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WO2006049451A1 - Utilisation de sphingosylphosphorylcholine ou de son derive - Google Patents

Utilisation de sphingosylphosphorylcholine ou de son derive Download PDF

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Publication number
WO2006049451A1
WO2006049451A1 PCT/KR2005/003711 KR2005003711W WO2006049451A1 WO 2006049451 A1 WO2006049451 A1 WO 2006049451A1 KR 2005003711 W KR2005003711 W KR 2005003711W WO 2006049451 A1 WO2006049451 A1 WO 2006049451A1
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WO
WIPO (PCT)
Prior art keywords
composition
process according
administering
animal
substance
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Application number
PCT/KR2005/003711
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English (en)
Inventor
Hyoung June Kim
Jun Won Yun
Dae Kwon Kim
Won Seok Park
Dae Seok Sung
Hye Jin Yang
Kwang Mi Kim
Chang Hoon Lee
Young Chul Sim
Original Assignee
Amorepacific Corporation
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Priority claimed from KR1020050104962A external-priority patent/KR101210008B1/ko
Application filed by Amorepacific Corporation filed Critical Amorepacific Corporation
Publication of WO2006049451A1 publication Critical patent/WO2006049451A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • the present invention relates to a use of sphingosylphosphorylcholine (SPC) or derivatives thereof. More particularly, the present invention relates to a process to induce an itch in an animal by administering sphingosylphosphorylcholine; a process to screen an anti-itching substance; and a process to evaluate the anti-itching effect of the screened substance. Sphingosylphosphorylcholine or derivatives thereof according to the present invention are useful for studying an itch, screening anti-itching drugs and evaluating the efficacy of a screened drug.
  • itch is being considered as the most concerning factor which lowers the quality of patient's life.
  • atopic dermatitis it was found that patients suffering from severe atopic dermatitis spend about 15% of their sleeping time in scratching (Br. J. Dermatol. 2001; 144: 305 ⁇ ). Therefore, extensive studies have been made to identify endogenous substances that induce an itch in many skin diseases, and many pruritogens have been developed. However, the relationship between the disease and the pruritogen is still unclear, and a new animal model relating to new pruritogens is highly required.
  • rodents In animal studies of itch, rodents are commonly used for the ease of execution and control of the experiments. It was found by Japanese researchers that rodents show peculiar behavior such as hind paw scratching of the pruritogen-injected site, which is not usually observed in normal condition (Br. J. Dermatol. 2004; 33-8). It was also found that intradermal injection, which is an injection between epidermis and dermis, is the most effective method, because the pruritogen could be localized at the injected site. This prevents the injected pruritogens from being spread to the whole body (Eur. J. Dermatol. 1995; 275: 229-23).
  • Suggested pruritogens conventionally used in the above prior art include kallikrein, compound 48/80, serotonin, histamine, substance P (WO 2004/027413, JP2004- 132794, JP2003-313138) and corrosive organic solvents (JP2001 -321016).
  • corrosive solvents their mechanism of action is unclear and considered to be very different from that of endogenous prutigotens.
  • histamine, serotonin and substance P are endogenous, and are more preferable than non-biological external substances in terms of toxicity, biocompatibility or similarity to clinical itch.
  • to induce an itch they need to be administered at high doses of 100 nmole /site, thus there is a problem in relation to clinical application.
  • Lysosphingolipids are the structures of sphingolipids in which a fatty acid moiety is absent.
  • Sphingosylphosphorylcholine (SPC) is an N-deacylated form of sphingomyelin (SM). It is structurally similar to sphingosine-1 -phosphate, but is characterized by the structure in which choline is bonded to phosphate, and its molecular weight is 465.6.
  • Lysophosphatidic aicd which is a similar lipid substance to SPC, is a hydrophilic phospholipid and is involved in proliferation, differentiation, survival and movement of various cells (TRENDS in Biochemical Sciences. 2003: 28: 377-83).
  • sphingosylphosphorylcholine induced release of Ca + from endoplasmic reticulum in various cells, inhibits or promotes cell growth or cell proliferation, and is deeply involved in cell death.
  • it plays various roles in various cells by regulating the reconstruction of the cell skeleton and the cell migration. For example, it shows a wound healing effect in fibroblast present in skin, and induces inflammation, Keratinocytes differentiation and melanin formation in melanocytes. Especially, it acts as a strong cell segmentation stimulator in Swiss 3T3 fibroblast.
  • sphingosyphosphorylcholine activates mitogen-associated protein kinase (MAP kinase) via several G-protein coupled receptors (GPCR) and protein kinase C (PKC), and thereby it promotes cell proliferation and cell differentiation.
  • GPCR G-protein coupled receptors
  • PKC protein kinase C
  • sphingosylphosphorylcholine takes on an aspect of substantial increase in the skin of patients suffering from atopic dermatitis (AD) (Journal of Lipid research, 2003: 44: 93-102). This could be confirmed by the fact that the activity of sphingomyelin deacylase is increased in or around the damaged site of the skin of AD patients (Biochem. J. 2000; 350: 747-756).
  • sphingosylphosphorylcholine which is endogenous, can induce sufficient itch at an extremely low concentration (100 ⁇ M), which is 1/200 times smaller amount than the required amount of histamine, serotonin, or substance P (2mM), and thereby completed the present invention.
  • the object of the present invention is to provide a composition comprising sphingosylphosphorylcholine or derivatives thereof, a process for inducing an itch using the composition, a process for screening an anti-itching substance and a process for evaluating the effect of the screened anti-itching substance.
  • Sphingosylphosphorylcholine or derivatives thereof effectively induce an itch, and can be used in an experiment for evaluating the anti-itching effect.
  • Figure 1 is a conceptual diagram showing the metabolism of sphingosylphosphorylcholine.
  • Figure 2 is a graph showing the effect of sphingosylphosphorylcholine inducing an itch according to the dose.
  • Figure 3 is a graph showing the effect of capsaicin, azelastine and cyproheptadine for inhibiting an itch induced by sphingosylphosphorylcholine.
  • Figure 4 is a graph showing experimental results on cell proliferation of sphingosylphosphorylcholine (The proliferation induced by sphingosylphosphorylcholine was determined by [6-H 3 ]thymidine incorporation).
  • Figure 5 is a graph showing experimental results on cell proliferation of sphingosylphosphorylcholine (The proliferation induced by sphingosylphosphorylcholine was determined by MTT
  • Figure 6 is a graph showing the search result for new substances that inhibits the biological effect of sphingosylphosphorylcholine.
  • Figure 7 is a graph showing the result of applying Substance #6 to the animal model in which an itch is induced by SPC.
  • the present invention provides a process for inducing an itch to an animal using sphingosylphosphorylcholine, a process for screening an anti-itching substance, and a process for evaluating the effect of the screened substance.
  • itch has the same meaning as "pruritus”
  • pruritogen has the same meaning as "itch-inducing substance”
  • anti-itching has the same meaning as "anti-pruritic”.
  • the present invention provides a composition for inducing an itch comprising sphingosylphosphorylcholine represented in Chemical Formula 1, or derivatives thereof as an itch-inducing substance.
  • Sphingosylphosphorylcholine used in the present invention is formed from sphingomyelin by the enzyme called sphingomyelin N-deacylase (Biochem J. 2000; 350: 747-56). It acts as a strong mitogen in various cell types, and is known to promote secretion of specific cytokines (Biochim Biohys Acta. 2002: 1582: 178-89).
  • the above metabolism process of sphingosylphosphorylcholine is shown in Fig. 1.
  • a large amount of sphingosylphosphorylcholine is found in the epidermis of AD patients (J. Lipid Res. 2003; 44: 93-102).
  • the present invention provides a process for inducing an itch by administering to an animal a composition comprising sphingosylphosphorylcholine or derivatives thereof.
  • the animal is preferably a rodent such as a mouse, rat or guinea pig, and more preferably is ICR mouse.
  • the method of administering the composition comprising sphingosylphosphorylcholine or derivatives thereof according to the present invention is not limited particularly; however, it is preferably intradermal injection, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, topical application, patch or iontophoresis, and is more preferably intradermal injection.
  • intradermal injection subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, topical application, patch or iontophoresis, and is more preferably intradermal injection.
  • the number of scratching behavior at the site where the an itch-inducing substance is injected is set as the index to the extent of itch.
  • the behavior of scratching means scratching the site where the itch- inducing substance was injected using the hind paw, and the behavior of scratching using the front leg or licking the site was excluded.
  • a series of behavior from scratching the site using the hind paw to dropping the leg was measured as 1 occurrence of scratching, and was made as the only index of the itch.
  • the composition comprising sphingosylphosphorylcholine or derivatives thereof was basically administered once.
  • the period of observing the scratching is not particularly limited; however, since scratching is rarely observed after 30-40 minutes after injecting the composition, scratching was recorded via video camera in an unmanned environment for 60 minutes, preferably for 40 minutes, after administering the composition.
  • the recorded images were reproduced and observed by two or more people simultaneously.
  • the images were observed twice by each person and the thus obtained values were averaged, in order to exclude the subjective views of the observers.
  • the preferred dose of the composition comprising sphingosylphosphorylcholine or derivatives thereof according to the present invention as well as observation time can be confirmed by the following experiment.
  • the preferred dose of the composition comprising sphingosylphosphorylcholine or derivatives is 0.01-1000 nmole/site (injection of 50 ⁇ £ of 0.2 ⁇ M ⁇ 20mM sphingosylphosphorylcholine).
  • the dose is less than 0.01 nmole/site, the induced scratching behavior is not significantly increased, and when the dose is more than 1000 nmole/site, a lesion such as hematoma was generated.
  • the amount of sphingosylphosphorylcholine or derivatives thereof in the composition is preferably 10 "5 ⁇ 1 wt%/ (2 x 10 "7 ⁇ 2 xlO "2 wt%/site) with respect to the total weight of the composition.
  • video tape recording was used in the present invention to analyze repeatedly the number of scratching occurences, which is a criterion of the itch, for accurate and effective estimation of the an itch.
  • the present invention provides a process of screening an anti-itching substance by administering to an animal the composition comprising sphingosylphosphorylcholine or derivatives thereof.
  • the process of screening an anti-itching substance according to the present invention comprises: 1) inducing an itch in an animal except for human by administering the composition comprising sphingosylphosphorylcholine or derivatives thereof; and
  • the animal used in the present invention is preferably a rodent such as a mouse, rat or guinea pig. More preferably it is ICR mouse.
  • the method of administering the composition comprising sphingosylphosphorylcholine or derivatives thereof in the above step 1) is not limited particularly; however, it is preferably intradermal injection, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, topical application, patch or iontophoresis, and is more preferably intradermal injection.
  • the preferred administration amount for the composition comprising sphingosylphosphorylcholine or derivatives is 0.01-1000 nmole/site (injection of 50 ⁇ £ of 0.2 ⁇ M ⁇ 20mM sphingosylphosphorylcholine).
  • the administration amount was less than 0.01 nmole/site, the induced scratching behavior was not significantly increased, and when the amount was more than 1000 nmole/site, a lesion such as hematoma was generated.
  • the screening process according to the present invention may further comprise orally administering an anti-itching substance prior to administering the composition; intradermally injecting an anti-itching substance at the same time as administering the composition; or topically administering an anti-itching substance at and around the site of administering the composition.
  • the anti-itching substance can be any conventional one used in the art, but preferably capsaicin, azelastine or cyproheptadine. Capsaicin is effective against an itch, especially in incurable an itch in topical areas.
  • Azelastine is a second-generation anti-histamine agent, and cyproheptadine has anti-serotonin action and is widely used in atopic dermatitis patients when they suffer from severe an itch at night.
  • the process of determining the number of scratching occurrences by the animal in step 2) is the same as that in the process of inducing an itch.
  • Another process of screening an anti-itching substance according to the present invention comprises:
  • composition of claim 1 1) using the composition of claim 1 to a cell line that induces cell proliferation of said composition;
  • the cell line used in the above process is selected from the group consisting of NIH 3T3 fibroblast, BALB/c 3T3 fibroblast, 3T3L1 adipocyte and Swiss 3T3 fibroblast originated from mice; melanocyte and keratinocyte from humans; and neonatal cardiac myocytes from rats (Desai NN et al, Biochem Biophys Res Commun, 1991 Nov 27; 181(1); 361-6; Seufferlein T et al, J. Biol. Chem, 1995 Oct 13; 270(41): 24334-42; Higuchi K. et al, Pigment Cell Res. 2003 Dec; 16(6): 670-8; Wakita, H. et al, J. Invest. Dermatol. 110: 253-258, 1998; and K. Sekiguchi et al, Circ. Res. 85(1999) 1000-1008).
  • the other conditions are the same as those in the above screening process.
  • the present invention provides a process of evaluating the anti-itching effect of the anti-itching substance which is screened.
  • the process comprises 1) inducing an itch in an animal except for human by administering the composition of sphingosylphosphorylcholine or derivatives thereof to the animal except for human; and
  • the animal used in the present invention is preferably a rodent such as a mouse, rat or guinea pig. More preferably it is ICR mouse.
  • the method of administering the composition comprising sphingosylphosphorylcholine or derivatives thereof in the above step 1 ) is not limited particularly; however, it is preferably intradermal injection, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, topical application, patch or iontophoresis, and is more preferably intradermal injection.
  • the preferred administration amount for the composition comprising sphingosylphosphorylcholine or derivatives is 0.01-1000 nmole/site.
  • the administration amount was less than 0.01 nmole/site, the induced scratching behavior was not significantly increased, and when the amount was more than 1000 nmole/site, a lesion such as hematoma was generated.
  • the evaluating process according to the present invention may further comprise orally administering an anti-itching substance prior to administering the composition; intradermally injecting an anti-itching substance at the same time as administering the composition; or topically administering an anti-itching substance at and around the site of administering the composition.
  • the anti-itching substance can be any conventional one used in the art, but preferably capsaicin, azelastine or cyproheptadine.
  • step 2 The process of determining the number of scratching occurrences by the animal in step 2) is the same as that in the process of inducing an itch.
  • results were shown as a mean value including its standard deviation. The significance of the results was tested by Student's t-test. When the p value, which is obtained by testing the control group and the experimental group, was less than 0.05, the difference of the experimental group and the control group was evaluated to be significant.
  • ICR mice were shaved on the upper dorsal area, and then were intradermally injected with a composition comprising sphingosylphosphorylcholine or derivatives thereof together with compound A (substance to be evaluated as anti-itching substance). After one administration of the composition of sphingosylphosphorylcholine or derivatives thereof, the scratching behavior of the mice for 40 minutes was recorded by video camera and observed. The control group was administered with saline solution in the same amount. Recorded images were observed by two or more people simultaneously at least 2 times, and the mean value was obtained.
  • mice 40 male ICR mice (age: 5-8 weeks, weight: 25-32 g) were used in total. 8 mice were used as control and 32 mice were used as experimental. All 40 mice were shaved on the upper dorsal area 24 hours before the experiment. The 32 experimental mice were divided into 4 groups, 8 mice for each group.
  • the drug sphingosylphosphorylcholine
  • PBS pH 7.4
  • PBS PBS was added to the control group and to the groups where the drug in lower concentration was administered so that the same amount of PBS was administered in all of the groups.
  • ICR mice were left in the observatory cage for 30 minutes before injection.
  • 50 ⁇ l of solution containing sphingosylphosphorylcholine which was diluted to 100 nM (drug amount: 5 pmole/site), was intradermally injected to the site between the back and neck.
  • SPC group To the Fifth group (called “SPC group”), 50 nmole of sphingosylphosphorylcholine was dissolved in saline solution and was intradermally injected. To the control group, the same amount of saline solution in which ethanol is diluted was intradermally injected.
  • mice After administration, animals were moved to the observatory case, and videotaped for 40 minutes. After recording and when the experiment was terminated, the animals were moved to the raising cage. After 24 hours, they were examined to determine if pathological symptom was found in the injection site and then all were sacrificed. If any pathological symptom such as edema or hematoma was found, the experimentation results were invalidated. The recorded images were observed by two or more people simultaneously.
  • This determination method was established to develop a novel substance that can inhibit the effect of sphingosylphosphorylcholine on the induction of an itch and other causes of disease.
  • the cell proliferation of SPC was induced using NIH 3T3 cell line; thereby the optimum concentration was obtained.
  • the results are shown in Figs. 4 and 5.
  • the proliferation of sphingosylphosphorylcholine was determined by [6-H 3 ] thymidine incorporation.
  • the proliferation of sphingosylphosphorylcholine was determined by MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide).
  • NIH 3T3 cells were inoculated on a culture plate, and cultivated. They were then synchronized by serum starvation, then treated with sphingosylphosphorylcholine to induce cell proliferation.
  • the cell proliferation induction was done by [6-H 3 ] thymidine incorporation and by MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide).
  • MTT 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide
  • substances #1, #4, #6, #7 and #8 show the best effect (When testing the group in which sphingosylphosphorylcholine was solely injected and the groups in which both sphingosylphosphorylcholine and the novel substance were injected together with Student's t-test, the p value was less than 0.05, which means the significant difference).
  • substances which are proposed to have an anti-an itch effect can be primarily screened.
  • new proposed drugs can be rapidly screened.
  • substance #6 was applied to the animal model in which an itch was induced by SPC.
  • Substance #6 was dissolved in saline solutions, and one of 1 mg/kg or 10 mg/kg of the solution was administrated orally to each ICR mouse. After 1 hour, SPC was intradermally injected (50 mmole/site). After injection, the scratching behavior of the mice was observed for 30 minutes. The results are shown in Fig. 7.
  • sphingosylphosphorylcholine and derivatives thereof according to the present invention are useful for studying an itch, searching for a drug for treating an itch and evaluating the drug effect.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Medicinal Chemistry (AREA)
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Abstract

L'invention concerne l'utilisation de sphingosylphosphorylcholine ou de ses dérivés. Il concerne plus particulièrement un procédé destiné à induire une démangeaison chez un animal, un procédé de criblage d'une substance antidémangeaison et un procédé d'évaluation de l'effet antidémangeaison d'une substance antidémangeaison, par régulation de l'administration de sphingosylphosphorylcholine. La sphingosylphosphorylcholine ou des dérivés de celle-ci sont utiles dans la compréhension d'une démangeaison, dans le criblage d'agents réactifs pour une démangeaison, et dans l'évaluation et le développement de cet agent.
PCT/KR2005/003711 2004-11-05 2005-11-04 Utilisation de sphingosylphosphorylcholine ou de son derive WO2006049451A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2004-0089800 2004-11-05
KR20040089800 2004-11-05
KR1020050104962A KR101210008B1 (ko) 2004-11-05 2005-11-03 스핑고실포스포릴콜린 또는 그 유도체의 용도
KR10-2005-0104962 2005-11-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009069966A3 (fr) * 2007-11-30 2009-08-20 Amorepacific Corp Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714478A (en) * 1995-09-29 1998-02-03 Spiegel; Sarah Sphingosylphosphorylcholine as a wound-healing agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714478A (en) * 1995-09-29 1998-02-03 Spiegel; Sarah Sphingosylphosphorylcholine as a wound-healing agent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HARA ET AL: "High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis", J. INVEST. DERMATOL., vol. 115, no. 3, September 2004 (2004-09-01), pages 406 - 413 *
HASHIMOTO ET AL: "Itch-scratch responses induced by lysophosphatidic acid in mice", PHARMACOLOGY, vol. 72, no. 1, September 2004 (2004-09-01), pages 51 - 56 *
OKAMOTO ET AL: "Sphingosylphosphorylcholine is upregulated in the stratum corneum of patients with atopic dermatitis", JOURNAL OF LIPID RESEARCH, vol. 44, 2003, pages 93 - 102 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009069966A3 (fr) * 2007-11-30 2009-08-20 Amorepacific Corp Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine

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