et al., Prog.
S in Dermatol. 12:17-22 (1978) as modified by A. &ilhar et al., Exp. Cell Biol. 54:263-274 (1986). The donors had stable plaque type psoriasis for at least one year preceding biopsy and had not received systemic anti-psoriatic therapy for the 4 weeks preceding biopsy. They had also not received topical therapy or U.V. therapy for the two weeks preceding biopsy. The severity of the psoriat}c lesion ~as evaluated and the PASI index was calculated as described by Fredrikson and Petterson (Der~natolo~ica 157:238-244 (1978)).
In this method the area (A) of the psoriasis in four main body parts (head (H), trunk (T), upper extremities (U) and lower extremities (L)) is assigned a value from 0-6 depending on the extent of psoriasis where O reflects no involvement and 6 reflects 90-100% involvement. The severity of the lesion is assessed based on three parameters: Erythema ~E), Desquamation (scaling) (D) and Infiltration (1). The severity of each of these parameters is measured on a scale of 0-4 where 0 is no involvement and 4 is very severe. The total severity score is calculated according to the following formula:
Severity score = V.l(EH ~ + D~)A~ ~ 0.2(EU ~ lu ~DU)AU
3(~T lT DT)AT + 0 4(EL +: IL + D~)AL
Split thickness blopsies of nonpustular psorlatic human tissue, 4x5 cm and 0.4mm thick were obtained from the edge of established plaques from various donor patients. Each specimen was divided~ into sections as follows: 4-5 s ctions, 2x2 mm each for thymidine incorporation and subsequent autoradiography in order to assess the rate of proliferation in the epidermis; 1-2 sections 0.5x1 cm each for histological examination prior to grafting in order to evaluate the severity of the disease, as quantitated by the ~ .
. ~ , 207669~
measure of epidermal thickness; and 3 sections 1.5 x 1 cm each for grafling on the dorsal side of each of three different nude mice. The grafts were allowed to heal for one week prior to topical appl;cation of the test preparations.
Outbred Balb/C nude mice, ~ to 3 months of age were used in this study. The mice were obtained from the pathogen free animal breeding facility at the University of Tel Aviv (Israel) and were raised in the pathogen-free animal facility at the Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
~ Following-?the one week healing period the graft area was treated daily with the test drug in a cream c~mposition according to ` Example 1 or vehicle alone by applying 200 ,ul of the preparation, once at 08:00 and once at 21:00 for the duration of 7 days.
On the day following the end of treatment the severity of the psoriatic lesion was assessed and then the animals were sacrificed and the entire graft was excised and divicled into two equal sections~ One section was used to assess changes in the rate of proliferation by autoradiography (tritiated thymidine incorporation) while the other section was sectioned for microscopic histological assessment, including acanthosis and parakeratosis.
Table 1 shows the effect of the topical preparations tested on human psoriatic skin transpiantcd In nude mice according to the procedure outlined above. The results of the experiment shown in Table 1 demonstrate that pentoxifylline is almost~ as effective as steroids in treating psoriasis and far more effective than dyphylline, a related xanthine which was shown to 2~ be virtually inactfve 2~76~9 = -O ~ O a~
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2076~99 ~ 13 --In another series of experimen-ts, human psoriatic skin of various severities was transplanted on each of 28 nude mice. The graft area was treated with various preparations as described above.
Table 2 shows the results of the application of topical skin ` 5 formulations to transplantcd human psoriatic skin in each of the 28 nude mice. The results are expressed as a success ratio where success is defined as a decrease of at least 15% in epidermal thickness (acanthosis) as a result of the 7 day topical treatment. The treatments were applied as creams and were administered as described above.
The experiment shown in Tab]e 2 demonstrates that pento-xifylline is almost as effective as topical steroids in treating psoriasis and far more effective than dyphylline which was inactive.
In summary the experiments performed with the animal model for psoriasis described above present a clear indication that PTX is effective 15 ;n the treatment of psoriasis.
:~RE~hlENT
2% Pentoxifylline* 6/10 8% Dyphylline ~ ~0/2 0~05% topical steroid~* 7/10 Placebo 0/6 * Cream co mposltion prepared accordmg to the formulation given ln ; 25 Example lA.
** The topical steroid was either 0.05% clobetasol propionate ointment (Dermovate~ -Glaxo) or 0.05% betametasone dipropionate crear (DiprosonelM Schering U.S.A.).
' ' ., .
2076~99 Fig. 1 shows photomicrographs of representative examples of transverse human psoriatic skin transplant sections. The transplants were made as described above and were all taken from the same patient.
Panel A shows a transplant before treatment and panels B and G show transplants after daily treatments for seven days with the 2% PTX
cream of Example 1 and an 0.05% clobetasol propionate ointment, respectively.
Fig. 2 shows similar photomicrographs be~ore and after daily treatment for seven days with 8% dyphylline.
Inhibition of Human Psoriatic Fibroblast Proliferation As excess proliferation of fibroblasts is one of the symptoms of psoriasis, the inhibition of fibroblasts proliferation was used as a test to determine the uti]ity of the drugs of the present invention in the treatment of psoriasis. PTX and PPF, alone as well as PTX in combination with other drugs were tested.
Human psoriatic ~ibroblasts were obtained from slcin biopsies of 5 individuals with plaque psoriasis. Cells in the 3-7th passages~were used for the experiments. Human psoriatic fibroblasts (4x103-6x103 cells) were ~ added in 24 well plates and cultured in Dulbecco's Modi~led Eagle's ;~ Medium (DMEM~ supplemented with~ lO% fetal~ caif serum, 2mM L-;
glutamine, 100 u/ml penicillin, 100 !lg/ml streptomycin (DMEM+) at~5%
C2 and 95% humidity at 37C.
:
~fter 3 days, rnedium was replaced with fresh DMEM~
(control) or with medium containing various concentrations of compounds alone or in combination with~pen~oxifylline and incubation was continued for additional 3 days. Stock solutions ~(10-' - 10-2 M) of the compounds tested were made in ethanol. For these compounds speci l control (DMEM+
, 2076~99 with 1~o ethanol) was made. The compounds tested together with pentoxi-fylline were 3-heptanone, 3,3-dimethylbutyric acid, lipoic acid, 1,25-dihydroxyvitamin D3 betamethasone dipropionate and hydrocortisone-17-butyrate.
On the last day of experiments, the medium was aspirated and the cells were obtained by trypsinization. The number of cells in each well was counted by the use of an hemocytometer.
The percentage of inhibition of fibroblast proliferation was calculated according to the formula:
100 amount of fibroblasts in the well in the presence of the drug 100 amoullt of fibroblasts ~n the well itl the abse~ce of the drug and the results are shown in Tables 3 and 4 ~C~mpo~ ' l coi~cèhtràtion ` `~ % I nhi~itio'n~ of;Prolifèràtion ~"~ ~additionàl~
~ . . . d ru g ( ) ~
Pentoxifylline (PTX) _ 3.7 16.9 2-Heptanone 10-5 N.D. 21.3 10-4 21.0 26.4 10-3 18.6 _ 45 _ 3,3dimethyl 10-4 - 19.3 1?.2 butyricacid 10-3 _ 36.3 21 Lipoicacid 1~-4 14;3 _ 50.2 1,25(0H)~D3 10-7 49 S N D
Betamethasone 10-7 43 .1 N.D.
dipropionate 10-4 _ 55.8 77.5 hydrocortisone 10-5 ~ N.D. 41.9 17-butyrate 10-5 N.D. 51.2 _ _ _ - _ N.D. = Not Determined 1,25(0H~)D3 is 1,25-dihydroxyvitamin D3 ~ 2~76699 ., ~ _ ~u~Compound ~ ~ Concentration~ ~ Inhibition of .~ ~ ~ (M)~-~`` ~ ji ti n Pentoxifylline 1()-~ ~.9 S (PTX) 10-' 16.9 + 4 8 Propentofylline 10-~ 20.3 + 6-6 (PPF) 10-3 39.0 + 7 _ _ ~ _ These results show that the drugs of the present invention do inhibit the proli~ration of fibroblasts which indicate their potential utility in treating psoriasis. The results are satisfactory both when these drugs are applied as the anly active compound and when they are applied in combination with other drugs.
EXA~PLE 4 Inhibit;on of the Mitogenic Stimulatinn of Human Lymphocvtes Studies in the literature have shown that atopic dermatitis is transferable by bone marrow Eells indicating that primary site of disease is in the immune and inflammatory cells which infiltrate the skin. Thus the Iymphocy~es are thought to be one of the targets for treatment of the disease.
Also, various cells (in:cluding Iymphocytes) and organs der;ved from atopic subjects showéd.a conimon impaired response to cAMP agonists. Thus the study of atopic Iymphocytes behavior in response to various agents is predictive of the atopic individuals response to these agents.
Studies have shown that cAMP agonists have an inhibitory effect on the mitogenic stimulation of peripheral blood mononuclear cells (PBMC) from atopic subjects (Ravid et al., J. Allergy Clin. Immunol.
86:881-885 (1990)). In these studies it was found that those compounds which have an inhibitory effect on PBMC from atopic subjects have a similar inhibitory effect on PBMC from healthy subjects. The primary -2~7~
difference noted was one of degree; the inhibitory effect on cells from atopic subjects was reduced when compared to healthy individuals. It was also shown that steroids such as dexamethasone, which are used in the treatment of atopic dermatitis, inhibited the mitogenic stimulation of PBMC. Thus the S inhibitory effect of certain compouncls on the mitogenic stimulation of PBMC isolated from healthy and atopic individuals is predictive of the effect of these compounds in the treatment of atopic diseases, including atopic dermatitis.
All materials and tissue culture media used were obtained from commerical sources.
Buffy coats from the Beilinson Medical Center Blood Bank or 20 mL samples of heparinized venous blood from healthy or atopic donors were used as a source for human peripheral blood mononuclear (PBM) cells.
PBM cells were separated by Ficoll-Hypaque density gradient centrifuga-tion. Partial depletion of adherent cells was achieved by incubating PBM
cells for 90 min in plastic petri dishes at 37C at a concentration of 5 x 104 cells/mL in RPMI-1640 medium containing 2% heat-inactivated newborn calf serum. The nonadhering cells were stirred gently and carefully collected.
The monocyte content of PBM cells was thus reduced to 3-7%.
PBM cells were suspencled (l x 104/mL) in ~PMI-1640 medium contalning 5% heat-inactivated pooled human AB serum supple-mented with penicillin (100 U/mL) and streptomycin (100 !lg/mL). Cells were incubated at 37C in a humidified 5% C~ -95% air atmosphere in 0.2 mL aliquots in 96-well llat bottomed Cooke microtiter plates. PHA
(1 ,ug/mL), indomethacin (5 ,ug/mL) and various xanthine derivatives were added at initiation of culture. Indomethacin was dissolved in ethanol. The concentration of ethanol in the cell cultures did not exceed 0.006%, a concentration that, in our hands, has no effect on any of the cellular functions studied in this work. [methyl-3H]Thymidine ~1 ,uCi/well) was 207~99 added at 68 h, and the cells were harvested 4 h later using an automated cell harvester (Dynatech, Alexandria, VA). Unless otherwise stated, all cultures were perforrned in triplicate.
The inhibition of the rnitogenic stimulation of P13MC by 5 pentoxyfilline was found to be similar regardless of whether the source of the cells was patients with atopic dermatitis or healthy volunteers.
The net inhibitory effect on the mitogenic stimulation of human Iymphocytes from healthy volunteers was compared for pentoxifylline, propentofyliine and two other xanthine derivatives, theophyl-10 line and diphylline (Table 5). Surprisingly, pentoxifylline and propentofyllineinhibited the mitogenic stimulation to a far greater effect than the other xanthine derivatives.
TABLE
`~ ~ ~ ~ ~ nthirie` ~iëd~
Concentration (M) PPF PIX HEOP DIPHY
3 x 10-4 88 4~ 37 12 . _ 1 x I0-3 89 70 59 24 _~ _ ' :
PPF - Propentofylline PTX - Pentoxifylline THEOP - Theophylline DIPHY - Diphylline 25 E~AMPL~E 5 Clinical Trial A clinical trial was performed comparing a cream composition of 2% pentoxifylline (formulation A of Example 1) to placebo. The trial was randomized, double blind, placebo controlled, right-left comparison within 30 patient design. ~ ~ ~
~:
207~99 Two similar plaque areas of psoriasis (i.e. both legs or forearms), were selected for treatment in each patient. In each patient one area Oll one side of the body was treated with 2% pentoxifylline formulated as in Example 1 and the other area on the other side of the body was treated with placebo cream form~llated identically but without the pentoxifylline.
The cream (formulation A in Example 1) was applied by the patient twice daily.
Patients were selected so that the lesions did not cover more than 30% of the total skin area. Patients stopped all forms of topical psoriatic treatment two weeks before entry into the study.
Systemic psoriatic treatments and phototherapy were stopped one month be-fore entry into the study.
The dermatological assessment was performed as follows. The dermatologist measured the area of the lesion in cm~. The severity of each lesion was evaluated by grading erythema, scaling and thickness on a 0-4 scale where 0 = none, 1 = slight, '' = moderate, 3 = severe and 4 =
exceptionally severe.
Based on these measurements the Psoriasis Area Severity Index (PASI) was calculated for each of the 2 lesions on each patient as follows:
PASI = Area x (Erythema ~ Thickness + Scaling) Patient 1: After 1.5 weeks of treatment the patient showed a 58%
decrease in PASI on the pentQxifylline treated side and 0%
clecrease in PASI on the placebo treated side.
25 Patient 2: After 2 weeks of treatment the patient showed a 53% decrease in PASI on the pentoxifylline treated side and 34% decrease in PASI on the placebo treated side.
Patient 3: After 2 weeks of treatment the patient showed a 73% decrease `~ in PASI on the pentoxifylline treated side and 45% decrease 2~766~9 .
in PASI on the placebo treated side. After 6 weeks of treat-ment the decrease in PASI on the pentoxifylline treated side was 90% and on the placebo treated side 56%.
Patient 4: After 6 weeks of treatment the patient showed a 91% decrease in PASI on the pentoxifylline treated side and 73% decrease in PASI on the placebo treated side. After 8 weeks of treat-ment the clecrease in PASI on the pentoxifylline treated side was 88% and on the placebo trea~ed side 57%.
Patient 5: After 2 weeks of treatment the patient showed a 73% decrease in PASI on the pentoxifylline treated side and 25% decrease ;n PASI on the placebo treated side.
In all patients ;the improvement in erythema was most pronounced. There was also good improvement in the thickness scores.
Clinical Trial In a different series of tests 5% dyphylline cream was applied in the same vehicle that had been used to apply PTX cream. Thus ~he formulation used in this series of tests was the same as in Example I with the exception that ~% dyphylline was used in place of 2% pentoxifylline The design of the trial~ was slmilar~ in all respects to the clinlcal trial ~of PTX
described m ~Example 5 except~that~ the~ number of patients was 33. The results~shown ~in Tabl~ 6~demonstrate that treatrnent with dyphylline was nearly ineffectlve wlth respect to placebo.
~ ~ .
`: : :
: : :
:: :
:
' ' ' ' ' ' - --, ~ .
2076~99 . _ _ _ ` Treàtme~ith `5`~`` dyphyllinè` ~s. Plà ` ebo ``~o ` Decrease`~
in~ PASIi as"~ a` Fùnction~ of Timè `( `~ 33 ~ pa`tients) "~ , , ",~, 1 week 2 weeks 4 weeks 6 weeks 5% Dyphylline 12.6 25.9 28.0 26.5 _ _ I
Placebo 12.4 30.0 21.5 15.6 . =__ _ _ I
In summary the clinical trials demonstrate that topical pentoxifylline, a xanthine derivative, is a very effective therapeutic for ~he 10 treatment of psoriatic lesions. However, dyphylline, a different xanthine derivative is virtually inactive in the treatment of psoriasis. These clinical trials also dernonstrate the close correlation between the results obtained in the animal model and the results obtained in the clinical trial.
Clinical Trials A randomized double blind, vehicle controlled, bilateral comparison study was performed, to determine the effect of pentoxify]line (PTX) in the treatment of atopic dermatiiis. The study medication contained 20 2% pentoxifylline in an oil-in-water cream vehicle, and the control treatment consisted of the same vehicle without the pentoxifylline. The exact formulations appear in Table 7.
Seven patients (aged 3-10 years) were enrolled in the trial and evaluated for pruritus, erythema, dryness/scaling and exudate. Pentoxifylline 25 cream, or the placebo (the identical cream, but without the pentoxifylline) were dispensed in identical tubes that were marked for application to right and left sides. Patients were instructed to apply medication twice a day (morning and evening) for four weeks.
~07~g~9 The patients were evaluated at the end of the four week period and the results demonstrated that the pentoxifylline treatment significantly improved each of tlle four symptoms evaluated.
T~BLE 7 ¦r~ ~
Pentoxifylline 2.0 Urea 5.0 5.0 Lactic acid : 2.0 2.0 Amrnonia 1.0 1.0 Germaben ii 1.0 1.0 Sorbitol 70% 4.0 4.0 Glycerol 4.0 4.0 White petrolatum 3.0 3.0 Glyeryl monostearate 3.5 3.5 Cetyl alcohol 3.5 3.5 Mineral oil 10.0 10.0 Octyldécanol: 5.0 5.0 Acetylated lanolin 3.0 3.0 Polyoxyl 40 stearate 3.0 : 3.0 Sorbitan monostearate: 1.5 : 1.5 Purified water: 64.5 : 66.5 . _ . . _ _ -, . _ .
: ~ .: : : : :
::
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.
.,
.
Compositions for topical treatment oî psoriasis and atopic dermatitis, comprising a xantlline derivative .
. : :
.
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FIELD OF THE INVENTION
This invention relates to topical pharmaceutical composltions ;for and~a method~ ~of treating inflammatory~ and~ proliferat*e skin~ diseases such~ as~ psoriasis and atopic dermatitis.
BACKGROUND~OFTHEIN~ENTION~
Psoriasis is a~ common~ chronic relapsing inf~am-matory skin ;d;~sease~;~which~àf~ects 1-3% of the~ population.~It~is~characterised~by the clrcumscrlbed~ scaling erythomatous~plaques ;of:~various: s~zes and ~forms 10 ~ ~; which;~in~somè cases may~ extend to more~than SQ%~ of the skin~area. Thepsoriatic condition is composed of two~;main~ processes: cellular hyper-proliferation~and inflammation Despité extensive research the etiology of ~the . . : :
disease is still;unknown. ` ~
:: : ~ , ~
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~07669g Psoriasis is currently treated by a number of methods which include topical applications consisting of tar derivatives, steroids, vitamin D
and its derivatives or vitamin A and its derivatives (J.P. Callen, Drug Therapy, April 1987, pp. 29-35). These therapies are only partially S successful and may be accompanied by undesired side affects. Thus although steroids can be very effective, they are also frequently associated with side effects. Other therapies include phototherapy with or without concomitant systemic administration of psoralen derivatives. Additionally, systemic administration of steroic!s, methotrexate and cyclosporine have been used for treatment of severe cases of psoriasis. All of these therapies are associated with side effects. There is thus an urgent need for new effective, non-toxic therapeutics for psoriasis.
Atopic dermatitis is a chronic skin condition of unknown etiology, and which may be continuous from infancy to adulthood. There is about 4% incidence of atopic dermatitis from birth to 7 years (Halpern et al., J. Allergy Clin. Immunol. 51:139-151 (1973)). In childhood, it is charaçter-ized by papules, erytherna, thickening and lichenification. In the adolescent, Ihe main symptoms are thickening and lichenification with erythema and scaling. Pruritis is a general feature of the disease. Systemic therapy includesantihistamine drugs and steroids, but the latter are reserved for unmanage-able cases and used for the shortest period possible. Topical therapy includes fluorinated and fluorochlorinated corticosteroid preparations, but striae and cataracts are likely complications. Clearly there is as yet no satisfactory and safe drug treatment for atopis dermatitis. ~ ~
Xanth;ne derivatives have been proposed for the treatment of psoriasis and atopic dermatitis. US 4jl41,976 proposes certain pharmaceuti-cal preparations for the topical treatment of psoriasis. Among the compounds described are certain substituted alkylxanthme derivatives and subs~ituted thioxanthines. However data demonstratmg efhc~iveness is~shown ooly for ' .
,J' ' ~
2~76699 RO 20-17"4 (d,1-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, which is not a xanthine derivative. There is no data showing that the xanthine clerivatives are effective therapeutics when topically administered to patients suffering from proliferative skin disease.
S WO 9101730 describes the use of certain xanthine clerivatives for the treatment of asthma, urticaria, eczema and rhinitis. Suggested modes of administration are listed as oral, rectal, topical, parenteral, intravenous, or intramuscular or through the respiratory tract. EP 195,496 describes the use of certain xanthine derivatives for treating proliferative skin disease such as psoriasis. The xanthine derivatives are administered orally. US 4,716,165 describes the use of certain theobromine derivatives for treating asthma, allergic rhinitis, atopic dermatitis or eczema. WO 8905145 describes the use of certain xanthine derivatives for the treatment of a wide variety o~ disease states inclucling psoriasis. EP 260,127 describes the oral administration of certain xanthine derivatives for the treatment of proliferative skin disease.
US 4,341,783 describes the use of topical dyphylline for the treatment of psoriasis. There is no $eaching or suggestion in any of the above-listed patents and patent applications that the topical administration of the compounds of the instant invention would be more effective in the treatmen$
of psoriasis or atopic dermatitis than the topical application of other xanthinederivatives described in the above-cited patents and patent applications.
Ravid et al. (Ravid et al., J. Allergy Clin. Immunol. 86:881-885 (1990) and J. Clin. Endocrinol. Metab. 70:1687-1692 (1990)) have shown that certain compounds which increase the levels of cyclic adenosine monophosphate (cAMP) are capable of inhibiting the mitogenic induced proliferation of pheripheral bloocl mononuclear cells (PBMC) from both healthy and atopic patients. The only~ xanthine derivative tested in these articles was isobutylmethylxanthine (IBMX). However, there is no teaching or suggestion in these publications that other xanthine derivatives may have {~
different or supeIior properties to IBMX. There is certainly no mention of pentoxifylline (PTX), propentofylline (PPF) or torbafylline (TBF).
Pentoxifylline (PTX) (3,7-dimethyl~ 5-oxohexyl)-xanthine), propentofylline (PPF) (3-methyl-7-propyl-1-(5-oxohexyl)-S xanthine,) and torbafylline (TBE;) (3-methyl-7-ethoxymethyl-1-(~-hydroxy-5-methylhexyl)-,Yanthine are related methyl-xanthine derivatives which are well known in the art for treatment of a variety of disease states.
PTX is widely used systemically for the treatment of peripheral vasçular diseases. PTX and PPF have been administered systemically for the 10 treatment of senile d~mentia whil,e s,ystemic administration of TBF is under investigation for treatment of,senile dementia, peripheral vascular disease and myopathy.
PTX has been used systemically for the treatment of various cutaneous lesions associated with or due to impaired or deficient blood flow 15 in the dermis layer of skin ancl its effectiveness in the treatment of peripheral vascular diseases is describecl by H. Ely, Dermatologic Clinics 6:585-608 (1988). There is no teaching that PTX, or any of its congeners, PPF or TBF, were effeçtive in the treatment of psoriasis or atopic dermatitis, which are lesions of the epidermis layer of the slcin rather than one of the 20 peripheral blood vessels.
DET~ILEO DESCRIPIION OF THE INVENTION
ln acsordance with the present invention it has surprisingly been found Ihat the topical administration of a~pharmaceutlcal composition 25 comprising a compound selected from the group of pentoxifylline, propento-fylline and torbafylline dramatically improves the psoriatic lesions of patients, Most surprisingly the improvement is greater~ than that achieved with other xanthine derivatives such as dyphylline which are taught in the prior art as useful for the topical treatment of psorlatic lesions.
. . .
. ~
~ 20766~
-- s --Accordingly, the present invention provides a pharmaceutical composition for the topical treatment of psoriasis or atopic dermatitis comprising an effective amount of an active compound selected from the group of pentoxifylline, propentofylline and torbafylline, and a pharmaceuti-cally acceptable carrier.
Preferably the concentration of the active compound is about 0.5%-5% (w/w). When the active compound is pentoxifylline its concen-tration is preferably 2% (w/w).
If desired, the compositions according to the invention may 10 additionally contain thërapeut~cally effectlve amounts of one or more compound which are known to be of use in the topical treatment of psoriasis and atopic dermatitis. These compounds are well known to those skilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and analogs, tar derivatives, steroids, vitamin A and its derivatives 15 vitamin D and its derivatives including l-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-cholecalciferol, 24,25-dihydroxy-cholecalciferol, 1,24-dihydroxy-cholecalciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
In addition or instead, the campositions according to the 20 invontion may contain one or more of the compounds adenosine and related purlnes, lipoxygenase inhibitors, substanco P an~agonists, delta~tocopherol, 2-heptanone, and fatty aclds and their esiers such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
The pharmaceutically acceptable carrier of the compositions 25 according to the invention may contain any of the components which are used in topical compositions and are well known to those skilled in the art.
:
If desired, thè pharmaceutically acceptable carrier of the compositions according to the invention may also contain penetration :
, , ' - 6 - 2076S~9 enhancers such as urea, lactic acid, ammonium lactate, salicylic acid or a C3-Cl~-straight chain alkanoic acid.
The compos;tions may be in the form of lotions, creams, ointments and gels, and also in the form of sprayable aerosols. Preferred S formulations of the compositions accorcling to the invention are creams, s which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, typically polyoxy-40-stearate.
The invention also ~rovides. a method for the treatment of a subject suffering from psoriasis or atopic dermatitis comprising topically applying to the subject a therapeutically effective amount of an active compound selected from the group consisting of pentoxifylline, propent-ofylline and torbafylline if c!esired together with a pharmaceutically acceptable carrier.
The preferred active compound for the performance of the method according to the invention is pentoxifylline.
If desired the said active compound may be applied together with a tkerapeutically effective amount of one or more additional compounds which are known to ~e of use in the topical troatment of psoriasis and atopic dermatitis. These compounds are well known to those sXilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and~analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, or vitamin D and its derivatives including 1-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-:
cholecalciferol24,25-dihydroxy-cholecalciferol,1,24-dihydroxy-cllolecal-ciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
Also if desired the said active substance may be applied together with an effective amount of at least one member of the group of adenosine and related purines, lipooxygenase inhibitors, ,ubstance P
2~ 39 , antagonists, delta tocopherol, ~-heptanone, and fatty acids and their esters such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
Still further the invention provides for use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline Eor the preparation of pharmaceutical compositions for the topical treatment of human patients suffering from psoriasis or atopic dermatitis.
BRIEF DESCRI~I:ION OF THE PICTURES
In the following E~ample 1 the advantages achieved in accordance with the invention are described, i.a. with reference to the annexed pictures in which:
Fig. 1 shows photomicrographs of transverse sections of human psoriatic skin transplants before and after treatment; and Fig. 2 shows two further similar photomicrographs.
Some embodiments of the present invention will now be described and exemplified in the following Examples, it being understood tha~ the invention is not limited thereto.
20 ~XAMPLE 1 . ~ Formulations A. Pentoxifylline was formulated mto a cream for topical application as follows:
:
207~99 ~o w/w Stearic Acid 15.0 Cetyl Alcohol 1.0 White Petrolatum 3.0 Polyoxy 40 Stearate 4.0 Methyl Paraben 0.025 Propyl Paraben 0.015 Pentoxifylline (PTX) 2.0 Propylene Glycol 9.5 Sorbitol 7.5 Purified Water To make up 100%
, ~
This formulation was used in Fxamples 2 and i.
15 B. Additional cream formulations of pentoxifylline suitable for topical application was prepared as follows:
: %w/w ~: :
:
Pentoxifylline (PTX) 2.0 ; 20 Urea 5.0 Lactic Acid ~ 2.0 Germaben ll 1.0 ~: : Sorbitol~70 solution : ; : 4.0 Glycerin ~ 4.0 ~ White Petrolatum ~ 3.0 Glyceryl monostearate : ~: ;3.0 : : Cetyl~ alcohol ~ 3.5 Heavy~ mineral o~ : IO.O
Eutanol G -Octylclodecanol : 5.0 ~ Acetylated lanolin (ModulanTM)~; 3.0 Myrg 52TM ~ ~ ~ 3.0 Span 601'M ~ .5 Ammonia solution to adjust pH to 4.S
Water ~ ~ To make up lOO%
:
:
, ~ : ;
.
,, 9_ ~76699 C. Pentoxifylline was formulated into an ointment for topical application as follows:
% wlw MîglyolT~I 840--B Gel 10.0 Eutanol G -Octyldodecanol 17~0 Cril 6 -Glyceryl isostearate 3.0 Hard paraffin wax 3.0 Zinc stearate 1.0 Amphisol K 0.5 Germaben II 1.0 Magnesium sulfate 0.2 Urea 10.0 Pentoxifylline (PTX) 2.0 Puri~ied water To make up to 100%
D. Pentoxifylline was formulated into a gel suitable for topical application as follows:
;%w/w Pentoxifylline (PTX) 2.0 Carbopol 940TM 1.5 Triethanolamine 1.5 Water 95.0 :
Nude mice with transplanted human skin Human psoriatic skin from psoriatic patients was transplanted to nude mice essentially according to the method of G. Kreuger et al., Prog.
S in Dermatol. 12:17-22 (1978) as modified by A. &ilhar et al., Exp. Cell Biol. 54:263-274 (1986). The donors had stable plaque type psoriasis for at least one year preceding biopsy and had not received systemic anti-psoriatic therapy for the 4 weeks preceding biopsy. They had also not received topical therapy or U.V. therapy for the two weeks preceding biopsy. The severity of the psoriat}c lesion ~as evaluated and the PASI index was calculated as described by Fredrikson and Petterson (Der~natolo~ica 157:238-244 (1978)).
In this method the area (A) of the psoriasis in four main body parts (head (H), trunk (T), upper extremities (U) and lower extremities (L)) is assigned a value from 0-6 depending on the extent of psoriasis where O reflects no involvement and 6 reflects 90-100% involvement. The severity of the lesion is assessed based on three parameters: Erythema ~E), Desquamation (scaling) (D) and Infiltration (1). The severity of each of these parameters is measured on a scale of 0-4 where 0 is no involvement and 4 is very severe. The total severity score is calculated according to the following formula:
Severity score = V.l(EH ~ + D~)A~ ~ 0.2(EU ~ lu ~DU)AU
3(~T lT DT)AT + 0 4(EL +: IL + D~)AL
Split thickness blopsies of nonpustular psorlatic human tissue, 4x5 cm and 0.4mm thick were obtained from the edge of established plaques from various donor patients. Each specimen was divided~ into sections as follows: 4-5 s ctions, 2x2 mm each for thymidine incorporation and subsequent autoradiography in order to assess the rate of proliferation in the epidermis; 1-2 sections 0.5x1 cm each for histological examination prior to grafting in order to evaluate the severity of the disease, as quantitated by the ~ .
. ~ , 207669~
measure of epidermal thickness; and 3 sections 1.5 x 1 cm each for grafling on the dorsal side of each of three different nude mice. The grafts were allowed to heal for one week prior to topical appl;cation of the test preparations.
Outbred Balb/C nude mice, ~ to 3 months of age were used in this study. The mice were obtained from the pathogen free animal breeding facility at the University of Tel Aviv (Israel) and were raised in the pathogen-free animal facility at the Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
~ Following-?the one week healing period the graft area was treated daily with the test drug in a cream c~mposition according to ` Example 1 or vehicle alone by applying 200 ,ul of the preparation, once at 08:00 and once at 21:00 for the duration of 7 days.
On the day following the end of treatment the severity of the psoriatic lesion was assessed and then the animals were sacrificed and the entire graft was excised and divicled into two equal sections~ One section was used to assess changes in the rate of proliferation by autoradiography (tritiated thymidine incorporation) while the other section was sectioned for microscopic histological assessment, including acanthosis and parakeratosis.
Table 1 shows the effect of the topical preparations tested on human psoriatic skin transpiantcd In nude mice according to the procedure outlined above. The results of the experiment shown in Table 1 demonstrate that pentoxifylline is almost~ as effective as steroids in treating psoriasis and far more effective than dyphylline, a related xanthine which was shown to 2~ be virtually inactfve 2~76~9 = -O ~ O a~
~ .Q ~ ~
. ~ ~
,~ ~, ~ ~ , ~ ~ ~ ~ ~e ~ o ~
c ~ . o ~ ; ~ , ~' 5~
E~ Y ~ c~
~ ~ ~ .
= m ~ ~ E ~ ~ ~ ~, ~ . ~ ~ ~ ~
.g~ ~ ~ :
~.
g ~ 1 ~ ~ _ ~ , ,, ¢ ~ ~ ~ 0~ ~
.~ B ~ L ~ ~o ~ r ~ ._ 0 ~3 Q. ~ '."~ '- ___ ~ ~
~ a ~ ~ : ~ ~0 ~ ~ .-~ ~O~,.,L~ . ~ C`~ ~ C~ CJ~ 8~
~ z ~ _ ~ ~ a : ***
~ o v~ O
2076~99 ~ 13 --In another series of experimen-ts, human psoriatic skin of various severities was transplanted on each of 28 nude mice. The graft area was treated with various preparations as described above.
Table 2 shows the results of the application of topical skin ` 5 formulations to transplantcd human psoriatic skin in each of the 28 nude mice. The results are expressed as a success ratio where success is defined as a decrease of at least 15% in epidermal thickness (acanthosis) as a result of the 7 day topical treatment. The treatments were applied as creams and were administered as described above.
The experiment shown in Tab]e 2 demonstrates that pento-xifylline is almost as effective as topical steroids in treating psoriasis and far more effective than dyphylline which was inactive.
In summary the experiments performed with the animal model for psoriasis described above present a clear indication that PTX is effective 15 ;n the treatment of psoriasis.
:~RE~hlENT
2% Pentoxifylline* 6/10 8% Dyphylline ~ ~0/2 0~05% topical steroid~* 7/10 Placebo 0/6 * Cream co mposltion prepared accordmg to the formulation given ln ; 25 Example lA.
** The topical steroid was either 0.05% clobetasol propionate ointment (Dermovate~ -Glaxo) or 0.05% betametasone dipropionate crear (DiprosonelM Schering U.S.A.).
' ' ., .
2076~99 Fig. 1 shows photomicrographs of representative examples of transverse human psoriatic skin transplant sections. The transplants were made as described above and were all taken from the same patient.
Panel A shows a transplant before treatment and panels B and G show transplants after daily treatments for seven days with the 2% PTX
cream of Example 1 and an 0.05% clobetasol propionate ointment, respectively.
Fig. 2 shows similar photomicrographs be~ore and after daily treatment for seven days with 8% dyphylline.
Inhibition of Human Psoriatic Fibroblast Proliferation As excess proliferation of fibroblasts is one of the symptoms of psoriasis, the inhibition of fibroblasts proliferation was used as a test to determine the uti]ity of the drugs of the present invention in the treatment of psoriasis. PTX and PPF, alone as well as PTX in combination with other drugs were tested.
Human psoriatic ~ibroblasts were obtained from slcin biopsies of 5 individuals with plaque psoriasis. Cells in the 3-7th passages~were used for the experiments. Human psoriatic fibroblasts (4x103-6x103 cells) were ~ added in 24 well plates and cultured in Dulbecco's Modi~led Eagle's ;~ Medium (DMEM~ supplemented with~ lO% fetal~ caif serum, 2mM L-;
glutamine, 100 u/ml penicillin, 100 !lg/ml streptomycin (DMEM+) at~5%
C2 and 95% humidity at 37C.
:
~fter 3 days, rnedium was replaced with fresh DMEM~
(control) or with medium containing various concentrations of compounds alone or in combination with~pen~oxifylline and incubation was continued for additional 3 days. Stock solutions ~(10-' - 10-2 M) of the compounds tested were made in ethanol. For these compounds speci l control (DMEM+
, 2076~99 with 1~o ethanol) was made. The compounds tested together with pentoxi-fylline were 3-heptanone, 3,3-dimethylbutyric acid, lipoic acid, 1,25-dihydroxyvitamin D3 betamethasone dipropionate and hydrocortisone-17-butyrate.
On the last day of experiments, the medium was aspirated and the cells were obtained by trypsinization. The number of cells in each well was counted by the use of an hemocytometer.
The percentage of inhibition of fibroblast proliferation was calculated according to the formula:
100 amount of fibroblasts in the well in the presence of the drug 100 amoullt of fibroblasts ~n the well itl the abse~ce of the drug and the results are shown in Tables 3 and 4 ~C~mpo~ ' l coi~cèhtràtion ` `~ % I nhi~itio'n~ of;Prolifèràtion ~"~ ~additionàl~
~ . . . d ru g ( ) ~
Pentoxifylline (PTX) _ 3.7 16.9 2-Heptanone 10-5 N.D. 21.3 10-4 21.0 26.4 10-3 18.6 _ 45 _ 3,3dimethyl 10-4 - 19.3 1?.2 butyricacid 10-3 _ 36.3 21 Lipoicacid 1~-4 14;3 _ 50.2 1,25(0H)~D3 10-7 49 S N D
Betamethasone 10-7 43 .1 N.D.
dipropionate 10-4 _ 55.8 77.5 hydrocortisone 10-5 ~ N.D. 41.9 17-butyrate 10-5 N.D. 51.2 _ _ _ - _ N.D. = Not Determined 1,25(0H~)D3 is 1,25-dihydroxyvitamin D3 ~ 2~76699 ., ~ _ ~u~Compound ~ ~ Concentration~ ~ Inhibition of .~ ~ ~ (M)~-~`` ~ ji ti n Pentoxifylline 1()-~ ~.9 S (PTX) 10-' 16.9 + 4 8 Propentofylline 10-~ 20.3 + 6-6 (PPF) 10-3 39.0 + 7 _ _ ~ _ These results show that the drugs of the present invention do inhibit the proli~ration of fibroblasts which indicate their potential utility in treating psoriasis. The results are satisfactory both when these drugs are applied as the anly active compound and when they are applied in combination with other drugs.
EXA~PLE 4 Inhibit;on of the Mitogenic Stimulatinn of Human Lymphocvtes Studies in the literature have shown that atopic dermatitis is transferable by bone marrow Eells indicating that primary site of disease is in the immune and inflammatory cells which infiltrate the skin. Thus the Iymphocy~es are thought to be one of the targets for treatment of the disease.
Also, various cells (in:cluding Iymphocytes) and organs der;ved from atopic subjects showéd.a conimon impaired response to cAMP agonists. Thus the study of atopic Iymphocytes behavior in response to various agents is predictive of the atopic individuals response to these agents.
Studies have shown that cAMP agonists have an inhibitory effect on the mitogenic stimulation of peripheral blood mononuclear cells (PBMC) from atopic subjects (Ravid et al., J. Allergy Clin. Immunol.
86:881-885 (1990)). In these studies it was found that those compounds which have an inhibitory effect on PBMC from atopic subjects have a similar inhibitory effect on PBMC from healthy subjects. The primary -2~7~
difference noted was one of degree; the inhibitory effect on cells from atopic subjects was reduced when compared to healthy individuals. It was also shown that steroids such as dexamethasone, which are used in the treatment of atopic dermatitis, inhibited the mitogenic stimulation of PBMC. Thus the S inhibitory effect of certain compouncls on the mitogenic stimulation of PBMC isolated from healthy and atopic individuals is predictive of the effect of these compounds in the treatment of atopic diseases, including atopic dermatitis.
All materials and tissue culture media used were obtained from commerical sources.
Buffy coats from the Beilinson Medical Center Blood Bank or 20 mL samples of heparinized venous blood from healthy or atopic donors were used as a source for human peripheral blood mononuclear (PBM) cells.
PBM cells were separated by Ficoll-Hypaque density gradient centrifuga-tion. Partial depletion of adherent cells was achieved by incubating PBM
cells for 90 min in plastic petri dishes at 37C at a concentration of 5 x 104 cells/mL in RPMI-1640 medium containing 2% heat-inactivated newborn calf serum. The nonadhering cells were stirred gently and carefully collected.
The monocyte content of PBM cells was thus reduced to 3-7%.
PBM cells were suspencled (l x 104/mL) in ~PMI-1640 medium contalning 5% heat-inactivated pooled human AB serum supple-mented with penicillin (100 U/mL) and streptomycin (100 !lg/mL). Cells were incubated at 37C in a humidified 5% C~ -95% air atmosphere in 0.2 mL aliquots in 96-well llat bottomed Cooke microtiter plates. PHA
(1 ,ug/mL), indomethacin (5 ,ug/mL) and various xanthine derivatives were added at initiation of culture. Indomethacin was dissolved in ethanol. The concentration of ethanol in the cell cultures did not exceed 0.006%, a concentration that, in our hands, has no effect on any of the cellular functions studied in this work. [methyl-3H]Thymidine ~1 ,uCi/well) was 207~99 added at 68 h, and the cells were harvested 4 h later using an automated cell harvester (Dynatech, Alexandria, VA). Unless otherwise stated, all cultures were perforrned in triplicate.
The inhibition of the rnitogenic stimulation of P13MC by 5 pentoxyfilline was found to be similar regardless of whether the source of the cells was patients with atopic dermatitis or healthy volunteers.
The net inhibitory effect on the mitogenic stimulation of human Iymphocytes from healthy volunteers was compared for pentoxifylline, propentofyliine and two other xanthine derivatives, theophyl-10 line and diphylline (Table 5). Surprisingly, pentoxifylline and propentofyllineinhibited the mitogenic stimulation to a far greater effect than the other xanthine derivatives.
TABLE
`~ ~ ~ ~ ~ nthirie` ~iëd~
Concentration (M) PPF PIX HEOP DIPHY
3 x 10-4 88 4~ 37 12 . _ 1 x I0-3 89 70 59 24 _~ _ ' :
PPF - Propentofylline PTX - Pentoxifylline THEOP - Theophylline DIPHY - Diphylline 25 E~AMPL~E 5 Clinical Trial A clinical trial was performed comparing a cream composition of 2% pentoxifylline (formulation A of Example 1) to placebo. The trial was randomized, double blind, placebo controlled, right-left comparison within 30 patient design. ~ ~ ~
~:
207~99 Two similar plaque areas of psoriasis (i.e. both legs or forearms), were selected for treatment in each patient. In each patient one area Oll one side of the body was treated with 2% pentoxifylline formulated as in Example 1 and the other area on the other side of the body was treated with placebo cream form~llated identically but without the pentoxifylline.
The cream (formulation A in Example 1) was applied by the patient twice daily.
Patients were selected so that the lesions did not cover more than 30% of the total skin area. Patients stopped all forms of topical psoriatic treatment two weeks before entry into the study.
Systemic psoriatic treatments and phototherapy were stopped one month be-fore entry into the study.
The dermatological assessment was performed as follows. The dermatologist measured the area of the lesion in cm~. The severity of each lesion was evaluated by grading erythema, scaling and thickness on a 0-4 scale where 0 = none, 1 = slight, '' = moderate, 3 = severe and 4 =
exceptionally severe.
Based on these measurements the Psoriasis Area Severity Index (PASI) was calculated for each of the 2 lesions on each patient as follows:
PASI = Area x (Erythema ~ Thickness + Scaling) Patient 1: After 1.5 weeks of treatment the patient showed a 58%
decrease in PASI on the pentQxifylline treated side and 0%
clecrease in PASI on the placebo treated side.
25 Patient 2: After 2 weeks of treatment the patient showed a 53% decrease in PASI on the pentoxifylline treated side and 34% decrease in PASI on the placebo treated side.
Patient 3: After 2 weeks of treatment the patient showed a 73% decrease `~ in PASI on the pentoxifylline treated side and 45% decrease 2~766~9 .
in PASI on the placebo treated side. After 6 weeks of treat-ment the decrease in PASI on the pentoxifylline treated side was 90% and on the placebo treated side 56%.
Patient 4: After 6 weeks of treatment the patient showed a 91% decrease in PASI on the pentoxifylline treated side and 73% decrease in PASI on the placebo treated side. After 8 weeks of treat-ment the clecrease in PASI on the pentoxifylline treated side was 88% and on the placebo trea~ed side 57%.
Patient 5: After 2 weeks of treatment the patient showed a 73% decrease in PASI on the pentoxifylline treated side and 25% decrease ;n PASI on the placebo treated side.
In all patients ;the improvement in erythema was most pronounced. There was also good improvement in the thickness scores.
Clinical Trial In a different series of tests 5% dyphylline cream was applied in the same vehicle that had been used to apply PTX cream. Thus ~he formulation used in this series of tests was the same as in Example I with the exception that ~% dyphylline was used in place of 2% pentoxifylline The design of the trial~ was slmilar~ in all respects to the clinlcal trial ~of PTX
described m ~Example 5 except~that~ the~ number of patients was 33. The results~shown ~in Tabl~ 6~demonstrate that treatrnent with dyphylline was nearly ineffectlve wlth respect to placebo.
~ ~ .
`: : :
: : :
:: :
:
' ' ' ' ' ' - --, ~ .
2076~99 . _ _ _ ` Treàtme~ith `5`~`` dyphyllinè` ~s. Plà ` ebo ``~o ` Decrease`~
in~ PASIi as"~ a` Fùnction~ of Timè `( `~ 33 ~ pa`tients) "~ , , ",~, 1 week 2 weeks 4 weeks 6 weeks 5% Dyphylline 12.6 25.9 28.0 26.5 _ _ I
Placebo 12.4 30.0 21.5 15.6 . =__ _ _ I
In summary the clinical trials demonstrate that topical pentoxifylline, a xanthine derivative, is a very effective therapeutic for ~he 10 treatment of psoriatic lesions. However, dyphylline, a different xanthine derivative is virtually inactive in the treatment of psoriasis. These clinical trials also dernonstrate the close correlation between the results obtained in the animal model and the results obtained in the clinical trial.
Clinical Trials A randomized double blind, vehicle controlled, bilateral comparison study was performed, to determine the effect of pentoxify]line (PTX) in the treatment of atopic dermatiiis. The study medication contained 20 2% pentoxifylline in an oil-in-water cream vehicle, and the control treatment consisted of the same vehicle without the pentoxifylline. The exact formulations appear in Table 7.
Seven patients (aged 3-10 years) were enrolled in the trial and evaluated for pruritus, erythema, dryness/scaling and exudate. Pentoxifylline 25 cream, or the placebo (the identical cream, but without the pentoxifylline) were dispensed in identical tubes that were marked for application to right and left sides. Patients were instructed to apply medication twice a day (morning and evening) for four weeks.
~07~g~9 The patients were evaluated at the end of the four week period and the results demonstrated that the pentoxifylline treatment significantly improved each of tlle four symptoms evaluated.
T~BLE 7 ¦r~ ~
Pentoxifylline 2.0 Urea 5.0 5.0 Lactic acid : 2.0 2.0 Amrnonia 1.0 1.0 Germaben ii 1.0 1.0 Sorbitol 70% 4.0 4.0 Glycerol 4.0 4.0 White petrolatum 3.0 3.0 Glyeryl monostearate 3.5 3.5 Cetyl alcohol 3.5 3.5 Mineral oil 10.0 10.0 Octyldécanol: 5.0 5.0 Acetylated lanolin 3.0 3.0 Polyoxyl 40 stearate 3.0 : 3.0 Sorbitan monostearate: 1.5 : 1.5 Purified water: 64.5 : 66.5 . _ . . _ _ -, . _ .
: ~ .: : : : :
::
~: :
: ~ :
~, ' ' :
.
.,
Claims (12)
1. A composition for the topical treatment of psoriasis or atopic dermatitis comprising an effective amount of an active compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline, and a pharmaceutically acceptable topical carrier.
2. The composition of Claim 1, wherein the active compound is present in amounts from about 0.5% to about 5% on a weight/weight basis.
3. The composition of Claim 1, wherein the active compound is pentoxifylline.
4. The composition of Claim 3, wherein the pentoxifylline is present in an amount of about 2% on a weight/weight basis.
5. The composition of Claim 1, comprising additionally a therapeutically effective amount of at least one compound selected from the group consisting of cyclosporine methotrexate, tamoxifen, forskolin and analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, vitamin D and its derivatives including 1-alpha-hydroxycholecalciferol, 1,25-dihydroxy-cholecalciferol, 24,25-dihydroxy-cholecalciferol, 1,24-dihydroxy-cholecalciferol and calcipotriol (MC 903) and beta agonists, adenosine and related purines, lipooxygenase inhibitors, substance P
agonists, delta tocopherol, 2-heptanone, and fatty acids and their esters.
agonists, delta tocopherol, 2-heptanone, and fatty acids and their esters.
6. The composition of Claim 1, comprising additionally at least one compound selected from the group consisting of adenosine and related purines, lipooxygenase inhibitors, substance P antagonists, delta tocopherol, 2-heptanone, and fatty acids and their esters.
7. The composition of Claim 6, wherein said fatty acids and their esters are selected from the group consisting of heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
8. A method for the treatment of a subject suffering from psoriasis or atopic dermatitis, comprising topically applying to said subject a therapeutically effective amount of an active compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline.
9. The method of Claim 8, wherein said active compound is pentoxifylline.
10. The method of Claim 9, wherein said active substance is applied together with a pharmaceutically acceptable topical carrier.
11. The method of Claim 9, wherein said active compound is administered together with an effective amount of at least one compound selected from the group consisting of cyclosporine, methotrexate, tamoxifen, forskolin and analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, vitamin D and its derivatives including 1-alpha-hyroxy-cholecalciferol, 1,25-dihydroxy-cholecalciferol, 24,25-dihydroxy-cholecalciferol, 1,24-dihydroxy-cholecalciferol and calcipotriol (MC903), and beta agonists.
12. The method of Claim 9, comprising applying said active compound together with an effective amount of at least one compound selected from the group consisting of adenosine and related purines, lipooxygenase inhibitors, substance P antagonists, delta tocopherol, 2-heptanone, and fatty acids and their esters such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
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US6190691B1 (en) | 1994-04-12 | 2001-02-20 | Adolor Corporation | Methods for treating inflammatory conditions |
US5962477A (en) | 1994-04-12 | 1999-10-05 | Adolor Corporation | Screening methods for cytokine inhibitors |
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- 1992-08-19 EP EP92307566A patent/EP0544391A1/en not_active Ceased
- 1992-08-19 ZA ZA926248A patent/ZA926248B/en unknown
- 1992-08-21 AU AU21187/92A patent/AU650995B2/en not_active Ceased
- 1992-08-24 CA CA002076699A patent/CA2076699A1/en not_active Abandoned
- 1992-08-31 JP JP4253501A patent/JPH06192101A/en active Pending
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- 1994-06-21 US US08/263,399 patent/US5565462A/en not_active Expired - Fee Related
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WO2022042390A1 (en) * | 2020-08-25 | 2022-03-03 | 广东众生睿创生物科技有限公司 | Use of hydroxypurine compounds for treatment of skin diseases |
Also Published As
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US5565462A (en) | 1996-10-15 |
AU650995B2 (en) | 1994-07-07 |
IL99368A (en) | 1996-01-19 |
EP0544391A1 (en) | 1993-06-02 |
JPH06192101A (en) | 1994-07-12 |
IL99368A0 (en) | 1992-08-18 |
ZA926248B (en) | 1993-03-03 |
AU2118792A (en) | 1993-03-11 |
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