WO2000061122A2 - Use of 6-methylmercaptopurine riboside in ophthalmologic compositions - Google Patents
Use of 6-methylmercaptopurine riboside in ophthalmologic compositions Download PDFInfo
- Publication number
- WO2000061122A2 WO2000061122A2 PCT/EP2000/002717 EP0002717W WO0061122A2 WO 2000061122 A2 WO2000061122 A2 WO 2000061122A2 EP 0002717 W EP0002717 W EP 0002717W WO 0061122 A2 WO0061122 A2 WO 0061122A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cornea
- angiogenesis
- outcomes
- treatment
- methylmercaptopurine riboside
- Prior art date
Links
Classifications
-
- 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
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00912652A EP1171138A2 (en) | 1999-04-12 | 2000-03-28 | Use of 6-methylmercaptopurine riboside in ophthalmologic compositions |
AU34323/00A AU3432300A (en) | 1999-04-12 | 2000-03-28 | Use of 6-methylmercaptopurine riboside in ophthalmologic compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT1999MI000738A IT1311913B1 (en) | 1999-04-12 | 1999-04-12 | USE OF 6-METHYLMERCAPTOPURIN RIBOSIDE IN OPHTHALMOLOGICAL COMPOSITIONS. |
ITMI99A000738 | 1999-04-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000061122A2 true WO2000061122A2 (en) | 2000-10-19 |
WO2000061122A3 WO2000061122A3 (en) | 2001-02-22 |
Family
ID=11382660
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/002717 WO2000061122A2 (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) |
Families Citing this family (1)
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 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4088756A (en) * | 1973-01-16 | 1978-05-09 | The Regents Of The University Of Michigan | Pharmaceutical composition and process of treatment |
-
1999
- 1999-04-12 IT IT1999MI000738A patent/IT1311913B1/en active
-
2000
- 2000-03-28 WO PCT/EP2000/002717 patent/WO2000061122A2/en not_active Application Discontinuation
- 2000-03-28 AU AU34323/00A patent/AU3432300A/en not_active Abandoned
- 2000-03-28 EP EP00912652A patent/EP1171138A2/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4088756A (en) * | 1973-01-16 | 1978-05-09 | The Regents Of The University Of Michigan | Pharmaceutical composition and process of treatment |
Non-Patent Citations (2)
Title |
---|
LESLIE, S. W. ET AL: "Adenosine analogs. Structure-activity relations in vascular and intestinal smoothe muscle" J. PHARM. SCI. (1973), 62(9), 1449-52 , XP000946576 * |
PRESTA, MARCO ET AL: "Purine analog 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process" CANCER RES. (1999), 59(10), 2417-2424 , XP000946571 * |
Also Published As
Publication number | Publication date |
---|---|
WO2000061122A3 (en) | 2001-02-22 |
AU3432300A (en) | 2000-11-14 |
ITMI990738A1 (en) | 2000-10-12 |
IT1311913B1 (en) | 2002-03-20 |
EP1171138A2 (en) | 2002-01-16 |
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