EP1171138A2 - Use of 6-methylmercaptopurine riboside in ophthalmologic compositions - Google Patents

Use of 6-methylmercaptopurine riboside in ophthalmologic compositions

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Publication number
EP1171138A2
EP1171138A2 EP00912652A EP00912652A EP1171138A2 EP 1171138 A2 EP1171138 A2 EP 1171138A2 EP 00912652 A EP00912652 A EP 00912652A EP 00912652 A EP00912652 A EP 00912652A EP 1171138 A2 EP1171138 A2 EP 1171138A2
Authority
EP
European Patent Office
Prior art keywords
cornea
angiogenesis
outcomes
treatment
methylmercaptopurine riboside
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.)
Withdrawn
Application number
EP00912652A
Other languages
German (de)
French (fr)
Inventor
Giorgio Zoppetti
Pasqua Oreste
Marco Presta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1171138A2 publication Critical patent/EP1171138A2/en
Withdrawn legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention refers to compositions suitable for the treatment of angiogenesis-dependent pathologies of the cornea.
  • the purine analogs represent a class of compounds with cytotoxic antineoplastic activity developed since the beginning of the fifties.
  • the 6- mercaptopurine and the 6-thioguanine continue being mainly used for the therapy of acute leukemias.
  • Other analogs such as the azathioprine exert an immunosuppressive action, the allopurinol acts as an inhibitor from xanthine oxidase and the acyclovir, the ganciclovir and the arabinosyladenine act as antiviral agents (Goodmann and Gilman's. The Pharmacological Basis of
  • the angiogenesis or neovascularization represents the process of formation and growth of new blood vessels of the microcirculatory system. The formation of new vessels occurs very rarely in the adult individual.
  • angiogenesis-dependent Folkman, J. Angiogenesis in Cancer, Vascular, Rheumatoid and Other Diseases.
  • compositions suitable to inhibit the formation of new vessels and to cause the regression of the neoformed vessels in the angiogenesis-dependent pathologies of the cornea consist of ointments containing 6-methylmercaptopurine riboside (6-MMPR) as an active substance. Therefore the present invention refers to the use of 6-MMPR for the preparation of compositions in the form of ointment suitable to the treatment of angiogenesis- dependent pathologies of the cornea. Detailed description of the invention
  • compositions consist of ointments containing 6-methylmercaptopurine riboside (6-MMPR) as an active substance and they are prepared according to the following procedure.
  • 6-MMPR is dissolved in a solvent selected from the group consisting of DMSO, ethanol and isopropyl alcohol at a concentration from 2 to 60 mM.
  • the obtained solution is incorporated into viscous vaseline into a laboratory mortar at room temperature mixing 0.5 ml of the solution itself with 9.5 ml of viscous vaseline pre-heated to 37 °C.
  • the stirring is carried out slowly with a glass rod and continued to the achievement of a homogeneous mixture, verifiable at the microscope at 20 magnifications.
  • one proceeds loading such a mixture into 1 ml tuberculin syringes which then will be used for the ophthalmic administration.
  • concentration of 6-MMPR in the ointment ranges from 0.1 to 3.0 mM.
  • compositions of 6-MMPR in the form of ointment according to the present invention may be successfully used in the treatment of the angiogenesis-dependent pathologies of the cornea.
  • Said pathologies include: ulcerative and not ulcerative keratites, pterygium, outcomes of corneal traumas, wounds and cauterizations, outcomes of corneal transplant operations, rejections of the cornea flap after transplant, outcomes of refractive surgery operations, kerato-uveites, trachoma and allergic conjunctivites.
  • the treatment is carried out administering with a syringe under the lower palpebral fissure an amount of ointment corresponding to 10-300 nanomoles of 6-MMPR each 12 hours.
  • the pharmacological experimentation has been carried out on New Zealand albinic rabbits having a weight equal to 2.7-3.2 kg, preliminarily treated with angiogenic growth factor FGF2 on which the tests as described below have been subsequently carried out.
  • Substance 1 consisting of ointment containing 6-MMPR at a concentration of 100 nanomoles in 100 ⁇ l, prepared according to the above described method;
  • Substance 2 consisting of ointment containing 6-methylmercaptopurine (6-MMP) at a concentration of 100 nanomoles in 100 ⁇ l, prepared according to the method described for the substance 1 ;
  • Substance 3 consisting of ointment prepared according to the method described for the substance 1 but without active substance;
  • Substance 4 consisting of sterile saline buffered solution (PBS) containing 100 nanomoles of 6- MMPR in 100 ⁇ l to be used as collyrium;
  • PBS sterile saline buffered solution
  • Substance 5 consisting of sterile saline buffered solution (PBS) containing 100 nanomoles of 6- MMP in 100 ⁇ l to be used as collyrium
  • Substance 6 consisting of sterile saline buffered solution (PBS) to be used as collyrium.
  • Teflon sheet and left to evaporate at room temperature under a vertical laminar flow hood. 50 ⁇ l of solution A are then poured on each evaporated drop which are kneaded with a micropaddle in order to incorporate the FGF2 into the copolymer. It is continued to the solidification of the mixture which is then cut out by a bistoury blade in pellets having sizes equal to 1.0 x 1.0 x 0.5 mm containing each 100 nanograms of FGF2. The so obtained pellets are positioned in the avascular zone of the rabbit cornea acting in the following way. The rabbits are anaesthetized with Penthotal sodium (30 mg/kg of corporal weight).
  • micropouch 1.5 x 3.0 mm
  • a pellet prepared as described above is located.
  • the method used for this operation is described by Ziche M. et al. in Lab. Invest.
  • the rabbits are random distributed in 6 groups of 4 rabbits per group which are topically treated with the above reported several substances in the following way.
  • the treatment is carried out applying 100 ⁇ l respectively of ointment and collyrium each 12 hours for the whole duration of the experiment (28 days).
  • the ointment is administered by a syringe under the lower palpebral fissure while the collyrium is administered by a dropper into the lachrymal pouch.
  • angiogenic index is estimated (angiogenic score).
  • the angiogenic index is calculated as the product of the vascular density by the length of the new formation vessels starting from limbus corneae.
  • the values of the vascular density are set equal to 1 , 2, 3, 4, and 5 for a number of new formation vessels respectively equal to 0-25, 25-50, 50-75, 75-100 and more than 100, per cornea (Ziche et al. Lab. Invest. 1989; 61 :629-634).
  • the experiment is interrupted on the 28 th day.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Use of 6-methylmercaptopurine riboside for the preparation of compositions in the form of ointment, suitable for the treatment of angiogenesis-dependent pathologies of the cornea, including ulcerative an not ulcerative keratites, pterygium, outcomes of corneal traumas, wounds and cauterizations, outcomes of corneal transplant operations, rejection of the cornea flap after transplant, outcomes of refractive surgery oeprations, kerato-uveites, trachoma and allergic conjunctivites.

Description

USE OF 6-METHYLMERCAPTOPURINE RIBOSIDE IN OPHTHALMOLOGIC
COMPOSITIONS
Field of the invention
The present invention refers to compositions suitable for the treatment of angiogenesis-dependent pathologies of the cornea.
Prior art
The purine analogs represent a class of compounds with cytotoxic antineoplastic activity developed since the beginning of the fifties. At present the 6- mercaptopurine and the 6-thioguanine continue being mainly used for the therapy of acute leukemias. Other analogs such as the azathioprine exert an immunosuppressive action, the allopurinol acts as an inhibitor from xanthine oxidase and the acyclovir, the ganciclovir and the arabinosyladenine act as antiviral agents (Goodmann and Gilman's. The Pharmacological Basis of
Therapeutics. 8th Edition, Pergamon Press). The angiogenesis or neovascularization represents the process of formation and growth of new blood vessels of the microcirculatory system. The formation of new vessels occurs very rarely in the adult individual.
The only exception is represented by the female reproductive system, wherein an intense angiogenesis is found in the ovarium and in the endometrium during the menstrual cycle and in the placenta during the pregnancy. The angiogenesis also develops an important role in the inflammatory phenomena and in the processes of wound healing. Such angiogenic episodes are limited in time and highly regulated. An uncontrolled angiogenic process is instead at the bases of several pathologies which, for such a reason, are defined "angiogenesis-dependent" (Folkman, J. Angiogenesis in Cancer, Vascular, Rheumatoid and Other Diseases.
Nature Med. 1995, 1 :27-31 ). In the ophthalmologic field, among the various angiogenesis-dependent pathologies we remember for example the diabetic retinopathy, the neovascularization of the transplanted cornea, the neovascular glaucoma, the trachoma and the retrolental fibrodysplasia. Always in the ophthalmologic field the angiogenesis represents a fundamental pathogenic moment in the development of vascular origin (hemangiomas) and not vascular origin (melanomas) tumours. Ophthalmologic compositions able to effectively inhibit the formation of new vessels and at the same time cause the regression of the neoformed vessels are not known.
Summary of the invention
We have surprisingly found ophthalmologic compositions suitable to inhibit the formation of new vessels and to cause the regression of the neoformed vessels in the angiogenesis-dependent pathologies of the cornea. Said compositions consist of ointments containing 6-methylmercaptopurine riboside (6-MMPR) as an active substance. Therefore the present invention refers to the use of 6-MMPR for the preparation of compositions in the form of ointment suitable to the treatment of angiogenesis- dependent pathologies of the cornea. Detailed description of the invention
The characteristics and the advantages of the ophthalmologic compositions according to the present invention will be mostly pointed out during the following detailed description.
Said compositions consist of ointments containing 6-methylmercaptopurine riboside (6-MMPR) as an active substance and they are prepared according to the following procedure. 6-MMPR is dissolved in a solvent selected from the group consisting of DMSO, ethanol and isopropyl alcohol at a concentration from 2 to 60 mM.
The obtained solution is incorporated into viscous vaseline into a laboratory mortar at room temperature mixing 0.5 ml of the solution itself with 9.5 ml of viscous vaseline pre-heated to 37 °C. The stirring is carried out slowly with a glass rod and continued to the achievement of a homogeneous mixture, verifiable at the microscope at 20 magnifications. Then one proceeds loading such a mixture into 1 ml tuberculin syringes which then will be used for the ophthalmic administration. Preferably the concentration of 6-MMPR in the ointment ranges from 0.1 to 3.0 mM. Thanks to the therapeutic activity as it turns out to be from the pharmacological experimentation reported below, the compositions of 6-MMPR in the form of ointment according to the present invention may be successfully used in the treatment of the angiogenesis-dependent pathologies of the cornea. Said pathologies include: ulcerative and not ulcerative keratites, pterygium, outcomes of corneal traumas, wounds and cauterizations, outcomes of corneal transplant operations, rejections of the cornea flap after transplant, outcomes of refractive surgery operations, kerato-uveites, trachoma and allergic conjunctivites. The treatment is carried out administering with a syringe under the lower palpebral fissure an amount of ointment corresponding to 10-300 nanomoles of 6-MMPR each 12 hours.
Pharmacological experimentations
The pharmacological experimentation has been carried out on New Zealand albinic rabbits having a weight equal to 2.7-3.2 kg, preliminarily treated with angiogenic growth factor FGF2 on which the tests as described below have been subsequently carried out.
For the tests the following substances have been used:
• Substance 1 : consisting of ointment containing 6-MMPR at a concentration of 100 nanomoles in 100 μl, prepared according to the above described method;
• Substance 2: consisting of ointment containing 6-methylmercaptopurine (6-MMP) at a concentration of 100 nanomoles in 100 μl, prepared according to the method described for the substance 1 ;
• Substance 3: consisting of ointment prepared according to the method described for the substance 1 but without active substance;
• Substance 4: consisting of sterile saline buffered solution (PBS) containing 100 nanomoles of 6- MMPR in 100 μl to be used as collyrium;
• Substance 5: consisting of sterile saline buffered solution (PBS) containing 100 nanomoles of 6- MMP in 100 μl to be used as collyrium; • Substance 6: consisting of sterile saline buffered solution (PBS) to be used as collyrium.
The substances from 2 to 6 have been used for comparison aim with the substance 1 relevant to the present invention. a) Preliminary treatment of the rabbits
Slow release pellets are prepared containing the angiogenic growth factor FGF2 acting as described by L. Morbidelli and M. Ziche (The Rat and Rabbit Cornea Assay, "Angiogenesis: Models, Modulators and Clinical Application" Ed. M.
Maragoudakis; Plenum Publishing Corporation, New York, Vol. 298:39-42, 1998).
1 gram of ethylene-vinyl-acetate copolymer (Elvax-40®, DuPont de Nemours,
Wilmington, DE; USA) is dissolved in 10 ml of methylene chloride obtaining the solution A. Separately, 10 micrograms of FGF2 are dissolved in 200 μl of PBS obtaining the solution B.
10 μl drops of solution B (containing 500 nanograms of FGF2) are poured on a
Teflon sheet and left to evaporate at room temperature under a vertical laminar flow hood. 50 μl of solution A are then poured on each evaporated drop which are kneaded with a micropaddle in order to incorporate the FGF2 into the copolymer. It is continued to the solidification of the mixture which is then cut out by a bistoury blade in pellets having sizes equal to 1.0 x 1.0 x 0.5 mm containing each 100 nanograms of FGF2. The so obtained pellets are positioned in the avascular zone of the rabbit cornea acting in the following way. The rabbits are anaesthetized with Penthotal sodium (30 mg/kg of corporal weight).
Then one proceeds surgically at the formation of a micropouch (1.5 x 3.0 mm) in the avascular zone of the cornea and within the micropouch a pellet prepared as described above is located. The method used for this operation is described by Ziche M. et al. in Lab. Invest.
1989; 61 :629-634. b) Test of Inhibition of the Formation and Growth of New Vessels in the Rabbit
Cornea
The day after the preliminary treatment as described at the point a) the rabbits are random distributed in 6 groups of 4 rabbits per group which are topically treated with the above reported several substances in the following way.
• Group 1 It is treated with the substance 1 (ointment containing 6-MMPR).
• Group 2
It is treated with the substance 2 (ointment containing 6-MMP).
• Group 3 It is treated with the substance 3 (ointment without active substance).
• Group 4
It is treated with the substance 4 (collyrium containing 6-MMPR).
• Group 5
It is treated with the substance 5 (collyrium containing 6-MMP). • Group 6
It is treated with the substance 6 (collyrium without active substance).
The treatment of the groups from 2 to 6 has been carried out for comparison aim.
The treatment is carried out applying 100 μl respectively of ointment and collyrium each 12 hours for the whole duration of the experiment (28 days). The ointment is administered by a syringe under the lower palpebral fissure while the collyrium is administered by a dropper into the lachrymal pouch.
Each day the observation of the corneas is carried out by slit lamp stereomicroscope and the angiogenic index is estimated (angiogenic score).
The angiogenic index is calculated as the product of the vascular density by the length of the new formation vessels starting from limbus corneae.
The values of the vascular density are set equal to 1 , 2, 3, 4, and 5 for a number of new formation vessels respectively equal to 0-25, 25-50, 50-75, 75-100 and more than 100, per cornea (Ziche et al. Lab. Invest. 1989; 61 :629-634).
The results of the treatment are reported in Table 1 wherein each data represents the average angiogenic index of the measures carried out on the 4 rabbits of each group. Table 1
σ>
From Table 1 it turns out clearly that only with the treatment of the group 1 the inhibition of the formation and growth of new vessels induced by the FGF2 factor in the rabbit cornea has been obtained.
From the data of Table 1 one may deduce that said inhibition is exclusively obtained by administration of 6-MMPR in the form of ointment (Group 1 ).
No inhibition result is obtained administering another analog of the purines as 6-
MMP in the same form of ointment and no inhibition result is obtained administering 6-MMPR or 6-MMP in the form of collyrium. c) Regression test of the neoformed vessels in the rabbit cornea 24 rabbits are submitted to the preliminary treatment with the FGF2 pellet implant as described at point a).
Each day the observation of the corneas is carried out by slit lamp stereomicroscope and the angiogenic index is estimated as described at the point b). On the 14th day from the implant of the FGF2 pellets, wherein the growth of the new formation vessels reached the maximum stimulation, the rabbits are divided in
6 experimental groups of 4 rabbits per group. From the same day the various groups are treated exactly as at the point b), that is the group 1 is treated with the substance 1 (ointment containing 6-MMPR) etc. Each day the observation of the corneas is carried out by slit lamp stereomicroscope and the angiogenic index is estimated.
The experiment is interrupted on the 28th day.
The obtained results, expressed as average angiogenic index, are reported in
Table 2.
Table 2
00
From Table 2 it turns out clearly that only by administration of 6-MMPR in the form of ointment (Group 1 ) the regression of the neoformed vessels is found in the rabbit cornea.
A different analog of the purines (6-MMP) or the administration of 6-MMPR in the form of collyrium do not exert this effect.

Claims

CLAIMS 1. Use of 6-methylmercaptopurine riboside for the preparation of a composition in the form of an ointment suitable to the treatment of angiogenesis-dependent pathologies of the cornea. 2. Use as claimed in claim 1 , characterized in that said composition includes viscous vaseline with 6-methylmercaptopurine riboside incorporated at a concentration from 0.1 to 3 mM. 3. Use as claimed in claim 1 , characterized in that said angiogenesis-dependent pathologies of the cornea include ulcerative and not ulcerative keratites, pterygium, outcomes of corneal traumas, wounds and cauterizations, outcomes of corneal transplant operations, rejection of the cornea flap after transplant, outcomes of refractive surgery operations, kerato-uveites, trachoma and allergic conjunctivites. 4. Composition in the form of ointment suitable to the treatment of angiogenesis- dependent pathologies of the cornea, comprising 6-methylmercaptopurine riboside as active substance. 5. Composition as claimed in claim 4, comprising viscous vaseline with 6- methylmercaptopurine riboside incorporated at a concentration from 0.1 to 3 mM. 6. Therapeutic method for the treatment of angiogenesis-dependent pathologies of the cornea wherein an amount of composition as claimed in claim 4 is administered under the lower palpebral fissure, corresponding to 10-300 nanomoles of 6-methylmercaptopurine riboside each 12 hours.
EP00912652A 1999-04-12 2000-03-28 Use of 6-methylmercaptopurine riboside in ophthalmologic compositions Withdrawn EP1171138A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI990738 1999-04-12
IT1999MI000738A IT1311913B1 (en) 1999-04-12 1999-04-12 USE OF 6-METHYLMERCAPTOPURIN RIBOSIDE IN OPHTHALMOLOGICAL COMPOSITIONS.
PCT/EP2000/002717 WO2000061122A2 (en) 1999-04-12 2000-03-28 Use of 6-methylmercaptopurine riboside in ophthalmologic compositions

Publications (1)

Publication Number Publication Date
EP1171138A2 true EP1171138A2 (en) 2002-01-16

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EP00912652A Withdrawn EP1171138A2 (en) 1999-04-12 2000-03-28 Use of 6-methylmercaptopurine riboside in ophthalmologic compositions

Country Status (4)

Country Link
EP (1) EP1171138A2 (en)
AU (1) AU3432300A (en)
IT (1) IT1311913B1 (en)
WO (1) WO2000061122A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023309B1 (en) * 2014-05-13 2015-05-05 Mahin Rameshni Process of conversion sulfur compounds to elemental sulfur by using direct reduction and oxidation catalysts in Claus units

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA7469B (en) * 1973-01-16 1974-11-27 J Voorhees Compositions and treatment of proliferative skin diseases with-c-amp analogs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0061122A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023309B1 (en) * 2014-05-13 2015-05-05 Mahin Rameshni Process of conversion sulfur compounds to elemental sulfur by using direct reduction and oxidation catalysts in Claus units

Also Published As

Publication number Publication date
ITMI990738A1 (en) 2000-10-12
IT1311913B1 (en) 2002-03-20
WO2000061122A3 (en) 2001-02-22
AU3432300A (en) 2000-11-14
WO2000061122A2 (en) 2000-10-19

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