EP1370267A2 - Use of propentofylline to control intraocular pressure - Google Patents
Use of propentofylline to control intraocular pressureInfo
- Publication number
- EP1370267A2 EP1370267A2 EP02719062A EP02719062A EP1370267A2 EP 1370267 A2 EP1370267 A2 EP 1370267A2 EP 02719062 A EP02719062 A EP 02719062A EP 02719062 A EP02719062 A EP 02719062A EP 1370267 A2 EP1370267 A2 EP 1370267A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- propentofylline
- composition
- iop
- additional agent
- glaucoma
- 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- Withdrawn
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
- A61K31/33—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
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Definitions
- the present invention is directed to the use of propentofylline for controlling 5 intraocular pressure (IOP), particularly the elevated intraocular pressure associated with glaucoma and/or ocular hypertension.
- IOP 5 intraocular pressure
- Glaucoma is an ocular disease associated with optic nerve head degeneration and loss of vision, which may lead to irreversible blindness. Elevated IOP (ocular hypertension) is a major risk factor of glaucoma. IOP is regulated by the balance between the rate of aqueous humor production from the ciliary epithelium and the rate of its outflow through the trabecular meshwork (TM) and the uveal scleral pathway. 5 In primary open angle glaucoma, the abnormal increase in IOP is mainly due to pathological changes in the TM leading to a significant reduction of outflow facility (Langham, The physiology and pathology of the intraocular pressure. In: Bellows, ed. Glaucoma: Contemporary international concepts.
- TM is normally regulated in part by the ongoing extracellular matrix turnover in the TM (Bradley, et al., Effective matrix metalloproteinases activity on outflow in perfused human organ culture, Investigative Ophthalmology & Visual Science, 1998;39:2649-2658).
- Matrix metalloproteinases (MMPs) have been proposed as o important enzymes regulating the turnover of extracellular matrix in the TM
- 5,260,059 have disclosed a method for treating open-angle glaucoma with a substance to modulate the ratio of matrix metalloproteinases (MMP) to tissue inhibitor of metalloproteinase (TIMP) or MMP/TIMP.
- MMP matrix metalloproteinases
- TRIP tissue inhibitor of metalloproteinase
- the inventors' most preferred substances to achieve this include matrix metalloproteinases, see Column 3, lines 33-37.
- Propentofylline (HWA 285; 3 -methyl- l-(5'-oxohexyl)-7-propyl-xanthine) is a peripheral vasodilator. It is disclosed in U.S. Patent No. 4,289,776 (Mohler, et al.) as useful for treating arterial blood flow disturbance or vascular dilatory insufficiency; in U.S. Patent 4,636,507 (Sheetz) for treating host defense mechanisms against trauma; in U.S. Patent No. 5,310,666 (Aretz, et al.) for the treatment of peripheral, cerebral, and ocular vascular disorders; and in U.S. Patent No.
- adenosine uptake inhibitors are disclosed as being useful for treating retinal and optic nerve head damage following acute or chronic glaucoma, edema, ischemia, hypoxia, or trauma.
- the adenosine uptake inhibitors disclosed in the patent (including propentofylline) inhibit the uptake or re-absorption of adenosine into the neural cells of ocular tissues and thus help protect the neural cells from damage triggered by or resulting from the above- referenced conditions.
- Propentofylline has also been determined to be a neurotrophic factor stimulator which could be useful to treat ophthalmic neurodegeneration resulting from various conditions, including glaucoma (WO/00/32197, Alcon Laboratories, Inc.)
- Pentoxifylline is a close analog of propentofylline. Topical instillation of 2% pentoxifylline was reported to produce a slight decrease in IOP in ocular normotensive rabbits (Hariton, Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterease inhibitors, European Journal of Pharmacology, 1994;258:85-94). This manuscript also describes the IOP-lowering effect of pentoxifylline when it was administered in combination with other compounds such as 3-(3-hydroxyphenyl)-N-n- propylpiperidine, and trifluperidol. However, propentofylline was not studied or mentioned in this report.
- the present invention is directed to methods for controlling intraocular pressure in humans with propentofylline.
- Propentofylline was unexpectedly discovered to stimulate the expression of metalloproteinase-3 (MMP-3; stromelysin) in cultured human trabecular meshwork cells. Incubation of the cells with 100 ⁇ M propentofylline for 72 hours significantly increased the expression of MMP-3 ( Figure 1, upper panel). This unexpected effect was unique to propentofylline, since other adenosine reuptake inhibitors and close chemical analogs of propentofylline, such as dipyridamole, pentoxifylline, and hydroxy-propentofylline, did not produce a statistically significant change in MMP-3 expression in the TM cells ( Figure 1, lower panel). This stimulatory effect unique to propentofylline on MMP-3 production by the TM cells suggests that it may modulate the aqueous hydrodynamics in the eye and affect IOP.
- MMP-3 metalloproteinase-3
- IOP responses in the rabbit eye to various pharmacological agents do not always correspond to IOP responses in primates.
- clinically active IOP- lowering compounds such as latanoprost or pilocarpine, had no measurable effect on IOP in the rabbit (Dinslage, et al., Intraocular pressure in rabbits by telemetry II: effects of animal handling and drugs, Investigative Ophthalmology & Visual Science, 1998;39:2485-2489; Nan Bijsterveld, et al., The effect of hypotensive drugs on the intraocular pressure after waterloading in rabbits, Documenta Ophthalmologica,
- compositions of the present invention comprise propentofylline and a pharmaceutically acceptable vehicle.
- a pharmaceutically acceptable vehicle refers to any formulation that is acceptable, i.e., is safe and provides the appropriate delivery of an effective amount of propentofylline for the desired route of administration.
- the compositions of the present invention may be administered orally, or they may be administered locally to the eye via topical dosing or by a continuous release device placed in the cul-de-sac of the eye.
- Propentofylline can be incorporated into a formulation, such as a tablet or a capsule, for oral administration.
- a formulation such as a tablet or a capsule
- 100-1000 mg of propentofylline may be combined with inactive ingredients such as starch, lactose and magnesium stearate and formulated according to procedures known to those skilled in the art of tablet or capsule formulation.
- An example of a tablet formulation is shown in Example 4. This formulation will be administered to patients 1 to 6 times daily, 1 to 3 tablets each time.
- Propentofylline can be incorporated into various types of ophthalmic formulations for delivery to the eye.
- the compound may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
- Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
- the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
- a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like.
- the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
- Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
- Propentofylline can also be incorporated in a continuous release system that will be placed in the cul-de-sac of the eye. Examples of such devices are shown by Zattaroni (U.S. Patent No. 4,186,184). The release rate of propentofylline in this device will be 10 ⁇ g/hour to 1 mg/hour.
- Propentofylline is preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4.5 to 8.0. It will normally be contained in these formulations in an amount 0.1% to 5% by weight, but preferably in an amount of 0.2% to 3% by weight.
- An example of a topical ophthalmic formulation is presented in Example 5. Thus, for topical presentation 1 to 3 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the routine discretion of a skilled clinician.
- Propentofylline can also be used in combination with other agents for treating glaucoma, such as, but not limited to, ⁇ -blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), ⁇ -i antagonists (e.g.
- ⁇ agonists e.g., iopidine and brimonidine
- miotics e.g., pilocarpine and epinephrine
- prostaglandin analogues e.g., latanoprost, travaprost, unoprostone, bimatoprost, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; 5,688,819; and 5,151,444, "hypotensive lipids" (e.g., compounds set forth in 5,352,708), serotonergics, and neuroprotectants (e.g., compounds from U.S. Patent No. 4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N.
- neuroprotectants e.g., compounds from U.S. Patent No. 4,690,931, particularly eliprodil and R
- HTM-35D Trabecular Meshwork
- Human TM cells were isolated, characterized and cultured as described (Steely et al, The effects of dexamethasone on fibronectin expression in cultured human trabecular meshwork cells, Investigative Ophthalmology and Visual Science,
- Human ocular perfusion organ culture was performed as described (Tschumper, et al. Glycosaminoglycans of human trabecular meshwork in perfusion organ culture. Current Eye Research, 1990;9:363-369; Clark et al, Dexamethasone- induced ocular hypertension in perfusion-cultured human eyes. Investigative Ophthalmology and Visual Science 1995;36:478-489). Briefly, human cadaver eyes, 16 to 20 hours post mortem, were dissected at the equator and the lens, vitreous and iris were removed.
- the anterior segment of the eye including cornea and sclera ring containing TM and ciliary body, was placed into a custom-made plexiglass culture dish and sealed in place with a plexiglass O-ring.
- Culture media (Dulbecco's modified Eagle medium) was placed in a reservoir and perfused through a central cannula in the bottom of the dish.
- the reservoir was raised to generate approximately 11 mmHg of hydrostatic pressure relative to the center of the perfused eye.
- the weight of the reservoir was recorded daily. Outflow rate was defined as the change in the weight of the reservoir per unit time.
- Top Panel IOP-lowering effect of Propentofylline (PPF) (500 ⁇ g) in lasered monkey eyes. It clearly reduced IOP at 1 hour after topical ocular dosing.
- PPF Propentofylline
- a tablet formulation suitable for oral administration, and useful for controlling intraocular pressure is provided.
- a topical ophthalmic composition useful for treating ocular hypertension is a topical ophthalmic composition useful for treating ocular hypertension:
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27754801P | 2001-03-21 | 2001-03-21 | |
US277548P | 2001-03-21 | ||
PCT/US2002/005456 WO2002076460A2 (en) | 2001-03-21 | 2002-02-22 | Use of propentofylline to control intraocular pressure |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1370267A2 true EP1370267A2 (en) | 2003-12-17 |
Family
ID=23061335
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02719062A Withdrawn EP1370267A2 (en) | 2001-03-21 | 2002-02-22 | Use of propentofylline to control intraocular pressure |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1370267A2 (en) |
JP (1) | JP2004528310A (en) |
AR (1) | AR032812A1 (en) |
BR (1) | BR0208146A (en) |
CA (1) | CA2434691A1 (en) |
MX (1) | MXPA03008491A (en) |
WO (1) | WO2002076460A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010016043A1 (en) * | 2008-08-05 | 2010-02-11 | University College Cork, National University Of Ireland, Cork | Treatment of retinal degeneration |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5780450A (en) * | 1995-11-21 | 1998-07-14 | Alcon Laboratories, Inc. | Use of adenosine uptake inhibitors for treating retinal or optic nerve head damage |
-
2002
- 2002-02-20 AR ARP020100581A patent/AR032812A1/en not_active Application Discontinuation
- 2002-02-22 WO PCT/US2002/005456 patent/WO2002076460A2/en not_active Application Discontinuation
- 2002-02-22 JP JP2002574975A patent/JP2004528310A/en active Pending
- 2002-02-22 BR BR0208146-6A patent/BR0208146A/en not_active IP Right Cessation
- 2002-02-22 CA CA002434691A patent/CA2434691A1/en not_active Abandoned
- 2002-02-22 EP EP02719062A patent/EP1370267A2/en not_active Withdrawn
- 2002-02-22 MX MXPA03008491A patent/MXPA03008491A/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO02076460A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2002076460A2 (en) | 2002-10-03 |
JP2004528310A (en) | 2004-09-16 |
WO2002076460A3 (en) | 2003-04-03 |
MXPA03008491A (en) | 2003-12-08 |
AR032812A1 (en) | 2003-11-26 |
BR0208146A (en) | 2004-03-02 |
CA2434691A1 (en) | 2002-10-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2297243C2 (en) | Inhibitors of glycogen synthase kinase-3 (gsk-3) in glaucoma treatment | |
CA2496797C (en) | Therapeutic agent for glaucoma comprising rho kinase inhibitor and prostaglandin | |
EP1740164B1 (en) | Statins for the treatment of ocular hypertension and glaucoma | |
AU724923B2 (en) | Therapeutic treatment for VEGF related occular diseases | |
KR20080016556A (en) | Prophylactic or therapeutic agent for corneal and conjunctival disorder | |
EP1752456B1 (en) | Corneal perception recovery drug containing amide compound | |
US7972612B2 (en) | Remedy for glaucoma comprising Rho kinase inhibitor and β-blocker | |
WO1997040831A9 (en) | Therapeutic treatment for vegf related occular diseases | |
RU2324483C2 (en) | Inhibitors of hystone deacetylase for treatment of degenerative eye diseases | |
KR100499903B1 (en) | 5ht2 agonists for controlling iop and treating glaucoma | |
AU2001216071A1 (en) | 5HT2 agonists for controlling IOP and treating glaucoma | |
AU1506600A (en) | Use of staurosporine derivatives for treating ocular neovascular diseases | |
US6214819B1 (en) | Method for treating ocular neovascular diseases | |
EP1370267A2 (en) | Use of propentofylline to control intraocular pressure | |
US20040110776A1 (en) | Use of propentofylline to control intraocular pressure | |
AU2002250168A1 (en) | Use of propentofylline to control intraocular pressure | |
EP2266559A1 (en) | Therapeutic agent for ophthalmic disease | |
US6927233B1 (en) | 5ht2 agonists for controlling IOP and treating glaucoma | |
KR20080111092A (en) | Prenyltransferase inhibitors for ocular hypertension control and the treatment of glaucoma | |
KR20050013238A (en) | Remedy or preventive for keratoconjunctival epithelial cell injury | |
US6534475B1 (en) | Use of TIMP-3 inducers of TIMP-3 expression, and TIMP-3 mimetics to treat ocular neovascularization | |
Lee et al. | Medical therapy for glaucoma | |
RENGARAJ VENKATESH | COMMONLY PRESCRIBED GLAUCOMA EYE DROPS AND ORAL MEDICATIONS | |
Clode | OCULAR HYPOTENSIVE AGENTS | |
CN101500558A (en) | Succinimide derivatives as ocular hypotensive agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20030919 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
17Q | First examination report despatched |
Effective date: 20040406 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1058760 Country of ref document: HK |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20050712 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: ALCON, INC. |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1058760 Country of ref document: HK |