CA2247460A1 - Recombinant tissue plasminogen activator (rtpa) for preventing secondary cataracts following cataract operations - Google Patents
Recombinant tissue plasminogen activator (rtpa) for preventing secondary cataracts following cataract operations Download PDFInfo
- Publication number
- CA2247460A1 CA2247460A1 CA002247460A CA2247460A CA2247460A1 CA 2247460 A1 CA2247460 A1 CA 2247460A1 CA 002247460 A CA002247460 A CA 002247460A CA 2247460 A CA2247460 A CA 2247460A CA 2247460 A1 CA2247460 A1 CA 2247460A1
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- Prior art keywords
- fibrosis
- following
- rtpa
- arginine
- capsule wall
- Prior art date
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- 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
- A61P27/12—Ophthalmic agents for cataracts
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Ophthalmology & Optometry (AREA)
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to the use of RTPA to prevent the post-operative proliferation of lens tissues, known as secondary cataracts, on the posterior sheath well (fibrosis) after extracapsular cataract extraction.
Description
~ L'''~ C"~,-)y ~ILE, L~3 ~ i $ l~CNDLQ
~ 7 12QN~LArlON
BASOTHERM GMBH ~ Case 1 1 /033-Ro D-88396 BIBERAC~ - Foreign Text rt-PA for the Prevention of Secondary Cat~ra~ Following a C-~t~ract Operation The present invention relates to the use o~ rt-PA for preventing the post-operative prolnferation of lens tlssue on the posterior capsule wall (fibrosis) in the case of extracapsular cataract extractiôn.
Fibrosis ôf the postenor capsule wall, a connective tissue proliferation also known as a secondary cataract, constitutes the most ~re~uent late co~ t:on of extracapsular cataract extraction (Z. prakt Augenheilkd.15, 488 ~1994)). Thusin 35-51% of cases~ follow-up treatment becomes necessary within five years.
Up untll the present time no effective prevention of fibrosis has been known.
Substances wlth an antiproliferative effect, such as ~-fluorouracil or corticoids, have been used without convincing success and with a negative use-r,isk ratio (A.
Knapp et al, Am. J. Ophthalmol. lQ~ 3-187 (1987); M.C. Gillie~ et al., Ausfrallan and New Zealand ~loumal of Ophthalmology, 19(4), 299-304~. YAG
laser c~ps~l'otomy is frequently employed in the case of severe fibrosis. This procedure has the disadvantage that it can ~ive rise to disturbanoes in the vitreous humour, as the lenshitreous humour barrier is impaired. The resultant loss of hyaluronic acid leads to an increased nsk of ablation. Equally, the dif~usion of prostaglandins and neovascular growth factors into the vitreous humour can lead to cystoid maculaoedema and rubeosis iridis (M.C. Boschi et al, New Trends Ophthalmol., 9,(1~, 55-57 (1994); D. Altamirano et al., Klin.
Monatsbl Augenheilkd., 2Q~(5), 286-287 (1994)).
Another very common complication following extracapsular cataract extraction c~nsists of the formation of fibrin membranes in the pupil plane or the ~ront chamber. A. Wedrich et al. descnbe in International Ophthalmology 18 (5), 277-280 (1g95), that it was possible to achieve complete fibrinolysis by an intrachamber injection of 25 ,ug recombinant tissue plasmlnogen activator (rt-PA).
The same fact is descnbed by K. Schmit~ et al. in German iournal of Ophthalmology 4(2), 75-79 (1995) i _ . . . _ . .
~ CA 02247460 1998-08-21 -Additionally, G.H. Strauss describes in Journal of Ocular Pharrnacology 7 (1)l g-19 (1991) that t-PA significantly reduces episcleral fibrosis (scarring) of the filter cushion following trabeculectomy (glaucoma ope!ation), a main cause of the failure of this therapy. In this operation technique a drainage fistula (filter cushion) is made through the conjunctiva, alth~ugh this readily closes up again ~ue to fibroblast proliferation. The authors attribute the assumed cause of the successful preventi-~n of this cornplication by means of t-PA to inhibition of the forrnation of a primary hbrinlfibronectin matrix, which possibly functions as supporting structure for the subsequent fibrosis.
EP-A-0 318 801 states that rt-PA prevents the forrnation of adhesions of organs or part of organs following invasive interventions in the chest- or abdominal-cavlty.
It was now discovered that the prollferation of lens tissue on the posterior capsule wall, known as a secondary cataract, is significantly reduced by the intraocular or subconjunctival application of rt-PA.
The present invention thus relates to the use of rt-PA for the oreventlon of hbrosis of the posterior capsule wall following extracapsular cataract extraction, known as a secondary cataract. ~he reduction of the fibrosis is associated with an impro~ement in the strength of vision The invention further relates to the use of rt-PA for the preparation of a medicament tor the prevention of secondary cataracts.
Instead of rt-PA of a native structure, it is also possible to use iso-forms or mutants derived therefrom, provided these have a comparable fibnnolytic activity.
Iso-forms or mutants are to be understood as forms which, compared to the native structure, additionally contaln one or more amino acids, differ from the naturally occurring t-PA in respect of the amino acid sequence of one or more amlno acids (thus possess a heterologous amlno acid sequence) or in which one or more amino acids occurring in the natural t-PA are not contained, and their glycosylated and non-glycosylated denvatiYes The application of rt-PA takes place post-operati\~eiy, where an amount of 1-20 1~9, preferably by paracentesis, is instilled into the front chamber or Is applied ,, . , ~,, ~ .
.
, .
" . .. ,;.. ;,.. ,.. ,, . ., .. , .. ,;, . . ..
i - CA 02247460 1998-08-21 subconJuctively A dose unit ot 10 1~9 rt-PA. dissolved in 100 ~l 0 2 M aqueous arginine/polysorbate buffer is applied particularly preferentially.
The rt-PA ~s present in a suitable dose unlt as l,~ophllizate for dissolution, where an aqueous arginine/polysorbate buffer is used as solvent. The concentration of the effective dose after the reconstitution of the solution amounts to 1-20 ,ug rt-~A In 0 01-0.1 ml per injec~ion.
A suitable medicament for prevention of hbrosis of t~ e posterior capsule wall following extracapsular cataract extractlon, known as a secondary cataract, contalns for example~ in one unit, the fibrinolyticum rt-PA as Iyophilizate in aquantity of 0 10-0.50 mg, preferably together with stabllisers or buffers such as arginine, phosphonc acid and polysorbate 80, and In a second unit, by way of diluting agent. 2 to 6 ml of an aqueous 0 1-0.3 M arginine/polysorbate buffer, expediently pre-introduced into a syringe~ so that following the reconstitution of the rt-PA solution the fibrinolyticum is present In a concentration of 0.05 to û.2 m~lml Of this solution, a dose of 1-20 ~9 rt-PA is applied by the injection of an appropnate volume of the reconstitute~ solution The Iyophilizate preferably contains 0 3 mg rt-PA, and preferably 3 ml 0 2 M
argininelphosphate buffer wrth a pH value of 7.3 is used as diluting agent. The preferred application amount is 10 !J9 rt-PA in 10û ,ul of the afore",cn~ioned ~uffer.
Investigations of Effectiveness:
The following tests were carried out to prove ~he effectiveness of rt-PA in preventing fibrosis of the postenor capsule wall following e~trac~psular cataract extracTion, known as a secondary cataract The effect of a single dose of rt-PA on the incidence of fibrosis of the postenor capsule wall following extracapsular cataract extraction was checked in a clinical study. The tests were carried out in a randomised. double-blind parallel-group study The effect of a single dose of 10 IJ9 rt-PA~ instllled into the front charnber of the eye directt~y upon the terrnination of a complication-free cataract operation, was investigated. The dose unit of 10 ~g rt-PA was present in solution form in tO0 ~l 0 2 M arginine-buffer, and 100 ~l 0 2 M arginine buffer alone was used as ..
r . .
_, . ~ .. ..
placebo. Altogether, 112 patients partlc~pated in the stlJdy, compnsing 56 patients in the age range of 41 to 90 years in the group takln~ the actlve substance and a further 56 patients in the age range of 37 to ~9 years In the placebo group.
The patients were subjected to full ophthalmological testing pre-operatively andin each case two days (all patlents). two weeks ~all patients), three months (111 of 112 patients) and again within a time interval of 11 to 31 months (108 of 112patients) after the operation.
After 3 months, central hbrosis of the posterior caps~le was discovered in ~5 ofthe 56 patients in the plac~bo group and 11 of the 56 patients in the group taking the active substance tstatistical signihcance: p-0.0056. determined in accordance with the Chi2 test). After 11 to 31 nnont~s the statistical significance of the differences was p=0.024 (Chl2-test).
Sight, whlch has a certain dependency upon fibrin formation or central capsular fibrosis, shows si~nificant differenr~s after 3 months in favour of the group taking the active substance (statistical significance: p=0 016~ Mann-Whitney U-Test).
The above data prove thal as a result of the instillation of a single dose of 10 ~Jg rt-PA directly following the termination of an extracapsular cataract extraction, the risk of occurrence of central fibrosis of the postenor capsule wall is reduced by more than half.
.
i . . . . .
.
~?a~ m~latlon ~, ~ .~. o~ a s~ tlon of ~h~ followlng ~~mposltlon (Actllyse~) Com~ Quantlty in 1 ml r~-PA 1 . O mg L-arginlne 34 84 mg phosp~oric acid 10 72 mg polysorbate ~0 < 0 10 mg water for the InJection up to 1 0 ml Is Introduced Into a ~lass flask and Iyophilized. The Iyophilizate then has the followlng oomposltion:
Com~onent Nominal ~uantity per Flask rt-PA 03mg L-arginine 10 45 mg phosphonc acid 3 22 mg polys~rbate 80 S0 03 mg By way of diluting agent~ 3 rnl sterile 0 2 M arginine/phosphate buffer is ntroduced into a 3 ml syringe The dilutlng agent has the following composltlon Com~onent Quantity in 1 ml L-arginine 34 84 mg phosphoric acld 10.72 mg polysorbate 80 <0.10 mg water for the injectlon up to 1.0 ml After reconstitution of the Iyophilizate with 3 ml of the diluting agent, the product has the following composition:
,, .
Component Quantity in l ml after reconstitution rt-PA
L-arginine 38.32 mg phosphoric acid 11 .79 mg polysorbate 8Q <O 10 m~
water for the injection up to 1 ~ ml Of this solutlon, 1ûO IJI, containing 0.01 rng rt-PA, was applied intraocularly.
~_ ...... ... _ i ... . ... .
~ 7 12QN~LArlON
BASOTHERM GMBH ~ Case 1 1 /033-Ro D-88396 BIBERAC~ - Foreign Text rt-PA for the Prevention of Secondary Cat~ra~ Following a C-~t~ract Operation The present invention relates to the use o~ rt-PA for preventing the post-operative prolnferation of lens tlssue on the posterior capsule wall (fibrosis) in the case of extracapsular cataract extractiôn.
Fibrosis ôf the postenor capsule wall, a connective tissue proliferation also known as a secondary cataract, constitutes the most ~re~uent late co~ t:on of extracapsular cataract extraction (Z. prakt Augenheilkd.15, 488 ~1994)). Thusin 35-51% of cases~ follow-up treatment becomes necessary within five years.
Up untll the present time no effective prevention of fibrosis has been known.
Substances wlth an antiproliferative effect, such as ~-fluorouracil or corticoids, have been used without convincing success and with a negative use-r,isk ratio (A.
Knapp et al, Am. J. Ophthalmol. lQ~ 3-187 (1987); M.C. Gillie~ et al., Ausfrallan and New Zealand ~loumal of Ophthalmology, 19(4), 299-304~. YAG
laser c~ps~l'otomy is frequently employed in the case of severe fibrosis. This procedure has the disadvantage that it can ~ive rise to disturbanoes in the vitreous humour, as the lenshitreous humour barrier is impaired. The resultant loss of hyaluronic acid leads to an increased nsk of ablation. Equally, the dif~usion of prostaglandins and neovascular growth factors into the vitreous humour can lead to cystoid maculaoedema and rubeosis iridis (M.C. Boschi et al, New Trends Ophthalmol., 9,(1~, 55-57 (1994); D. Altamirano et al., Klin.
Monatsbl Augenheilkd., 2Q~(5), 286-287 (1994)).
Another very common complication following extracapsular cataract extraction c~nsists of the formation of fibrin membranes in the pupil plane or the ~ront chamber. A. Wedrich et al. descnbe in International Ophthalmology 18 (5), 277-280 (1g95), that it was possible to achieve complete fibrinolysis by an intrachamber injection of 25 ,ug recombinant tissue plasmlnogen activator (rt-PA).
The same fact is descnbed by K. Schmit~ et al. in German iournal of Ophthalmology 4(2), 75-79 (1995) i _ . . . _ . .
~ CA 02247460 1998-08-21 -Additionally, G.H. Strauss describes in Journal of Ocular Pharrnacology 7 (1)l g-19 (1991) that t-PA significantly reduces episcleral fibrosis (scarring) of the filter cushion following trabeculectomy (glaucoma ope!ation), a main cause of the failure of this therapy. In this operation technique a drainage fistula (filter cushion) is made through the conjunctiva, alth~ugh this readily closes up again ~ue to fibroblast proliferation. The authors attribute the assumed cause of the successful preventi-~n of this cornplication by means of t-PA to inhibition of the forrnation of a primary hbrinlfibronectin matrix, which possibly functions as supporting structure for the subsequent fibrosis.
EP-A-0 318 801 states that rt-PA prevents the forrnation of adhesions of organs or part of organs following invasive interventions in the chest- or abdominal-cavlty.
It was now discovered that the prollferation of lens tissue on the posterior capsule wall, known as a secondary cataract, is significantly reduced by the intraocular or subconjunctival application of rt-PA.
The present invention thus relates to the use of rt-PA for the oreventlon of hbrosis of the posterior capsule wall following extracapsular cataract extraction, known as a secondary cataract. ~he reduction of the fibrosis is associated with an impro~ement in the strength of vision The invention further relates to the use of rt-PA for the preparation of a medicament tor the prevention of secondary cataracts.
Instead of rt-PA of a native structure, it is also possible to use iso-forms or mutants derived therefrom, provided these have a comparable fibnnolytic activity.
Iso-forms or mutants are to be understood as forms which, compared to the native structure, additionally contaln one or more amino acids, differ from the naturally occurring t-PA in respect of the amino acid sequence of one or more amlno acids (thus possess a heterologous amlno acid sequence) or in which one or more amino acids occurring in the natural t-PA are not contained, and their glycosylated and non-glycosylated denvatiYes The application of rt-PA takes place post-operati\~eiy, where an amount of 1-20 1~9, preferably by paracentesis, is instilled into the front chamber or Is applied ,, . , ~,, ~ .
.
, .
" . .. ,;.. ;,.. ,.. ,, . ., .. , .. ,;, . . ..
i - CA 02247460 1998-08-21 subconJuctively A dose unit ot 10 1~9 rt-PA. dissolved in 100 ~l 0 2 M aqueous arginine/polysorbate buffer is applied particularly preferentially.
The rt-PA ~s present in a suitable dose unlt as l,~ophllizate for dissolution, where an aqueous arginine/polysorbate buffer is used as solvent. The concentration of the effective dose after the reconstitution of the solution amounts to 1-20 ,ug rt-~A In 0 01-0.1 ml per injec~ion.
A suitable medicament for prevention of hbrosis of t~ e posterior capsule wall following extracapsular cataract extractlon, known as a secondary cataract, contalns for example~ in one unit, the fibrinolyticum rt-PA as Iyophilizate in aquantity of 0 10-0.50 mg, preferably together with stabllisers or buffers such as arginine, phosphonc acid and polysorbate 80, and In a second unit, by way of diluting agent. 2 to 6 ml of an aqueous 0 1-0.3 M arginine/polysorbate buffer, expediently pre-introduced into a syringe~ so that following the reconstitution of the rt-PA solution the fibrinolyticum is present In a concentration of 0.05 to û.2 m~lml Of this solution, a dose of 1-20 ~9 rt-PA is applied by the injection of an appropnate volume of the reconstitute~ solution The Iyophilizate preferably contains 0 3 mg rt-PA, and preferably 3 ml 0 2 M
argininelphosphate buffer wrth a pH value of 7.3 is used as diluting agent. The preferred application amount is 10 !J9 rt-PA in 10û ,ul of the afore",cn~ioned ~uffer.
Investigations of Effectiveness:
The following tests were carried out to prove ~he effectiveness of rt-PA in preventing fibrosis of the postenor capsule wall following e~trac~psular cataract extracTion, known as a secondary cataract The effect of a single dose of rt-PA on the incidence of fibrosis of the postenor capsule wall following extracapsular cataract extraction was checked in a clinical study. The tests were carried out in a randomised. double-blind parallel-group study The effect of a single dose of 10 IJ9 rt-PA~ instllled into the front charnber of the eye directt~y upon the terrnination of a complication-free cataract operation, was investigated. The dose unit of 10 ~g rt-PA was present in solution form in tO0 ~l 0 2 M arginine-buffer, and 100 ~l 0 2 M arginine buffer alone was used as ..
r . .
_, . ~ .. ..
placebo. Altogether, 112 patients partlc~pated in the stlJdy, compnsing 56 patients in the age range of 41 to 90 years in the group takln~ the actlve substance and a further 56 patients in the age range of 37 to ~9 years In the placebo group.
The patients were subjected to full ophthalmological testing pre-operatively andin each case two days (all patlents). two weeks ~all patients), three months (111 of 112 patients) and again within a time interval of 11 to 31 months (108 of 112patients) after the operation.
After 3 months, central hbrosis of the posterior caps~le was discovered in ~5 ofthe 56 patients in the plac~bo group and 11 of the 56 patients in the group taking the active substance tstatistical signihcance: p-0.0056. determined in accordance with the Chi2 test). After 11 to 31 nnont~s the statistical significance of the differences was p=0.024 (Chl2-test).
Sight, whlch has a certain dependency upon fibrin formation or central capsular fibrosis, shows si~nificant differenr~s after 3 months in favour of the group taking the active substance (statistical significance: p=0 016~ Mann-Whitney U-Test).
The above data prove thal as a result of the instillation of a single dose of 10 ~Jg rt-PA directly following the termination of an extracapsular cataract extraction, the risk of occurrence of central fibrosis of the postenor capsule wall is reduced by more than half.
.
i . . . . .
.
~?a~ m~latlon ~, ~ .~. o~ a s~ tlon of ~h~ followlng ~~mposltlon (Actllyse~) Com~ Quantlty in 1 ml r~-PA 1 . O mg L-arginlne 34 84 mg phosp~oric acid 10 72 mg polysorbate ~0 < 0 10 mg water for the InJection up to 1 0 ml Is Introduced Into a ~lass flask and Iyophilized. The Iyophilizate then has the followlng oomposltion:
Com~onent Nominal ~uantity per Flask rt-PA 03mg L-arginine 10 45 mg phosphonc acid 3 22 mg polys~rbate 80 S0 03 mg By way of diluting agent~ 3 rnl sterile 0 2 M arginine/phosphate buffer is ntroduced into a 3 ml syringe The dilutlng agent has the following composltlon Com~onent Quantity in 1 ml L-arginine 34 84 mg phosphoric acld 10.72 mg polysorbate 80 <0.10 mg water for the injectlon up to 1.0 ml After reconstitution of the Iyophilizate with 3 ml of the diluting agent, the product has the following composition:
,, .
Component Quantity in l ml after reconstitution rt-PA
L-arginine 38.32 mg phosphoric acid 11 .79 mg polysorbate 8Q <O 10 m~
water for the injection up to 1 ~ ml Of this solutlon, 1ûO IJI, containing 0.01 rng rt-PA, was applied intraocularly.
~_ ...... ... _ i ... . ... .
Claims (3)
1. The use of rt-PA for preventing the post-operative proliferation of lens tissue on the posterior capsule wall (fibrosis) following extracapsular cataractextraction, known as a secondary cataract.
2. The use of rt-PA for the preparation of a medicament for preventing the post-operative proliferation of lens tissue on the posterior capsule wall (fibrosis) following extracapsular cataract extraction, known as a secondary cataract.
3. A medicament, composed of two units, for preventing the post-operative proliferation of lens tissue on the posterior capsule wall (fibrosis) following extracapsular cataract extraction, known as a secondary cataract, characterised in that the first unit contains the fibrinolyticum rt-PA as lyophilizate in a quantity of 0.10-0.50 mg, optionally together with stabilisers or buffers such as arginine, phosphoric acid and polysorbate 80, and the second unit contains, as diluting agent, 2 to 6 ml of an aqueous 0.1-0.3 M arginine/polysorbate buffer, where the diluting agent is optionally pre-introduced into a syringe, so that following the reconstitution of the rt-PA solution the fibrinolyticum is present in a concentration of 0.05 to 0 2 mg/ml.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19606551.8 | 1996-02-22 | ||
| DE19606551A DE19606551C2 (en) | 1996-02-22 | 1996-02-22 | rt-PA for the prevention of cataract after cataract surgery |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2247460A1 true CA2247460A1 (en) | 1997-08-28 |
Family
ID=7786075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002247460A Abandoned CA2247460A1 (en) | 1996-02-22 | 1997-02-18 | Recombinant tissue plasminogen activator (rtpa) for preventing secondary cataracts following cataract operations |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0881909A1 (en) |
| JP (1) | JP2000504737A (en) |
| AR (1) | AR005949A1 (en) |
| AU (1) | AU1874197A (en) |
| CA (1) | CA2247460A1 (en) |
| DE (1) | DE19606551C2 (en) |
| WO (1) | WO1997030724A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3624299A (en) * | 1998-02-04 | 1999-08-23 | Kiyoshi Okada | Compositions and methods for separating lens epithelial cells and preventing posterior capsular opacification |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2483234A2 (en) * | 1980-05-29 | 1981-12-04 | Fabre Sa Pierre | OPHTHALMIC COMPOSITION CONTAINING A PLASMINOGEN ACTIVATOR |
| US4777043A (en) * | 1985-12-17 | 1988-10-11 | Genentech, Inc. | Stabilized human tissue plasminogen activator compositions |
| JPH0640943A (en) * | 1991-04-22 | 1994-02-15 | Senju Pharmaceut Co Ltd | Agent for intraocular operation |
-
1996
- 1996-02-22 DE DE19606551A patent/DE19606551C2/en not_active Expired - Fee Related
-
1997
- 1997-02-18 WO PCT/EP1997/000756 patent/WO1997030724A1/en not_active Application Discontinuation
- 1997-02-18 CA CA002247460A patent/CA2247460A1/en not_active Abandoned
- 1997-02-18 EP EP97905042A patent/EP0881909A1/en not_active Withdrawn
- 1997-02-18 AU AU18741/97A patent/AU1874197A/en not_active Abandoned
- 1997-02-18 JP JP9529779A patent/JP2000504737A/en active Pending
- 1997-02-21 AR ARP970100705A patent/AR005949A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000504737A (en) | 2000-04-18 |
| WO1997030724A1 (en) | 1997-08-28 |
| EP0881909A1 (en) | 1998-12-09 |
| AR005949A1 (en) | 1999-07-21 |
| AU1874197A (en) | 1997-09-10 |
| DE19606551C2 (en) | 2000-06-08 |
| DE19606551A1 (en) | 1997-08-28 |
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